Mutation Research-Reviews in Mutation Research 789 (2022) 108412

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Mutation Research-Reviews in Mutation Research

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Recurrent driver mutations in benign tumors

Carolina Cavalieri Gomes *, 1
Department of Pathology, Biological Sciences Institute, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil

A R T I C L E I N F O A B S T R A C T

Keywords: The understanding of the molecular pathogenesis of benign tumors may bring essential information to clarify the
Benign neoplasia process of tumorigenesis, and ultimately improve the understanding of events such as malignant transformation.
Malignant transformation The definition of benign neoplasia is not always straightforward and herein the issues surrounding this concept
Cancer hallmarks
are discussed. Benign neoplasms share all cancer hallmarks with malignancies, except for metastatic potential.
Precursor lesions
Translocations
Recently, next-generation sequencing has provided unprecedented opportunities to unravel the genetic basis of
Tumor evolution benign neoplasms and, so far, we have learned that benign neoplasms are indeed characterized by the presence of
genetic mutations, including genes rearrangements. Driver mutations in advanced cancer are those that confer
growth advantage, and which have been positively selected during cancer evolution. Herein, some discussion
will be brought about this concept in the context of cancer prevention, involving precursor lesions and benign
neoplasms. When considering early detection and cancer prevention, a driver mutation should not only be ad­
vantageous (i.e., confer survival advantage), but predisposing (i.e., promoting a cancer phenotype). By including
the benign counterparts of malignant neoplasms in tumor biology studies, it is possible to evaluate the risk posed
by a given mutation and to differentiate advantageous from predisposing mutations, further refining the concept
of driver mutations. Therefore, the study of benign neoplasms should be encouraged because it provides valuable
information on tumorigenesis central for understanding the progression from initiation to malignant
transformation.

1. Introduction
Malignant neoplasms, i.e., cancer, often lead to morbidities and are
associated with high mortality rates. Therefore, most scientific in­
vestigations focus on the understanding of cancer biology. From a
medical perspective, cancer studies are undeniably important [1].
However, from the perspective of pathology, the study of benign neo­
plasms (herein used interchangeably with “benign tumors”) is equally
relevant to the study of cancer. The understanding of the molecular
pathogenesis of benign neoplasms may contribute to the clarification of
the process of tumorigenesis and ultimately facilitate the understanding
of events such as malignant transformation.
2. The hallmarks of human neoplasms
Several studies have highlighted the hallmarks of malignant neo­
plasms. “The hallmarks constitute an organizing principle for rationalizing
the complexities of neoplastic disease” [2]. The six core biological capa­
bilities acquired by cancer cells are sustaining proliferative signaling,
evading growth suppressors, resisting cell death, enabling replicative
immortality, inducing angiogenesis, and activating invasion and
metastasis. Other properties of neoplastic cells have been incorporated
into these hallmarks, namely reprogramming of energy metabolism, and
evading immune destruction [2]. Other features may emerge as new
hallmarks of cancer, considering the complexity of tumorigenesis and
the unprecedented data that has been recently generated by new
research technologies.
Benign neoplasms outnumber malignant neoplasms, but given the
indolent behavior of most benign tumors, funding for research on benign
neoplasms is limited. Given the discrete number of studies focusing on
benign neoplasms (compared to malignant tumors), the hallmarks of
such lesions remain elusive. Although this review does not aim to
comprehensively address this issue, some examples of the overlap of
hallmark features of benign and malignant neoplasms are given.

* Correspondence to: Department of Pathology, Biological Sciences Institute (G3, Room 60), Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais
CEP 31270-901, Brazil.
E-mail addresses: carolinacgomes@ufmg.br, gomes.carolinac@gmail.com.
1
https://orcid.org/0000-0003-1580-4995

https://doi.org/10.1016/j.mrrev.2022.108412
Received 12 November 2021; Received in revised form 2 February 2022; Accepted 9 February 2022
Available online 11 February 2022
1383-5742/© 2022 Elsevier B.V. All rights reserved.
C.C. Gomes
Benign tumors have the capacity of sustaining proliferative
signaling. To illustrate this, there are several examples in which
constitutive activation of signaling pathways occur, leading to growth
factor independence. For instance, ameloblastomas, amongst other tu­
mors, are benign neoplasms characterized by BRAF p.V600E activating
mutations, which lead to the constant activation of the MAPK/ERK
pathway in the absence of growth factor binding [3]. Benign tumors are
also able to evade growth suppressors, as illustrated by the presence of
TP53 tumor suppressor gene mutations or loss-of-heterozygosity in
benign salivary gland neoplasms and colorectal adenomas [4,5]. Other
example of evasion of suppressor signals are the frequent NF2 mutations
that occur in sporadic meningiomas and vestibular schwannomas [6].
Cytoplasmic NF2 protein orchestrates contact inhibition by coupling
cell-surface adhesion molecules to transmembrane receptor tyrosine
kinases, and, therefore, strengthening the adhesivity of
cadherin-mediated cell-to-cell attachments [reviewed by 2]. NF2 pro­
tein can also sequester growth factors receptors. Thus, loss-of-function
mutations in this gene contribute to contact inhibition evasion. With
regard to the hallmark “resisting cell death”, several studies have shown
increased immunoexpression of antiapoptotic BCL2 protein in benign
neoplasms. Of note, benign salivary gland neoplasms (pleomorphic ad­
enomas) have been shown to express BCL2 mRNA and to exhibit similar
anti-apoptotic indexes as malignant salivary gland tumors [7]. Repli­
cative immortality is one of the cancer hallmarks, and benign neoplasia
can also exhibit this property. For example, benign urothelial lesions
have been shown to harbor TERT promoter mutation [8]. TERT
gain-of-function mutations lead to increased telomerase activity and,
therefore, to cell immortality. Of note, benign tumors also have the
ability of inducing angiogenesis. Illustrating this capacity, benign and
malignant ovarian tumors have not shown differences in microvessel
density [9] and it has been demonstrated that cardiac myxomas produce
vascular endothelial growth factor (VEGF), consistent with angiogenesis
induction [10]. Thus, one can conclude that benign neoplasms may
share all of the cancer hallmarks, except metastatic capability.
Rupert Willis defined neoplasia as “an abnormal mass of tissue, the
growth of which exceeds and is uncoordinated with that of the normal
tissues and persists in the same excessive manner after cessation of the
stimuli which evoked the change” [cited by 11]. In clinical practice this
definition fails in differentiating neoplasms from other proliferative
non-neoplastic lesions, sometimes including developmental abnormal­
ities. Other features are incorporated into this concept to try to better
define a true neoplasm, including the occurrence of autonomous and
continuous growth, independent of external factors and stimuli. While
conceptually these features help in the definition of a neoplasm, clini­
cally it is not always easy to ascertain if a given lesion is growing
continuously. In addition, there are examples that challenge this
concept. Odontoma, an odontogenic hamartoma, is a locally destructive
lesion that can grow to considerable size, clinically resembling benign
neoplasms. Non-ossifying fibroma of bone has recently been defined as a
genetically-driven benign neoplasm [12] that shows spontaneous
regression over the years. Additionally, it has been previously shown
that epithelial skin tumors, including keratoacanthomas, basal cell
carcinomas and melanomas [13], as well as neuroblastomas [14] can
show regression. These examples illustrate that under some circum­
stances, the classification of lesions as neoplasm based on autonomous
and continuous growth does not strictly fit the classic neoplasia concept.
3. Benign versus malignant neoplasms
Conventionally, neoplasms are classified into two categories, benign
and malignant. The main feature that separates these categories is the
ability to give rise to metastasis, which is exclusive to malignant tumors.
Interestingly, there are tumors that are histologically benign but give
origin to metastasis. From the basic pathology perspective, if a given
tumor is able to produce metastasis, then such tumor fulfills the criteria
to be categorized as malignant, irrespective of the primary tumor
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Mutation Research-Reviews in Mutation Research 789 (2022) 108412
microscopic features or clinical behavior.
Considering metastasis is usually a late event in tumor progression,
clinicians cannot wait and see if a given tumor will produce metastasis,
so that the tumor can be unequivocally classified as benign or malignant.
Therefore, other clinicopathological features are used in combination, to
define the benign or malignant nature of a given neoplasm. Specifically,
a benign neoplasm is a mass of tissue that can be encapsulated (or not),
usually grows slowly and shows an expansive pattern of growth that
may lead to compression of adjacent structures. Additionally, areas of
necrosis and hemorrhage are not expected in a benign neoplasm.
Microscopically, benign tumors most often show well-defined limits,
and tend to recapitulate the same morphology of the tissue of origin,
with cellular atypia and pleomorphism being absent or restricted to a
minimum. However, not all neoplasms will perfectly fit the binary
neoplasm categorization system as benign or malignant. Behavior of
some benign neoplasms can range from indolent to significantly morbid
[1]. From the basic pathology perspective, some advocate for the in­
clusion of a third intermediate category to the spectrum of neoplasms.
Tumors in this category should fall in between benign and malignant
tumors, i.e., tumors too aggressive to be classified as benign, but with
less marked features of malignancy and without the ability to give origin
to metastasis. Reflecting this need, intermediate categories are used in a
number of clinical areas regarding pathological entities, including but
not restricted to intermediate soft tissue tumors and borderline tumors
of the female genital tract, amongst others.
The somatic mutation theory remains the prevalent theory of carci­
nogenesis [2]. It is cell-centered, and it is based on three core ideas: 1)
cancer is derived from a single somatic cell that has acquired multiple
DNA mutations over time, i.e., they are monoclonal in origin, 2) the
default state of cell proliferation in humans is quiescence, and 3) cancer
is a disease of cell proliferation and, therefore, mutations that cause
cancer occur in genes that control cell proliferation and/or the cell cycle,
leading to continuous proliferation [reviewed by 15]. Despite this the­
ory being widely accepted, there are some caveats that hinder its
confirmation. For example, there is compelling evidence that not all
tumors are monoclonal in origin [16]. In addition, not all mutant cells
proliferate; they can also be dormant [17,18]. The presence of dissem­
inated tumor cells that survive in a dormant state in target organs, for
instance, is one of the explanations for the occurrence of metastases
decades after primary tumor treatment [18].
In pathology, the fact that most benign tumors show a lower prolif­
eration index than their malignant counterparts is a consensus. There­
fore, using markers of cell proliferation in a given tumoral tissue may
help differentiate a benign from a malignant neoplasm. However, it
should be acknowledged that the differentiation between malignant and
benign neoplasms should not rely on a single feature. There are malig­
nant neoplasms that can show low proliferation indexes, and benign
ones that can show high proliferative activity.
4. Recurrent diver mutations in malignant neoplasms
We have witnessed accelerated growth in understanding the genomic
profile of cancer in the past decades. Next-generation sequencing has
provided robust data on the genomic landscape of many cancer types
and there are online platforms and repositories where this information is
freely available. There is no single database or published study that can
alone provide unequivocal information on the prevalence of mutated
genes across all cancer types combined. In this sense, a search on
cBioPortal http://www.cbioportal.org/ (accessed on October 19th,
2021) was conducted to identify prevalent driver genes in malignancies.
When searching for all TCGA (The Cancer Genome Atlas) Pan-Cancer
studies at http://www.cbioportal.org/ (accessed on October 19th,
2021), the query resulted in a combined result containing samples from
32 studies, with 10,967 evaluated cancer samples spanning 35 cancer
types. The 15 genes more frequently mutated across several cancer types
are listed in Table 1. In addition, the MSK-IMPACT Clinical Sequencing
C.C. Gomes Mutation Research-Reviews in Mutation Research 789 (2022) 108412

Table 1
Frequency distribution of genes harboring hotspot mutations in pan-cancer studies.
Cancer Hotspots MSKCC Chang et al. [21] and Chang MSK-IMPACT Clinical Sequencing Cohort Zehir et al. Pan-Cancer TCGA## (cBioPortal)
et al. [22] [19]

Gene* # of samples # profiled Freq Gene* * # of samples profiled Freq Gene* # of samples #profiled Freq
with mutations samples with mutations Samples ** with mutations samples

1 TP53 7842 24,592 32% TP53 4538 10,945 41.5% TP53 3839 10,359 37.1%
2 KRAS 2802 24,592 11% APC 1121 10,945 10.2% PIK3CA 1371 9752 14.1%
3 PIK3CA 2627 24,592 11% KRAS 1643 10,945 15.0% LRP1B 1297 10,196 12.7%
4 BRAF 1144 24,592 5% TERT 1460 10,945 13.3% PCLO 1087 10,439 10.4%
5 IDH1 766 24,592 3% PIK3CA 1355 10,945 12.4% KMT2D 972 10,353 9.4%
6 EGFR 686 24,592 3% KMT2D 851 10,945 7.8% FAT4 934 10403 9.0%
7 PTEN 648 24,592 3% ARID1A 875 10,945 8.0% KMT2C 904 10359 8.7%
8 CTNNB1 560 24,592 2% KMT2C 642 10,945 5.9% PTEN 859 9443 9.1%
9 NRAS 544 24,592 2% EGFR 636 10,945 5.8% ARID1A 810 9902 8.2%
10 CDKN2A 525 24,592 2% FAT1 595 10,945 5.4% APC 793 10,165 7.8%
11 FBXW7 441 24,592 2% PTEN 665 10,945 6.1% KRAS 763 10,025 7.6%
12 ERBB2 363 24,592 1% NF1 591 10,945 5.4% BRAF 744 9460 7.9%
13 SMAD4 360 24,592 1% ATM 533 10,945 4.9% FAT1 698 10,316 6.8%
14 APC 266 24,592 1% PTPRT 486 10,945 4.4% RELN 688 9974 6.9%
15 RB1 225 24,592 1% BRAF 564 10,945 5.2% ATRX 633 9579 6.6%

*Frequency distribution of genes containing one or more single-codon hotspots and in-frame indel hostspots. Retrospective mutational data were obtained from three
publicly available sources: 1) The Cancer Genome Atlas (TCGA), 2) International Cancer Genome Consortium (ICGC), and 3) independent published sequencing
projects [21] and 10,000 samples were prospectively sequenced using a validated capture-based next-generation sequencing assay called MSK-IMPACT that is New
York state-approved for clinical use. * *targeted-sequenced using the MSK-IMPACT NGS Panel * **Data from 32 TCGA Pan-Cancer studies obtained at cBioPortal,
excluding the genes that are not classified as cancer-genes according to OncoKB precision oncology database [20]. ## Combined study with samples from 32 TCGA
studies: Acute Myeloid Leukemia (TCGA, PanCancer Atlas), Adrenocortical Carcinoma (TCGA, PanCancer Atlas), Bladder Urothelial Carcinoma (TCGA, PanCancer
Atlas), Brain Lower Grade Glioma (TCGA, PanCancer Atlas), Breast Invasive Carcinoma (TCGA, PanCancer Atlas), Cervical Squamous Cell Carcinoma (TCGA, Pan­
Cancer Atlas), Cholangiocarcinoma (TCGA, PanCancer Atlas), Colorectal Adenocarcinoma (TCGA, PanCancer Atlas), Diffuse Large B-Cell Lymphoma (TCGA, Pan­
Cancer Atlas), Esophageal Adenocarcinoma (TCGA, PanCancer Atlas), Glioblastoma Multiforme (TCGA, PanCancer Atlas), Head and Neck Squamous Cell Carcinoma
(TCGA, PanCancer Atlas), Kidney Chromophobe (TCGA, PanCancer Atlas), Kidney Renal Clear Cell Carcinoma (TCGA, PanCancer Atlas), Kidney Renal Papillary Cell
Carcinoma (TCGA, PanCancer Atlas), Liver Hepatocellular Carcinoma (TCGA, PanCancer Atlas), Lung Adenocarcinoma (TCGA, PanCancer Atlas), Lung Squamous Cell
Carcinoma (TCGA, PanCancer Atlas), Mesothelioma (TCGA, PanCancer Atlas), Ovarian Serous Cystadenocarcinoma (TCGA, PanCancer Atlas), Pancreatic Adeno­
carcinoma (TCGA, PanCancer Atlas), Pheochromocytoma and Paraganglioma (TCGA, PanCancer Atlas), Prostate Adenocarcinoma (TCGA, PanCancer Atlas), Sarcoma
(TCGA, PanCancer Atlas), Skin Cutaneous Melanoma (TCGA, PanCancer Atlas), Stomach Adenocarcinoma (TCGA, PanCancer Atlas), Testicular Germ Cell Tumors
(TCGA, PanCancer Atlas), Thymoma (TCGA, PanCancer Atlas), Thyroid Carcinoma (TCGA, PanCancer Atlas), Uterine Carcinosarcoma (TCGA, PanCancer Atlas),
Uterine Corpus Endometrial Carcinoma (TCGA, PanCancer Atlas), Uveal Melanoma (TCGA, PanCancer Atlas). Genes in bold font are the ones common to the three
studies/databases.

Cohort prospectively sequenced 10,945 tumor samples from 62 prin­
cipal tumor types and > 300 detailed tumor types using a validated
capture-based next-generation sequencing assay called MSK-IMPACT
that is New York state-approved for clinical use [19] (Table 1).
The biggest challenge in evaluating the results of these genomic
studies, however, is the interpretation of the clinical significance of the
genetic alterations reported. Notably, a few mutations are clinically
actionable and used to guide treatment selection [20], while the vast
majority lack clinical and biological validation, and are classified as
variants of uncertain significance (VUS), precluding their use in preci­
sion oncology [21]. Recently, 24,592 cancer samples were analyzed to
identify mutations arising more frequently than expected in the absence
of selection [22], and cancer genes showed different rates of hotspot
discovery with increasing sample size. The results of this study are
available at the Cancer hotspots website (accessed at https://www.
cancerhotspots.org/#/home). It provides information about statisti­
cally significantly recurrent mutations identified in large scale cancer
genomics data. At its current release (accessed on October 17th, 2021)
information on single residue and in-frame indel mutation hotspots
identified in 24,592 tumor samples by the algorithm described in [21,
22] is available. These tumor samples included 10,336 prospectively
sequenced patients with advanced cancer with recurrent and metastatic
disease and 14,256 samples that were retrospectively sequenced and
predominantly corresponded to untreated cancer cases. The samples
represent 322 cancer types from 32 organ sites. 1165 mutational hot­
spots (1110 single-codon and 55 indel) were identified in 247 genes.
Interestingly, 82% of all identified hotspot mutations were identified in
1/1000 or fewer patients [22].
Table 1 shows the top 15 cancer-genes recurrently mutated in pan-
cancer samples in the above-mentioned datasets and analyses.
Collectively, these results revealed 6 genes that were among the most
frequently mutated across these pan-cancer studies: TP53, KRAS,
PIK3CA, BRAF, PTEN and APC. Remarkably, different hotspot mutations
in individual genes may depend on allele-specificity, conferring
different drug sensitivity [22]. As shown in Table 2, the 15 most
frequently affected single residues across cancer samples are restricted
to 6 genes: TP53, KRAS, PIK3CA, BRAF, IDH1 and NRAS.
5. Recurrent driver mutations in benign neoplasms
Should one expect to detect somatic mutations in benign neoplasms?
With the advent of next-generation sequencing, comprehensive genomic
characterization of tissues and tumors occurs now with unprecedented
speed. It is widely accepted that even normal tissues in patients without
cancer may harbor genetic mutations, with the presence of such muta­
tions reported in normal skin [23], normal esophagus [24], normal
endometrium [25], among others [26]. Interestingly, some of these
mutations are the oncogenic mutations previously considered hallmarks
of malignant neoplasms. Additionally, developmental abnormalities
such as vascular malformations, and inflammatory or proliferative
non-neoplastic lesions harbor genetic mutations, for example giant cell
granulomas of the jaws associated with dental implants [27]. Therefore,
the mere presence of oncogenic mutations is not sufficient to determine
if a lesion is neoplastic or not.
Benign neoplasms harbor genetic mutations, like malignant ones.
Nevertheless, most benign tumors have a quiet and stable genome, and
tend to have ultralow tumor mutational burden (TMB) compared with
malignant neoplasms [28]. There is an abundance of information about
mutational profile of malignant tumors, whereas the number of studies
focusing on the genomic characterization of benign neoplasms and

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C.C. Gomes Mutation Research-Reviews in Mutation Research 789 (2022) 108412

Table 2 Table 3
Frequency distribution of mutant single residues across 24,592 pan-cancer Selected examples of genes recurrently mutated in samples of common and rare
samples. sporadic benign human neoplasms and precursor lesions.
Gene Residue # of samples with Variants: # samples Implicated gene Tumor Reference
mutations
AKT1 Sclerosing hemangioma of Jung et al [30]
1 KRAS G12 2175 D:757|V:657|C:384|R:166| lung
A:134|S:68|F:6|G:1|I:1|L:1 BRAF Ameloblastoma Kurppa et al. [3]
2 BRAF V600 897 E:833|M:29|K:24|R:4|V:4|G:3 BRAF Papillary Brastianos et al. [31]
3 IDH1 R132 766 H:570|C:139|G:28|S:16|L:12| craniopharyngioma
I:1 BRAF Ameloblastic fibroma Coura et al. [32]
4 PIK3CA H1047 647 R:537|L:85|Y:18|Q:7 BRAF Cutaneous nevus Pollock et al. [33]
5 PIK3CA E545 633 K:575|G:21|Q:20|A:12|D:5 BRAF Oral melanocytic nevus Cohen et al. [34]; Resende
6 TP53 R273 609 C:283|H:251|L:56|S:12|P:5| et al. [35]
G:2 BRAF Metanephric adenoma of the Choueiri et al. [36]
7 TP53 R248 560 Q:292|W:222|L:21|P:11|G:8| kidney
R:6 BRAF Bile duct adenomas Pujals et al. [37]
8 NRAS Q61 422 R:204|K:142|L:46|H:27|P:2|* BRAS, KRAS, NRAS Lobular capillary Groesser et al. [38]
:1 hemangioma
9 TP53 R175 416 H:386|G:14|C:8|L:8 CTNNB1 Pilomatricoma Chan et al. [39]
10 PIK3CA E542 372 K:356|A:6|Q:5|V:3|G:2 CTNNB1 Adamantinomatous Sekine et al. [40]
11 KRAS G13 264 D:214|C:32|G:6|V:6|E:3|R:2| craniopharyngioma
A:1 CTNNB1 Calcifying odontogenic cyst Sekine et al. [41]; de Sousa
12 TP53 R213 256 * :208|Q:25|L:17|G:4|P:2 et al. [42]
13 TP53 G245 242 S:128|D:50|V:31|C:22|R:7|A:3| CTNNB1 Desmoid tumor Le Guellec et al. [43]
N:1 CTNNB1 Hepatocellular adenoma Chen et al. [44]
14 TP53 R282 219 W:201|G:9|P:4|Q:3|L:1|R:1 CTNNB1 Salivary gland basal cell Jo et al. [45]
15 KRAS Q61 190 H:108|R:37|L:21|K:20|P:2|A:1| adenoma
E:1 EGFR, KRAS Atypical adenomatous Sakamoto et al. [46]
hyperplasia (lung)
Data deposited at Cancer hotspots (accessed at https://www.cancerhotspots. ERBB2 (HER2)* Lobular carcinoma in situ * Harrison et al. [47]
org/#/home) ** (breast)
ERBB2 (HER2)* * Urothelial carcinoma in situ Barth et al. [48]
* **
precursor lesions is relatively small. Additionally, there is no initiative
FGFR1 Dysembryoplastic Rivera et al. [49]
focused on cataloguing the genomic alterations of benign lesions, and neuroepithelial tumors
there is a lack of public repositories or databases specifically created for FGFR3 Epidermal nevi Hafner et al. [50]
benign lesions. For instance, much has been discussed about creating the FGFR3, PIK3CA Seborrheic keratosis Logié et al. [51]; Hafner
Pre-Cancer Genome Atlas (PCGA), in parallel with TCGA, or a et al. [52]; Thomson et al.
[53]
Pre-Cancer Atlas. This initiative would shed some light on the still
IDH1–2 Enchondroma Cleven et al. [54]; Amary
obscure sequence of molecular events that drive progression from pre­ et al. [55]
malignant lesions to invasive cancer and would additionally improve the H3F3A Giant cell tumor of bone Behjati et al. [56]
prediction of malignant progression [29]. Currently, however, such a H3F3B Condroblastoma Behjati et al. [56]
HNF1A, CTNNB1, IL- Hepatocellular adenomas Nault et al. [57]
resource does not exist.
6/JAK/STAT genes
There are several examples to illustrate the presence of recurrent KIR2DL5 Sporadic dermal Anastasaki et al. [58]
pathogenic mutations that occur at high prevalence in a given benign neurofibroma
tumor. To search systematically for such information, a search in KRAS Adenomatoid odontogenic Gomes et al. [59]; Coura
PubMed as well as Google was conducted. In the search strategy, the tumor et al. [60]
KRAS, FGFR1 Non-ossifying fibroma of Baumhoer et al. [61]
terms “genetics”, “exome” and “mutations” were used along with
bone
“benign” OR “benign tumors” OR “benign neoplasms” OR “precursor KRAS, FGFR1, Giant cell granuloma Gomes et al. [62]
lesions”. Important references and information derived from back­ TRPV4
ground knowledge have also been included as part of this narrative re­ MED12 Uterine leiomyoma Makinen et al. [63]; Pérot
view. Table 3 shows examples of genes recurrently mutated in benign et al. [64]
MED12 Breast fibroadenoma Lim et al. [65]
neoplasms and precursor lesions. Studies reporting molecular alter­ MEN1 Sporadic parathyroid Newey et al. [66]
ations in a few cases or very low prevalence of the mutation in a given adenoma
entity are not listed in the table. As shown in Table 3, BRAF, KRAS, NF2 Schwannoma Twist et al. [67]; Mérel et al.
PIK3CA genes, which were amongst the most mutated in malignant [68]
NF2, TRAF7, AKT1, Meningioma Mérel et al. [68]; Yuzawa
neoplasms, are also among the ones that are recurrently mutated in
KLF4, PIK3CA, et al. [69]; Brastianos et al.
several benign neoplasms. SMO [70]
The overlap between mutations that occur in malignant and benign NRAS Congenital melanocytic nevi Bauer et al. [71]
tumors has been revealed by genomic studies, with not only activating V-ATPase genes Granular cell tumor Pareja et al. [72]; Sekimizu
mutations in oncogenes being reported, but also loss-of-function muta­ et al. [73]; França et al.
[74]
tions in tumor suppressor genes [1] and mutations occurring at less PDGFRB Sporadic myofibromas Arts et al. [75]; Agaimy
well-characterized genes. These mutations of so-called “cancer genes” et al. [76]
that occur in malignant neoplasms are frequent in benign tumors PDGFRB Myoperiocytomas Hung et al. [77]
(Table 3). However, most benign tumors and precursor lesions will not PIK3CA Breast ductal carcinoma in Miron et al. [78]
situ* **
undergo malignant transformation. Based on current evidence, it seems
PIK3CA Sporadic angiolipoma Saggini et al. [79]
reasonable to assume that the effect of mutations is tissue and context PIK3CA, AKT1, Breast myoepithelioma Geyer et al. [80]
dependent. For example, KRAS p.G12V mutation is the second most PIK3R1, HRAS
prevalent KRAS mutation in pancreatic adenocarcinomas [89], known PRKACA Adrenocortical adenoma Beuschlein et al. [81]
for their aggressive behavior. Intriguingly, this is a signature mutation of (cortisol-producing)

adenomatoid odontogenic tumor [59], a benign, encapsulated lesion of (continued on next page)

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C.C. Gomes Mutation Research-Reviews in Mutation Research 789 (2022) 108412

Table 3 (continued ) 6. Revisiting the concept of a driver mutation

Implicated gene Tumor Reference
The overlap of mutations that occur in benign and malignant tumors
PRKAR1A Cardiac myxoma Maleszewski et al. [82]
PTCH1 Odontogenic keratocyst Barreto et al. [83]; Qu et al.
raises the issue of how such mutations should be defined. Malignant
[84] neoplasia driver mutations have been defined as those that “confer
PTEN Thyroid adenomas Dahia et al. [85] growth advantage on the cells carrying them and have been positively
SPOP, EZH1 and Adenomatoid nodules Ye etal. [86] selected during the evolution of the cancer. They reside, by definition, in
ZNF148 (thyroid)
the subset of genes known as cancer genes” [117]. Such definition is
TCF1 Hepatic adenoma Bluteau et al. [87]
TRAF7 Intraneural perineurioma Klein et al. [88] helpful in the case of advanced cancer but considering the scenario of
precursor lesions and benign neoplasia, the use of the term ‘driver’
*Mutation or amplification; * * immunohistochemical overexpression (Her2
mutation can be further refined, as previously proposed by Kuhner and
Dako score of 2 + and 3 +) * ** These studies included carcinomas in situ, but
colleagues [118]. According to these authors, “a mutation or epigenetic
they were listed here since there is a lack of standardization of clear and
objective criteria to distinguish high-grade precursor lesions and in situ
change can be termed ‘advantageous’ when it confers a somatic growth
carcinomas or survival advantage in a given environment, so that cells possessing it
increase in number at the expense of other cells. (…) A mutation can be
termed ‘predisposing’ when it tends toward a cancer phenotype (tissue
indolent behavior.
invasion and metastasis), either by conferring one of the hallmarks of
Genetic signatures for benign neoplasms include not only the pres­
cancer or by destabilizing the genome and thus promoting the occur­
ence of point mutations, but also genetic translocations that result in
rence of other mutations. A classical driver is both advantageous and
gene fusion [90]. Balanced structural rearrangements result in the for­
predisposing” [118]. The employment of the terms ‘advantageous’ and
mation of gene fusions and exert their actions either by overexpression
‘predisposing’ to describe mutations will be briefly discussed in the
of a gene at one of the breakpoints or by creating a chimeric hybrid gene
context of malignant transformation in the following paragraphs.
through the fusion of two different genes [reviewed in 91]. The identi­
Although the use of such terms is stricter than the conventional use of
fication of balanced structural chromosome changes is of undeniable
‘driver’ mutations, they add clarity to our understanding of precursor
importance since the breakpoints involved indicate the location of
lesions in the process of malignant transformation.
neoplasia-relevant genes. Several layers of evidence support that such
Given the conventional use of the term ‘driver mutation,’ an ad­
rearrangements represent early steps in the initiation of malignant
vantageous nonpredisposing mutation in a given tissue or precursor
neoplasms [reviewed in 91], but their importance in the context of
lesion may be mistakenly confused as a driver, even though it will not
benign tumors pathogenesis remains to be further explored. Table 4
drive malignant transformation (Fig. 1A). For example, there is strong
displays several examples of genes that show rearrangement in benign
positive selection of clones carrying NOTCH1 mutations in normal
neoplasms. In addition to chromosomal rearrangements that lead to
esophagus, and the prevalence of such mutations in normal esophagus is
transcript fusion, events resembling chromothripsis (complex chromo­
several times higher than in esophageal cancers [24], suggesting they
somal rearrangements and focal losses resulting from a single genomic
are advantageous, but not predisposing. In normal esophageal epithe­
event) have also been reported in a few benign tumors, namely uterine
lium, there is positive selection of cells presenting mutations in NOTCH1
leiomyomas [115] and meningiomas [116].
and other genes that confer a competitive advantage over cells with
wild-type genotype. A recent study has evaluated the spatial competi­
tion of these clones in murine normal esophageal epithelium and
Table 4 concluded that clones with similar ‘fitness’ expand and collide leading to
Selected examples of genes that show rearrangement in samples of sporadic a decrease in their proliferative activity, and, therefore, to a reac­
benign human neoplasms. quisition of homeostasis [119]. Additionally, cells with CDKN2A inac­
Implicated Gene Tumor Reference
tivation are positively selected early in the development of Barrett
esophagus. However, individuals whose Barrett esophagus contains
ACTB,GLI1 Pericytoma Dahlén et al. [92]
CDKN2A molecular alterations are no more likely to develop esophagus
ALK Inflammatory Lawrence et al. [93]
myofibroblastic tumors adenocarcinoma than those without [reviewed by 118].
BRAF Pylocitic astrocytomas Jones et al. [94] Notably, a predisposing mutation which is not advantageous may
COL6A3,CSF1 Tenosynovial giant-cell West et al. [95] either be selectively neutral or confer a growth or survival disadvantage.
tumor
This is not very clear for somatic mutations, but if we consider BRCA2
FN1 Synovial chondromatosis Amary et al. [96]
FOS, FOSB Osteoblastoma and Fittal et al. [97]
germline mutations, these lead to high risk of breast and ovarian cancer.
osteoid osteoma However, in vitro studies show that cell lines with deletion of both copies
GRM1 Chondromyxoid fibroma Nord et al. [98] of BRCA2 exhibit growth disadvantage compared with wild-type lines,
HMGA2a Breast myoepithelioma Pareja et al. [99] which may explain the reason why BRCA2 mutations are not signifi­
NAB2, STAT Solitary fibrous tumor Robinson et al. [100];
cantly enriched in sporadic breast cancers [reviewed by 118]. Predis­
Chmielecki et al. [101]
NFATC2 (FUS,NFATC2 Simple bone cyst; benign Pižem et al. [102]; Hung posing nonadvantageous mutations can expand under specific
or EWRS1,NFACT2) vascular tumors et al. [103]; Ong et al. situations, such as tissue turnover (Fig. 1B) and genetic hitchhiking with
[104] an advantageous nonpredisposing mutation (Fig. 1C) [118]. In this last
NOTCH1–3 Glomus tumor Mosquera et al. [105] scenario, the predisposing mutation takes advantage of an advantageous
PLAG1, HMGA2 Breast pleomorphic Pareja et al. [106]
adenoma
nonpredisposing mutation (Fig. 1C), even though none of them can
PLAG1, HMGA2 Lacrimal gland Andreasen et al. [107] individually be classified as a driver mutation, because each individual
pleomorphic adenoma mutation does not lead to malignant transformation. Predisposing
PLAG1, HMGA2 Salivary gland Kaz et al. [108]; Hess nonadvantageous mutations tend to be uncommon, and might be
pleomorphic adenoma [109]; Persson et al. [110]
mistakenly classified as ‘passenger mutations’, nevertheless, they confer
PRKCB and PRKCD Benign fibrous Płaszczyca et al. [111]
histiocytoma elevated relative malignant transformation risk when they occur [118].
USP6 Nodular fasciitis Sápi et al. [112] According to the aforementioned concept of a driver mutation as
USP6 Aneurismal bone cyst Oliveira et al. [113]; proposed by Stratton et al., 2009 (i.e., “it should confer growth advan­
Oliveira et al. [114] tage on the cells carrying them and have been positively selected during
a
In cases lacking HRAS, PIK3CA and AKT1 somatic mutations. the evolution of the cancer” [117]) theoretically, mutations that are not

5
C.C. Gomes Mutation Research-Reviews in Mutation Research 789 (2022) 108412

Fig. 1. Driver mutations in the context of precursor lesions and

benign neoplasms. In this simplified schematic representation, the
fate of precursor lesions and/or benign neoplasms across time is
shown. While the presence of advantageous mutations may pro­
mote neoplastic transformation and tumor growth (A), only in the
presence of an advantageous and predisposing mutations a given
lesion may undergo malignant transformation and give origin to a
malignant neoplasm (D). Because only when a mutation is ad­
vantageous and predisposing can it lead to a malignant pheno­
type, it seems reasonable that these should be referred to as
“driver” mutations. Predisposing nonadvantageous mutations
might either be selectively neutral or give a growth or survival
disadvantage. Therefore, the fate of a precursor lesion harboring a
predisposing mutation will depend on the effects of the predis­
posing mutation on cell growth and survival (B). Predisposing
nonadvantageous mutations can expand under specific situations,
such as tissue turnover (B) or genetic hitchhiking with an ad­
vantageous nonpredisposing mutation (C) [118]. In this last sce­
nario, where the predisposing mutation takes advantage of an
advantageous nonpredisposing mutation (C) neither mutation
would be classified individually as a driver mutation [118]. Pre­
disposing nonadvantageous mutations tend to be uncommon (B,
C), and might be mistakenly classified as ‘passenger mutations’,
however, they confer elevated relative malignant transformation
risk when they occur. The inclusion of the benign counterpart of
malignant neoplasms in molecular pathology studies may facili­
tate the evaluation of the risk posed by a given mutation. In
addition, the comparison of precursor lesions and malignant
neoplasms in specific contexts may reveal which mutations are
advantageous (i.e., confers survival advantage) and which ones
are predisposing (i.e., promoting a cancer phenotype) [118].
Because for some precursor lesions malignant transformation
seems to occur through neutral clonal evolution, i.e., randomly
[reviewed in 128], it might be difficult to identify a given muta­
tion that confers predisposition to malignant transformation, even
if benign counterparts of malignant tumors are included in the
analyses.

6
C.C. Gomes
advantageous and predisposing should not be considered drivers in the
context of cancer prevention, and the use of ‘driver mutation’ nomen­
clature should be restricted to mutations that are both advantageous and
predisposing (Fig. 1D). The objective of this discussion into the use of
these terms is not to cause confusion, but to highlight the many
complexity layers surrounding the issue of genetic mutations in benign
tumors and precursor lesions.
In addition, the aim of this review is not to revise carcinogenesis
organ by organ, but rather to critically (re)evaluate the role of the so
called “cancer genes” mutations in the scenario of benign neoplasms and
precursor lesions through the analysis of some examples. Paradoxically,
for a subset of mutations in precursor lesions or benign tumors, which
have known signature mutations (i.e., specific patterns of selected
events) and a malignant counterpart, the prevalence of the cancer gene
mutation may be greater in the precursor lesion than in the corre­
sponding tumor. This concept has been explored by several authors
[120,121]. For example, the frequency of BRAF p.V600E activating
mutations is higher in melanocytic nevus than in cutaneous melanomas
[120]. Curiously, an exceedingly small proportion of melanocytic nevi
(lifetime risk by age 80 years is approximately 0.03% for men and
0.009% for women) [122] and dysplastic nevi (4.8%) [123] will even­
tually transform in melanomas. Shain and colleagues have sequenced
290 genes in primary melanomas and their adjacent precursor lesions.
They have elegantly shown that while histopathologically benign areas
exclusively harbored BRAF p.V600E, areas categorized as intermediate
(dysplastic nevi) were enriched for NRAS mutations [124]. Additionally,
these intermediate lesions and in situ melanomas harbored TERT mu­
tations, and CDKN2A inactivation occurred during melanoma invasion.
Advanced melanoma cases showed PTEN and TP53 mutations [124].
The concept of a “driver” mutation implies that this given mutation is
both, advantageous (i.e., it confers survival advantage) and predisposing
(i.e., promoting a cancer phenotype) [118]. As mentioned above, in the
context of melanomagenesis, BRAF p.V600E seems to be advantageous.
However, this mutation has not been proven to be predisposing.
Therefore, it seems reasonable to consider that BRAF p.V600E does not
entirely fulfil the definition of a “driver” mutation in the context of
melanomagenesis.
Another example of higher frequency of a cancer gene mutation in
the benign lesion is PIK3CA mutations in breast lesions. Such mutations
are more prevalent in breast hyperplasia than in ductal carcinoma in situ
and invasive ductal carcinomas according to the COSMIC database.
Illustrating this paradox, PIK3CA mutations were identified in 50% of
breast proliferative lesions (ductal hyperplasia and columnar cell
change), 71% of breast atypical hyperplasia (atypical ductal hyperplasia
and flat epithelial atypia), 44% lobular neoplasia (atypical lobular hy­
perplasia and lobular carcinoma in situ), 48% of ductal carcinoma in situ
and in 35% invasive carcinomas [125]. Notably, in this aforementioned
study, proliferative lesion samples were positive for PIK3CA mutation,
whereas carcinoma sample derived from the same patient was either
wild-type for the mutation or showed a different point mutation [125].
The authors of the study interpreted these results in a very straightfor­
ward manner, concluding that these discordant genotypes not only
indicate molecular heterogeneity, but also suggest that PIK3CA muta­
tions might exert an effect in breast epithelial proliferation but not
necessarily contribute to malignant transformation [125]. These con­
clusions reinforce the findings of other groups, which have previously
shown that the frequency of PIK3CA mutations is similar in pure ductal
carcinoma in situ, ductal carcinoma in situ adjacent to invasive ductal
carcinomas and in invasive ductal carcinomas [78]. It seems that
PIK3CA mutations are advantageous in the context of breast epithelial
proliferation, however, there is lack of convincing evidence of their role
as predisposing mutations, and, therefore, one should be critical about
its classification as a ‘diver’ mutation in breast carcinogenesis context.
Examples of the opposite situations have also been reported, i.e.,
mutations found to be more prevalent in malignancies than in benign
neoplasms or precursor lesions. For example, 30% of pancreas
7
Mutation Research-Reviews in Mutation Research 789 (2022) 108412
hyperplastic ductal lesions (pancreatic intraepithelial neoplasia, PanIN),
which are believed to represent precursors of ductal adenocarcinomas,
harbor KRAS codon 12 mutations, while the majority of pancreas pri­
mary adenocarcinomas harbor such mutations [126]. If we restrict the
analysis to adenomatoid hyperplasia of the pancreas, KRAS codon 12
mutations occur in 50% of cases, but even normal ducts presented such
mutations [126]. Since KRAS mutations have been detected in all his­
topathological grades of PanIN, they are not useful in discriminating
PanIN according to their malignant potential [127]. While KRAS mu­
tations are common to PanIN and pancreas adenocarcinomas, it seems
that inactivation of TP53 and DCP4 are late events in pancreatic carci­
nogenesis, occurring only in high-grade PanINs and invasive carci­
nomas. This, again, suggests that in the context of pancreatic
carcinogenesis, KRAS mutations are probably advantageous, but not
predisposing.
7. Concluding remarks
The presence of genetic mutations, including translocations, in
benign neoplasms and the fact that some benign neoplasms and pre­
cursor lesions can eventually transform into cancer reinforce the
importance of inclusion of benign neoplasms in molecular pathology
studies. By including the benign counterpart of malignant neoplasms, it
is possible to evaluate the risk posed by a given mutation and to un­
derstand in specific contexts in which mutations are advantageous (i.e.,
confer survival advantage) and which ones are predisposing (i.e., pro­
moting a cancer phenotype) [118]. It should be highlighted, though,
that such achievements are not as easy to be accomplished as it might
seem. For some precursor lesions malignant transformation seems to
occur through neutral clonal evolution, i.e., randomly [reviewed in
128], making it difficult to identify a given mutation that confers pre­
disposition to malignant transformation. To add another layer of
complexity to this subject, non-random events and neutral clonal evo­
lution are not mutually exclusive and they can either occur simulta­
neously or at different time points during tumor evolution [reviewed in
129].
In summary, because benign neoplasms can harbor the same genetic
events as malignancies, studies investigating the biological aspect of
tumor evolution may benefit from the inclusion of benign neoplasms. In
addition, given the limitations in our understanding of tumorigenesis
and the context-dependent role of genetic mutations, the study of benign
neoplasms may provide information on the complex genotypic-
phenotypic correlation in tumors, as well as provide the basis for the
differentiation of advantageous and predisposing mutations, further
refining the concept of driver mutations. The creation of a Pre-Cancer
Genome Atlas (or Pre-Cancer Atlas) has been previously proposed, and
will be of paramount importance to propel premalignant lesions and
benign neoplasms research.
Funding
The work was supported by Fundação de Amparo à Pesquisa do
Estado de Minas Gerais (FAPEMIG)/Brazil and The National Council of
Scientific and Technological Development (CNPq)/Brazil.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Acknowledgements
The author thanks Fundação de Amparo à Pesquisa do Estado de
Minas Gerais (FAPEMIG)/Brazil and The National Council of Scientific
and Technological Development (CNPq)/Brazil. CCG is a research fellow
C.C. Gomes
at CNPq. The author would like to thank Victor Coutinho Bastos for the
figure preparation.
References
[1] A. Marino-Enriquez, C.D. Fletcher, Shouldn’t we care about the biology of benign
tumours? Nat. Rev. Cancer 14 (11) (2014) 701–702, https://doi.org/10.1038/
nrc3845.
[2] D. Hanahan, R.A. Weinberg, Hallmarks of cancer: the next generation, Cell 144
(5) (2011) 646–674, https://doi.org/10.1016/j.cell.2011.02.013.
[3] K.J. Kurppa, J. Catón, P.R. Morgan, et al., High frequency of BRAF V600E
mutations in ameloblastoma, J. Pathol. 232 (5) (2014) 492–498, https://doi.org/
10.1002/path.4317.
[4] C.C. Gomes, M.G. Diniz, L.A. Orsine, et al., Assessment of TP53 mutations in
benign and malignant salivary gland neoplasms, PLoS One 7 (7) (2012), e41261,
https://doi.org/10.1371/journal.pone.0041261.
[5] X.P. Hao, I.M. Frayling, J.G. Sgouros, et al., The spectrum of p53 mutations in
colorectal adenomas differs from that in colorectal carcinomas, Gut 50 (6) (2002)
834–839, https://doi.org/10.1136/gut.50.6.834.
[6] R.H. Lekanne Deprez, A.B. Bianchi, N.A. Groen, et al., Frequent NF2 gene
transcript mutations in sporadic meningiomas and vestibular schwannomas, Am.
J. Hum. Genet 54 (6) (1994) 1022–1102.
[7] C.C. Gomes, V.F. Bernardes, M.G. Diniz, L. De Marco, R.S. Gomez, Anti-apoptotic
gene transcription signature of salivary gland neoplasms, BMC Cancer 12 (2012)
61, https://doi.org/10.1186/1471-2407-12-61.
[8] L. Cheng, D.D. Davidson, M. Wang, et al., Telomerase reverse transcriptase
(TERT) promoter mutation analysis of benign, malignant and reactive urothelial
lesions reveals a subpopulation of inverted papilloma with immortalizing genetic
change, Histopathology 69 (1) (2016) 107–113, https://doi.org/10.1111/
his.12920.
[9] M. Emoto, H. Iwasaki, K. Mimura, T. Kawarabayashi, M. Kikuchi, Differences in
the angiogenesis of benign and malignant ovarian tumors, demonstrated by
analyses of color Doppler ultrasound, immunohistochemistry, and microvessel
density, Cancer 80 (5) (1997) 899–907.
[10] T. Kono, N. Koide, Y. Hama, et al., Expression of vascular endothelial growth
factor and angiogenesis in cardiac myxoma: a study of fifteen patients, J. Thorac.
Cardiovasc. Surg. 119 (1) (2000) 101–107, https://doi.org/10.1016/s0022-5223
(00)70223-6.
[11] V. Kumar, A.K. Abbas, J.C. Aster, Robbins & Cotran Pathologic Basis of Disease,
Elsevier, Amsterdam, 2020, 10th Ed.
[12] D. Baumhoer, M. Kovac, J. Sperveslage, et al., Activating mutations in the MAP-
kinase pathway define non-ossifying fibroma of bone, J. Pathol. 248 (1) (2019)
116–122, https://doi.org/10.1002/path.5216.
[13] R.S. Barnetson, G.M. Halliday, Regression in skin tumours: a common
phenomenon, Austral J. Dermatol. 38 (Suppl 1) (1997) S63–S65, https://doi.org/
10.1111/j.1440-0960.1997.tb01013.x.
[14] G.M. Brodeur, Neuroblastoma: biological insights into a clinical enigma, Nat. Rev.
Cancer 3 (3) (2003) 203–216, https://doi.org/10.1038/nrc1014.
[15] A.M. Soto, C. Sonnenschein, The somatic mutation theory of cancer: growing
problems with the paradigm? Bioessays 26 (10) (2004) 1097–1107, https://doi.
org/10.1002/bies.20087.
[16] B.L. Parsons, Multiclonal tumor origin: evidence and implications, Mutat. Res.
Rev. Mutat. Res. 777 (2018) 1–18, https://doi.org/10.1016/j.
mrrev.2018.05.001.
[17] C. Sonnenschein, A.M. Soto, The death of the cancer cell, Cancer Res. 71 (13)
(2011) 4334–4337, https://doi.org/10.1158/0008-5472.CAN-11-0639.
[18] N. Linde, G. Fluegen, J.A. Aguirre-Ghiso, The relationship between dormant
cancer cells and their microenvironment, Adv. Cancer Res 132 (2016) 45–71,
https://doi.org/10.1016/bs.acr.2016.07.002.
[19] A. Zehir, R. Benayed, R.H. Shah, et al., Mutational landscape of metastatic cancer
revealed from prospective clinical sequencing of 10,000 patients [published
correction appears in Nat Med. 2017 Aug 4;23 (8):1004], Nat. Med 23 (6) (2017)
703–713, https://doi.org/10.1038/nm.4333.
[20] D. Chakravarty, J. Gao, S.M. Phillips, et al., OncoKB: a precision oncology
knowledge base, JCO Precis Oncol. (2017), https://doi.org/10.1200/
PO.17.00011.
[21] M.T. Chang, S. Asthana, S.P. Gao, et al., Identifying recurrent mutations in cancer
reveals widespread lineage diversity and mutational specificity, Nat. Biotechnol.
34 (2) (2016) 155–163, https://doi.org/10.1038/nbt.3391.
[22] M.T. Chang, T.S. Bhattarai, A.M. Schram, et al., Accelerating discovery of
functional mutant alleles in cancer, Cancer Disco 8 (2) (2018) 174–183, https://
doi.org/10.1158/2159-8290.CD-17-0321.
[23] I. Martincorena, A. Roshan, M. Gerstung, et al., Tumor evolution. High burden
and pervasive positive selection of somatic mutations in normal human skin,
Science 348 (6237) (2015) 880–886, https://doi.org/10.1126/science.aaa6806.
[24] I. Martincorena, J.C. Fowler, A. Wabik, et al., Somatic mutant clones colonize the
human esophagus with age, Science 362 (6417) (2018) 911–917, https://doi.org/
10.1126/science.aau3879.
[25] V. Lac, T.M. Nazeran, B. Tessier-Cloutier, et al., Oncogenic mutations in
histologically normal endometrium: the new normal? J. Pathol. 249 (2) (2019)
173–181, https://doi.org/10.1002/path.5314.
[26] S. Mustjoki, N.S. Young, Somatic mutations in “benign” disease, New Engl. J. Med
384 (21) (2021) 2039–2052, https://doi.org/10.1056/NEJMra2101920.
8
Mutation Research-Reviews in Mutation Research 789 (2022) 108412
[27] R.R. Martins-Chaves, L.M. Guimarães, T.D.S.F. Pereira, et al., KRAS mutations in
implant-associated peripheral giant cell granuloma, Oral. Dis. 26 (2) (2020)
334–340, https://doi.org/10.1111/odi.13241.
[28] K. Hatakeyama, T. Nagashima, K. Ohshima, et al., Characterization of tumors
with ultralow tumor mutational burden in Japanese cancer patients, Cancer Sci.
111 (10) (2020) 3893–3901, https://doi.org/10.1111/cas.14572.
[29] J.D. Campbell, S.A. Mazzilli, M.E. Reid, et al., The case for a pre-cancer genome
atlas (PCGA), Cancer Prev. Res. 9 (2) (2016) 119–124, https://doi.org/10.1158/
1940-6207.CAPR-16-0024.
[30] S.H. Jung, M.S. Kim, S.H. Lee, et al., Whole-exome sequencing identifies recurrent
AKT1 mutations in sclerosing hemangioma of lung, Proc. Natl. Acad. Sci. USA 113
(38) (2016) 10672–10677, https://doi.org/10.1073/pnas.1606946113.
[31] P.K. Brastianos, A. Taylor-Weiner, P.E. Manley, et al., Exome sequencing
identifies BRAF mutations in papillary craniopharyngiomas, Nat. Genet. 46 (2)
(2014) 161–165, https://doi.org/10.1038/ng.2868.
[32] B.P. Coura, V.F. Bernardes, S.F. de Sousa, et al., Targeted next-generation
sequencing and allele-specific quantitative PCR of laser capture microdissected
samples uncover molecular differences in mixed odontogenic tumors, J. Mol.
Diagn. 22 (12) (2020) 1393–1399, https://doi.org/10.1016/j.
jmoldx.2020.08.005.
[33] P.M. Pollock, U.L. Harper, K.S. Hansen, et al., High frequency of BRAF mutations
in nevi, Nat. Genet 33 (1) (2003) 19–20, https://doi.org/10.1038/ng1054.
[34] Y. Cohen, N. Goldenberg-Cohen, S. Akrish, et al., BRAF and GNAQ mutations in
melanocytic tumors of the oral cavity, Oral. Surg. Oral. Med Oral. Pathol. Oral.
Radio. 114 (6) (2012) 778–784, https://doi.org/10.1016/j.oooo.2012.09.001.
[35] T.A.C. Resende, B.A.B. de Andrade, V.F. Bernardes, et al., BRAFV600E mutation
in oral melanocytic nevus and oral mucosal melanoma, Oral. Oncol. 114 (2021),
105053, https://doi.org/10.1016/j.oraloncology.2020.105053.
[36] T.K. Choueiri, J. Cheville, E. Palescandolo, et al., BRAF mutations in metanephric
adenoma of the kidney, Eur. Urol. 62 (5) (2012) 917–922, https://doi.org/
10.1016/j.eururo.2012.05.051.
[37] A. Pujals, P. Bioulac-Sage, C. Castain, C. Charpy, E.S. Zafrani, J. Calderaro, BRAF
V600E mutational status in bile duct adenomas and hamartomas, Histopathology
67 (4) (2015) 562–567, https://doi.org/10.1111/his.12674.
[38] L. Groesser, E. Peterhof, M. Evert, M. Landthaler, M. Berneburg, C. Hafner, BRAF
and RAS mutations in sporadic and secondary pyogenic granuloma, J. Invest
Dermatol. 136 (2) (2016) 481–486, https://doi.org/10.1038/JID.2015.376.
[39] E.F. Chan, U. Gat, J.M. McNiff, E. Fuchs, A common human skin tumour is caused
by activating mutations in beta-catenin, Nat. Genet 21 (4) (1999) 410–413,
https://doi.org/10.1038/7747.
[40] S. Sekine, T. Shibata, A. Kokubu, et al., Craniopharyngiomas of
adamantinomatous type harbor beta-catenin gene mutations, Am. J. Pathol. 161
(6) (2002) 1997–2001, https://doi.org/10.1016/s0002-9440(10)64477-x.
[41] S. Sekine, S. Sato, T. Takata, et al., Beta-catenin mutations are frequent in
calcifying odontogenic cysts, but rare in ameloblastomas, Am. J. Pathol. 163 (5)
(2003) 1707–1712, https://doi.org/10.1016/s0002-9440(10)63528-6.
[42] S.F. de Sousa, R.G. Moreira, R.S. Gomez, C.C. Gomes, Interrogation of cancer
hotspot mutations in 50 tumour suppressor genes and oncogenes in calcifying
cystic odontogenic tumour, Oral. Oncol. 57 (2016) e1–e3, https://doi.org/
10.1016/j.oraloncology.2016.04.010.
[43] S. Le Guellec, I. Soubeyran, P. Rochaix, et al., CTNNB1 mutation analysis is a
useful tool for the diagnosis of desmoid tumors: a study of 260 desmoid tumors
and 191 potential morphologic mimics, Mod. Pathol. 25 (12) (2012) 1551–1558,
https://doi.org/10.1038/modpathol.2012.115.
[44] Y.W. Chen, Y.M. Jeng, S.H. Yeh, P.J. Chen, P53 gene and Wnt signaling in benign
neoplasms: beta-catenin mutations in hepatic adenoma but not in focal nodular
hyperplasia, Hepatology 36 (4 Pt 1) (2002) 927–935, https://doi.org/10.1053/
jhep.2002.36126.
[45] V.Y. Jo, L.M. Sholl, J.F. Krane, Distinctive patterns of CTNNB1 (β-Catenin)
alterations in salivary gland basal cell adenoma and basal cell adenocarcinoma,
Am. J. Surg. Pathol. 40 (8) (2016) 1143–1150, https://doi.org/10.1097/
PAS.0000000000000669.
[46] H. Sakamoto, J. Shimizu, Y. Horio, et al., Disproportionate representation of
KRAS gene mutation in atypical adenomatous hyperplasia, but even distribution
of EGFR gene mutation from preinvasive to invasive adenocarcinomas, J. Pathol.
212 (3) (2007) 287–294, https://doi.org/10.1002/path.2165.
[47] B.T. Harrison, F. Nakhlis, D.A. Dillon, et al., Genomic profiling of pleomorphic
and florid lobular carcinoma in situ reveals highly recurrent ERBB2 and ERRB3
alterations, Mod. Pathol. 33 (7) (2020) 1287–1297, https://doi.org/10.1038/
s41379-020-0459-6.
[48] I. Barth, U. Schneider, T. Grimm, et al., Progression of urothelial carcinoma in situ
of the urinary bladder: a switch from luminal to basal phenotype and related
therapeutic implications, Virchows Arch. 472 (5) (2018) 749–758, https://doi.
org/10.1007/s00428-018-2354-9.
[49] B. Rivera, T. Gayden, J. Carrot-Zhang, et al., Germline and somatic FGFR1
abnormalities in dysembryoplastic neuroepithelial tumors, Acta Neuropathol.
131 (6) (2016) 847–863, https://doi.org/10.1007/s00401-016-1549-x.
[50] C. Hafner, J.M. van Oers, T. Vogt, et al., Mosaicism of activating FGFR3 mutations
in human skin causes epidermal nevi, J. Clin. Invest 116 (8) (2006) 2201–2207,
https://doi.org/10.1172/JCI28163.
[51] A. Logié, C. Dunois-Lardé, C. Rosty, et al., Activating mutations of the tyrosine
kinase receptor FGFR3 are associated with benign skin tumors in mice and
humans, Hum. Mol. Genet. 14 (9) (2005) 1153–1160, https://doi.org/10.1093/
hmg/ddi127.
[52] C. Hafner, E. López-Knowles, N.M. Luis, et al., Oncogenic PIK3CA mutations
occur in epidermal nevi and seborrheic keratoses with a characteristic mutation
C.C. Gomes
pattern, Proc. Natl. Acad. Sci. USA 104 (33) (2007) 13450–13454, https://doi.
org/10.1073/pnas.0705218104.
[53] J. Thomson, F. Bewicke-Copley, C.A. Anene, et al., The genomic landscape of
actinic keratosis, J. Invest Dermatol. 141 (7) (2021) 1664–1674, https://doi.org/
10.1016/j.jid.2020.12.024.
[54] A.H.G. Cleven, J. Suijker, G. Agrogiannis, et al., IDH1 or -2 mutations do not
predict outcome and do not cause loss of 5-hydroxymethylcytosine or altered
histone modifications in central chondrosarcomas, Clin. Sarcoma Res 7 (2017) 8,
https://doi.org/10.1186/s13569-017-0074-6.
[55] M.F. Amary, K. Bacsi, F. Maggiani, et al., IDH1 and IDH2 mutations are frequent
events in central chondrosarcoma and central and periosteal chondromas but not
in other mesenchymal tumours, J. Pathol. 224 (3) (2011) 334–343, https://doi.
org/10.1002/path.2913.
[56] S. Behjati, P.S. Tarpey, N. Presneau, et al., Distinct H3F3A and H3F3B driver
mutations define chondroblastoma and giant cell tumor of bone, Nat. Genet. 45
(12) (2013) 1479–1482, https://doi.org/10.1038/ng.2814 [published correction
appears in Nat Genet. 2014 Mar;46(3):316. Goodie, Victoria [corrected to Goody,
Victoria]].
[57] J.C. Nault, P. Bioulac-Sage, J. Zucman-Rossi, Hepatocellular benign tumors-from
molecular classification to personalized clinical care, Gastroenterology 144 (5)
(2013) 888–902, https://doi.org/10.1053/j.gastro.2013.02.032.
[58] C. Anastasaki, S. Dahiya, D.H. Gutmann, KIR2DL5 mutation and loss underlies
sporadic dermal neurofibroma pathogenesis and growth, Oncotarget 8 (29)
(2017) 47574–47585, https://doi.org/10.18632/oncotarget.17736.
[59] C.C. Gomes, S.F. de Sousa, G.H. de Menezes, et al., Recurrent KRAS G12V
pathogenic mutation in adenomatoid odontogenic tumours, Oral. Oncol. 56
(2016) e3–e5, https://doi.org/10.1016/j.oraloncology.2016.03.001.
[60] B.P. Coura, V.F. Bernardes, S.F. de Sousa, et al., KRAS mutations drive
adenomatoid odontogenic tumor and are independent of clinicopathological
features, Mod. Pathol. 32 (6) (2019) 799–806, https://doi.org/10.1038/s41379-
018-0194-4.
[61] D. Baumhoer, M. Kovac, J. Sperveslage, et al., Activating mutations in the MAP-
kinase pathway define non-ossifying fibroma of bone, J. Pathol. 248 (1) (2019)
116–122, https://doi.org/10.1002/path.5216.
[62] C.C. Gomes, T. Gayden, A. Bajic, et al., TRPV4 and KRAS and FGFR1 gain-of-
function mutations drive giant cell lesions of the jaw, Nat. Commun. 9 (1) (2018)
4572, https://doi.org/10.1038/s41467-018-06690-4.
[63] N. Makinen, et al., MED12, the mediator complex subunit 12 gene, is mutated at
high frequency in uterine leiomyomas, Science 334 (2011) 252–255.
[64] G. Pérot, S. Croce, A. Ribeiro, et al., MED12 alterations in both human benign and
malignant uterine soft tissue tumors, PLoS One 7 (6) (2012), e40015, https://doi.
org/10.1371/journal.pone.0040015.
[65] W.K. Lim, C.K. Ong, J. Tan, et al., Exome sequencing identifies highly recurrent
MED12 somatic mutations in breast fibroadenoma, Nat. Genet. 46 (8) (2014)
877–880, https://doi.org/10.1038/ng.3037.
[66] P.J. Newey, M.A. Nesbit, A.J. Rimmer, et al., Whole-exome sequencing studies of
nonhereditary (sporadic) parathyroid adenomas, J. Clin. Endocrinol. Metab. 97
(10) (2012) E1995–E2005, https://doi.org/10.1210/jc.2012-2303.
[67] E.C. Twist, M.H. Ruttledge, M. Rousseau, et al., The neurofibromatosis type 2
gene is inactivated in schwannomas, Hum. Mol. Genet 3 (1) (1994) 147–151,
https://doi.org/10.1093/hmg/3.1.147.
[68] P. Mérel, K. Hoang-Xuan, M. Sanson, et al., Predominant occurrence of somatic
mutations of the NF2 gene in meningiomas and schwannomas, Genes
Chromosomes Cancer 13 (3) (1995) 211–216, https://doi.org/10.1002/
gcc.2870130311.
[69] S. Yuzawa, H. Nishihara, S. Tanaka, Genetic landscape of meningioma, Brain
Tumor Pathol. 33 (4) (2016) 237–247, https://doi.org/10.1007/s10014-016-
0271-7.
[70] P.K. Brastianos, P.M. Horowitz, S. Santagata, et al., Genomic sequencing of
meningiomas identifies oncogenic SMO and AKT1 mutations, Nat. Genet. 45 (3)
(2013) 285–289, https://doi.org/10.1038/ng.2526.
[71] J. Bauer, J.A. Curtin, D. Pinkel, B.C. Bastian, Congenital melanocytic nevi
frequently harbor NRAS mutations but no BRAF mutations, J. Invest Dermatol.
127 (1) (2007) 179–182, https://doi.org/10.1038/sj.jid.5700490.
[72] F. Pareja, A.H. Brandes, T. Basili, et al., Loss-of-function mutations in ATP6AP1
and ATP6AP2 in granular cell tumors, Nat. Commun. 9 (1) (2018) 3533, https://
doi.org/10.1038/s41467-018-05886-y.
[73] M. Sekimizu, A. Yoshida, S. Mitani, et al., Frequent mutations of genes encoding
vacuolar H+ -ATPase components in granular cell tumors, Genes Chromosomes
Cancer 58 (6) (2019) 373–380, https://doi.org/10.1002/gcc.22727.
[74] J.A. França, T. Gayden, E. Bareke, et al., Whole-exome sequencing reveals novel
vacuolar ATPase genes’ variants and variants in genes involved in lysosomal
biology and autophagosomal formation in oral granular cell tumors, J. Oral.
Pathol. Med 50 (4) (2021) 410–417, https://doi.org/10.1111/jop.13148.
[75] F.A. Arts, R. Sciot, B. Brichard, et al., PDGFRB gain-of-function mutations in
sporadic infantile myofibromatosis, Hum. Mol. Genet. 26 (10) (2017) 1801–1810,
https://doi.org/10.1093/hmg/ddx081.
[76] A. Agaimy, M. Bieg, M. Michal, et al., Recurrent somatic PDGFRB mutations in
sporadic infantile/solitary adult myofibromas but not in angioleiomyomas and
myopericytomas, Am. J. Surg. Pathol. 41 (2) (2017) 195–203, https://doi.org/
10.1097/PAS.0000000000000752.
[77] Y.P. Hung, C.D.M. Fletcher, Myopericytomatosis: clinicopathologic analysis of 11
cases with molecular identification of recurrent PDGFRB alterations in
myopericytomatosis and myopericytoma, Am. J. Surg. Pathol. 41 (8) (2017)
1034–1044, https://doi.org/10.1097/PAS.0000000000000862.
9
Mutation Research-Reviews in Mutation Research 789 (2022) 108412
[78] A. Miron, M. Varadi, D. Carrasco, et al., PIK3CA mutations in in situ and invasive
breast carcinomas, Cancer Res. 70 (14) (2010) 5674–5678, https://doi.org/
10.1158/0008-5472.CAN-08-2660.
[79] A. Saggini, C. Santonja, L. Nájera, G. Palmedo, H. Kutzner, Frequent activating
PIK3CA mutations in sporadic angiolipoma, J. Cutan. Pathol. 48 (2) (2021)
211–216, https://doi.org/10.1111/cup.13809.
[80] F.C. Geyer, A. Li, A.D. Papanastasiou, et al., Recurrent hotspot mutations in HRAS
Q61 and PI3K-AKT pathway genes as drivers of breast adenomyoepitheliomas,
Nat. Commun. 9 (1) (2018) 1816, https://doi.org/10.1038/s41467-018-04128-5.
Published 2018 May 8.
[81] F. Beuschlein, M. Fassnacht, G. Assié, et al., Constitutive activation of PKA
catalytic subunit in adrenal Cushing’s syndrome, N. Engl. J. Med 370 (11) (2014)
1019–1028, https://doi.org/10.1056/NEJMoa1310359.
[82] J.J. Maleszewski, B.T. Larsen, N.S. Kip, et al., PRKAR1A in the development of
cardiac myxoma: a study of 110 cases including isolated and syndromic tumors,
Am. J. Surg. Pathol. 38 (8) (2014) 1079–1087, https://doi.org/10.1097/
PAS.0000000000000202.
[83] D.C. Barreto, R.S. Gomez, A.E. Bale, W.L. Boson, L. De Marco, PTCH gene
mutations in odontogenic keratocysts, J. Dent. Res 79 (6) (2000) 1418–1422,
https://doi.org/10.1177/00220345000790061101.
[84] J. Qu, F. Yu, Y. Hong, et al., Underestimated PTCH1 mutation rate in sporadic
keratocystic odontogenic tumors, Oral. Oncol. 51 (1) (2015) 40–45, https://doi.
org/10.1016/j.oraloncology.2014.09.016.
[85] P.L. Dahia, D.J. Marsh, Z. Zheng, et al., Somatic deletions and mutations in the
Cowden disease gene, PTEN, in sporadic thyroid tumors, Cancer Res. 57 (21)
(1997) 4710–4713.
[86] L. Ye, X. Zhou, F. Huang, et al., The genetic landscape of benign thyroid nodules
revealed by whole exome and transcriptome sequencing, Nat. Commun. 8 (2017)
15533, https://doi.org/10.1038/ncomms15533 [published correction appears in
Nat Commun. 2017 Jul 04;8:16129].
[87] O. Bluteau, E. Jeannot, P. Bioulac-Sage, et al., Bi-allelic inactivation of TCF1 in
hepatic adenomas, Nat. Genet. 32 (2) (2002) 312–315, https://doi.org/10.1038/
ng1001.
[88] C.J. Klein, Y. Wu, M.E. Jentoft, et al., Genomic analysis reveals frequent TRAF7
mutations in intraneural perineuriomas, Ann. Neurol. 81 (2) (2017) 316–321,
https://doi.org/10.1002/ana.24854.
[89] K.M. Haigis, KRAS alleles: the devil is in the detail, Trends Cancer 3 (10) (2017)
686–697, https://doi.org/10.1016/j.trecan.2017.08.006.
[90] P. Aman, Fusion genes in solid tumors, Semin Cancer Biol. 9 (4) (1999) 303–318,
https://doi.org/10.1006/scbi.1999.0130.
[91] F. Mitelman, B. Johansson, F. Mertens, The impact of translocations and gene
fusions on cancer causation, Nat. Rev. Cancer 7 (4) (2007) 233–245, https://doi.
org/10.1038/nrc2091.
[92] A. Dahlén, C.D. Fletcher, F. Mertens, et al., Activation of the GLI oncogene
through fusion with the beta-actin gene (ACTB) in a group of distinctive pericytic
neoplasms: pericytoma with t(7;12), Am. J. Pathol. 164 (5) (2004) 1645–1653,
https://doi.org/10.1016/s0002-9440(10)63723-6.
[93] B. Lawrence, A. Perez-Atayde, M.K. Hibbard, et al., TPM3-ALK and TPM4-ALK
oncogenes in inflammatory myofibroblastic tumors, Am. J. Pathol. 157 (2) (2000)
377–384, https://doi.org/10.1016/S0002-9440(10)64550-6.
[94] D.T. Jones, S. Kocialkowski, L. Liu, et al., Tandem duplication producing a novel
oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas,
Cancer Res 68 (21) (2008) 8673–8677, https://doi.org/10.1158/0008-5472.
CAN-08-2097.
[95] R.B. West, B.P. Rubin, M.A. Miller, et al., A landscape effect in tenosynovial giant-
cell tumor from activation of CSF1 expression by a translocation in a minority of
tumor cells, Proc. Natl. Acad. Sci. USA 103 (3) (2006) 690–695, https://doi.org/
10.1073/pnas.0507321103.
[96] F. Amary, L. Perez-Casanova, H. Ye, et al., Synovial chondromatosis and soft
tissue chondroma: extraosseous cartilaginous tumor defined by FN1 gene
rearrangement, Mod. Pathol. 32 (12) (2019) 1762–1771, https://doi.org/
10.1038/s41379-019-0315-8.
[97] M.W. Fittall, W. Mifsud, N. Pillay, et al., Recurrent rearrangements of FOS and
FOSB define osteoblastoma, Published 2018 Jun 1, Nat. Commun. 9 (1) (2018)
2150, https://doi.org/10.1038/s41467-018-04530-z.
[98] K.H. Nord, H. Lilljebjörn, F. Vezzi, et al., GRM1 is upregulated through gene
fusion and promoter swapping in chondromyxoid fibroma, Nat. Genet 46 (5)
(2014) 474–477, https://doi.org/10.1038/ng.2927.
[99] F. Pareja, F.C. Geyer, D.N. Brown, et al., Assessment of HMGA2 and PLAG1
rearrangements in breast adenomyoepitheliomas, NPJ Breast Cancer 5 (2019) 6,
https://doi.org/10.1038/s41523-018-0101-7.
[100] D.R. Robinson, Y.M. Wu, S. Kalyana-Sundaram, et al., Identification of recurrent
NAB2-STAT6 gene fusions in solitary fibrous tumor by integrative sequencing,
Nat. Genet. 45 (2) (2013) 180–185, https://doi.org/10.1038/ng.2509.
[101] J. Chmielecki, A.M. Crago, M. Rosenberg, et al., Whole-exome sequencing
identifies a recurrent NAB2-STAT6 fusion in solitary fibrous tumors, Nat. Genet.
45 (2) (2013) 131–132, https://doi.org/10.1038/ng.2522.
[102] J. Pižem, D. Šekoranja, A. Zupan, et al., FUS-NFATC2 or EWSR1-NFATC2 fusions
are present in a large proportion of simple bone cysts, Am. J. Surg. Pathol. 44 (12)
(2020) 1623–1634, https://doi.org/10.1097/PAS.0000000000001584.
[103] Y.P. Hung, A.S. Fisch, J.A. Diaz-Perez, et al., Identification of EWSR1-NFATC2
fusion in simple bone cysts, Histopathology 78 (6) (2021) 849–856, https://doi.
org/10.1111/his.14314.
[104] S.L.M. Ong, S.W. Lam, B.E.W.M. van den Akker, et al., Expanding the Spectrum of
EWSR1-NFATC2-rearranged Benign Tumors: A Common Genomic Abnormality in
C.C. Gomes
Vascular Malformation/Hemangioma and Simple Bone Cyst, Am. J. Surg. Pathol.
(2021 3) ([published online ahead of print).
[105] J.M. Mosquera, A. Sboner, L. Zhang, et al., Novel MIR143-NOTCH fusions in
benign and malignant glomus tumors, Genes Chromosomes Cancer 52 (11)
(2013) 1075–1087, https://doi.org/10.1002/gcc.22102.
[106] F. Pareja, A. Da Cruz Paula, R. Gularte-Mérida, et al., Pleomorphic adenomas and
mucoepidermoid carcinomas of the breast are underpinned by fusion genes,
Published 2020 Jun 5, NPJ Breast Cancer 6 (2020) 20, https://doi.org/10.1038/
s41523-020-0164-0.
[107] S. Andreasen, S.L. von Holstein, P. Homøe, S. Heegaard, Recurrent
rearrangements of the PLAG1 and HMGA2 genes in lacrimal gland pleomorphic
adenoma and carcinoma ex pleomorphic adenoma, Acta Ophthalmol. 96 (7)
(2018) e768–e771, https://doi.org/10.1111/aos.13667.
[108] K. Kas, M.L. Voz, E. Röijer, et al., Promoter swapping between the genes for a
novel zinc finger protein and beta-catenin in pleiomorphic adenomas with t(3;8)
(p21;q12) translocations [published correction appears in Nat Genet 1997 Apr;15
(4):411], Nat. Genet 15 (2) (1997) 170–174, https://doi.org/10.1038/ng0297-
170.
[109] J.L. Hess, Chromosomal translocations in benign tumors: the HMGI proteins, Am.
J. Clin. Pathol. 109 (3) (1998) 251–261, https://doi.org/10.1093/ajcp/
109.3.251.
[110] F. Persson, Y. Andrén, M. Winnes, et al., High-resolution genomic profiling of
adenomas and carcinomas of the salivary glands reveals amplification,
rearrangement, and fusion of HMGA2, Genes Chromosomes Cancer 48 (1) (2009)
69–82, https://doi.org/10.1002/gcc.20619.
[111] A. Płaszczyca, J. Nilsson, L. Magnusson, et al., Fusions involving protein kinase C
and membrane-associated proteins in benign fibrous histiocytoma, Int. J.
Biochem. Cell Biol. 53 (2014) 475–481, https://doi.org/10.1016/j.
biocel.2014.03.027.
[112] Z. Sápi, Z. Lippai, G. Papp, et al., Nodular fasciitis: a comprehensive, time-
correlated investigation of 17 cases, Mod. Pathol. (2021), https://doi.org/
10.1038/s41379-021-00883-x [published online ahead of print, 2021 Aug 11].
[113] A.M. Oliveira, B.L. Hsi, S. Weremowicz, et al., USP6 (Tre2) fusion oncogenes in
aneurysmal bone cyst, Cancer Res. 64 (6) (2004) 1920–1923, https://doi.org/
10.1158/0008-5472.can-03-2827.
[114] A.M. Oliveira, A.R. Perez-Atayde, P. Dal Cin, et al., Aneurysmal bone cyst variant
translocations upregulate USP6 transcription by promoter swapping with the
ZNF9, COL1A1, TRAP150, and OMD genes, Oncogene 24 (21) (2005) 3419–3426,
https://doi.org/10.1038/sj.onc.1208506.
[115] M. Mehine, E. Kaasinen, N. Mäkinen, et al., Characterization of uterine
leiomyomas by whole-genome sequencing, New Engl. J. Med. 369 (1) (2013)
43–53, https://doi.org/10.1056/NEJMoa1302736.
[116] C. Baltus, S. Toffoli, F. London, P. Delrée, C. Gilliard, T. Gustin, Chromothripsis in
an early recurrent chordoid meningioma, World Neurosurg. 130 (2019) 380–385,
https://doi.org/10.1016/j.wneu.2019.07.003.
10
Mutation Research-Reviews in Mutation Research 789 (2022) 108412
[117] M. Stratton, P. Campbell, P. Futreal, The cancer genome, Nature 458 (2009)
719–724, https://doi.org/10.1038/nature07943.
[118] M.K. Kuhner, R. Kostadinov, B.J. Reid, Limitations of the driver/passenger model
in cancer prevention, Cancer Prev. Res. 9 (5) (2016) 335–338, https://doi.org/
10.1158/1940-6207.CAPR-15-0343.
[119] B. Colom, M.P. Alcolea, G. Piedrafita, et al., Spatial competition shapes the
dynamic mutational landscape of normal esophageal epithelium, Nat. Genet. 52
(6) (2020) 604–614, https://doi.org/10.1038/s41588-020-0624-3.
[120] S. Kato, S.M. Lippman, K.T. Flaherty, R. Kurzrock, The conundrum of genetic
“drivers” in benign conditions, J. Natl. Cancer Inst. 108 (8) (2016) djw036,
https://doi.org/10.1093/jnci/djw036. Published 2016 Apr 7.
[121] J.J. Adashek, S. Kato, S.M. Lippman, R. Kurzrock, The paradox of cancer genes in
non-malignant conditions: implications for precision medicine, Genome Med. 12
(1) (2020) 16, https://doi.org/10.1186/s13073-020-0714-y. Published 2020 Feb
17.
[122] H. Tsao, C. Bevona, W. Goggins, T. Quinn, The transformation rate of moles
(melanocytic nevi) into cutaneous melanoma: a population-based estimate, Arch.
Dermatol. 139 (3) (2003) 282–288, https://doi.org/10.1001/
archderm.139.3.282.
[123] A.D. Tiersten, C.M. Grin, A.W. Kopf, et al., Prospective follow-up for malignant
melanoma in patients with atypical-mole (dysplastic-nevus) syndrome,
J. Dermatol. Surg. Oncol. 17 (1) (1991) 44–48, https://doi.org/10.1111/j.1524-
4725.1991.tb01592.x.
[124] A.H. Shain, I. Yeh, I. Kovalyshyn, et al., The genetic evolution of melanoma from
precursor lesions, N. Engl. J. Med. 373 (20) (2015) 1926–1936, https://doi.org/
10.1056/NEJMoa1502583.
[125] D.C. Ang, A.L. Warrick, A. Shilling, C. Beadling, C.L. Corless, M.L. Troxell,
Frequent phosphatidylinositol-3-kinase mutations in proliferative breast lesions,
Mod. Pathol. 27 (5) (2014) 740–750, https://doi.org/10.1038/
modpathol.2013.197.
[126] J. Lüttges, B. Schlehe, M.A. Menke, I. Vogel, D. Henne-Bruns, G. Klöppel, The K-
ras mutation pattern in pancreatic ductal adenocarcinoma usually is identical to
that in associated normal, hyperplastic, and metaplastic ductal epithelium,
Cancer 85 (8) (1999) 1703–1710.
[127] J. Lüttges, H. Galehdari, V. Bröcker, et al., Allelic loss is often the first hit in the
biallelic inactivation of the p53 and DPC4 genes during pancreatic carcinogenesis,
Am. J. Pathol. 158 (5) (2001) 1677–1683, https://doi.org/10.1016/S0002-9440
(10)64123-5.
[128] L.M. Guimarães, M.G. Diniz, S.R. Rogatto, R.S. Gomez, C.C. Gomes, The genetic
basis of oral leukoplakia and its key role in understanding oral carcinogenesis,
J. Oral. Pathol. Med. 50 (7) (2021) 632–638, https://doi.org/10.1111/jop.13140.
[129] A. Davis, R. Gao, N. Navin, Tumor evolution: linear, branching, neutral or
punctuated? Biochim Biophys. Acta Rev. Cancer 1867 (2) (2017) 151–161,
https://doi.org/10.1016/j.bbcan.2017.01.003.