Biomolecular Genetics of Basal Cell Carsinoma

dr. R.A.Reizkhi Fitriyana

04012722125007
Ilmu Bedah

Pembimbing
dr. Rachmat Hidayat, M.Sc

PROGRAM PENDIDIKAN DOKTER SPESIALIS

FAKULTAS KEDOKTERAN
UNIVERSITAS SRIWIJAYA

Molecular Genetics Mutations of Basal Cell Carsinoma

Abstract
Non-melanoma skin cancer (NMSC) is the most common types of human skin cancer.
Clinically, there are five types of KSB, namely nodular, superficial, morpheaform, pigmented,
and fibro epitelioma Pinkus. There are 2 types of NSMC, the most common are basal cell
carcinoma (BCC) and squamous cell carcinoma (SCC). The most important risk factor for
development is a positive family history of BCC, although approximately (30-60%)(2). The
incidence of both BCC has been increasing . Mostly, gender plays an important role in the
incidence of BCC.(2) Men is greater than that of women (1.5-2: 1). ). The incidence of NMSC
skin cancer and melanoma has been increasing .
All this evidence suggests a complex genetic network of tumor suppressor genes and
different pathways contribute to BCC carcinogenesis, supporting genetic heterogeneity. should,
it is clear that a more complex genetic network of cancer-related genes than previously
hypothesized is involved in BCC carcinogenesis, the gene involved is the Hodgehog pathaway.

Abstrak
Kanker kulit non-melanoma (NMSC) adalah jenis kanker kulit manusia yang paling
umum.
Secara klinis terdapat lima jenis KSB, yaitu nodular, superficial, morpheaform, pigmented, dan
fibro epitelioma pinkus. Ada 2 jenis NSMC, yang paling umum adalah karsinoma sel basal
(BCC) dan karsinoma sel skuamosa (SCC). Faktor risiko terpenting untuk perkembangannya
adalah riwayat keluarga BCC yang positif, meskipun kira-kira (30-60%). Insiden kedua BCC
telah meningkat. Sebagian besar, gender memainkan peran penting dalam kejadian BCC. (2) Pria
lebih besar dari wanita (1.5-2: 1). ). Insiden kanker kulit NMSC dan melanoma telah meningkat.
Semua bukti ini menunjukkan jaringan genetik yang kompleks dari gen penekan tumor
dan jalur yang berbeda berkontribusi pada karsinogenesis BCC, mendukung heterogenitas
genetik. Seharusnya, jelas bahwa jaringan genetik yang lebih kompleks dari gen terkait kanker
daripada yang dihipotesiskan sebelumnya terlibat dalam karsinogenesis BCC, gen yang terlibat
adalah jalur Hodgehog.

Keywords: basal cell carcinoma; molecular genetics; PTCH1; TP53

1. Introduction

Non-melanoma skin cancer (NMSC) is the most common types of human skin cancer.
Clinically, there are five types of KSB, namely nodular, superficial, morpheaform, pigmented,
and fibro epitelioma Pinkus. The KSB subtype can be determined by history and clinical
manifestations, supported by histopathological examination. There are 2 types of NSMC, the
most common are basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). The most
important risk factor for development is a positive family history of BCC, although
approximately (30-60%)(2). Management based on location and histopathological features. The
recurrence rate of KSB is very high low if appropriate therapy(5). BCC is the most common
skin malignancy in the world (3).
The incidence of both BCC has been increasing . Mostly, gender plays an important role
in the incidence of BCC.(2) Men is greater than that of women (1.5-2: 1). ). The incidence of
NMSC skin cancer and melanoma has been increasing . It was reported that the incidence rate in
New Zealand with 50 cases per 100,000 people and Australia with 48 cases per 100,000 people
(59 for men and 39 for women in 2011), followed by the US (21.6 new cases per 100,000 in
2012) and Europe (13.2 and 13.1 new cases annual cases, per 100,000 for men and women,
respectively).(3).

2. Cell Basal Carsinoma and Gene Mutations

2. Established BCC-Associated Gene
 2.1. HH Pathway Genes
HH is a highly-conserved development pathway involved in organogenesis, stem cell
maintenance, tissue repair, and regeneration. In the skin, the HH pathway is responsible for
maintaining the stem cell population and for controlling development of hair follicles and
sebaceous glands. Aspects of tumorigenesis include initiation, progression controlled by the
activation of various aberrant HH pathways and relapse, by directing the phenotype of cancer
stem cells at least in part.
Indian HH, and Desert HH, transmembrane receptor proteins PTCH1 and PTCH2, G
protein coupled to receptors such as SMO protein, and transcription factors GLI 1, 2, and 3
(GLI1, GLI2, and GLI3) [32] belong to the canonical HH pathway.
The primary cilia structures are related to each other HH signaling transduction, of
the plasma membrane in almost all visible cell types highly specialized microtubule-based
organelles that protrude and act as sensors for extracellular signaling.
The pathway is activated when HH ligands bind PTCH1 to relieve PTCH-mediated
SMO inhibition at the base of primary cilium. Then, self-renewal, the fate of the cell is
governed by GLI transcription factors move to the nucleus and activate the transcription of
context-specific genes that regulate survival, and angiogenesis. In addition, HH signaling via
modulation regulated by GLI1 forms a feedback loop that automatically regulates PTCH1
an increase in GLI1 expression resulted from mutations at each level of the HH
signaling pathway (e.g., PTCH1, SMO, and SUFU) will produce.
 (a) (b)

(c)

Figure 1. Physiologic and oncogenic Hedgehog signaling. (a) because SMO was suppressed
resulting in constitutive absence of HH, PTCH1 ligands, and HH signal transduction is blocked;
(b) The family of extracellular HH ligands binds to PTCH1, de-represses SMO thereby allowing
its translocation on the tip of the primary cilium. possible translocation at the end of the primary
cilia thus removal of stress SMO and the extracellular HH ligand group binds to PTCH1,
(c) HH pathway induced Loss of PTCH1 function (red cross) or activation of SMO mutations
(blue asterisk) in the absence of the HH ligand. HH; Porcupine; PTCH1; Homologous Patched 1;
SMO; Smoother; SUFU; fused suppressor; GLI; glioma-related oncogenes.

n addition to the signaling pathways mentioned above, activation of the GLI transcription factor
independent of HH or PTCH1 / SMO ligands is generated by the resulting non-canonical HH
cascade. GLI activity has been shown to be positively regulated by KRAS, TGF-β, PI3K-AKT,
and PKC-α [37-43], and negatively by p53, PKA, and PKC-δ
the most significant pathogenic incidence in BCC
Upregulation of HH signaling is More than 90% BCC represents a loss of PTCH1 function by
deactivating the PTCH1 mutation, as well as deviant SMO activation via activation of the SMO
mutation
insufficient, a carcinogenetic event allows Inactivation of PTCH1 in BCC if required. Inactive
point mutations BCC brought about sporadically reported loss of copy heterozygosity (LOH),
and copy-neutral LOH (due to uniparental disomy) in PTCH1 [19,49,50]. PTCH1 somatic
mutations range between 11% and 75% (Table1) and without evidence of hot-spot areas. non-
synonymous mutations represent predominance of nonsense mutations and splice sites across the
length of the PTCH1 gene, the C-T "UV-signature" transition and the CC-TT tandem comprised
half of these mutations; Oxidative stress, has been implicated in gene mutagenesis due to the
presence of UV radiation, the mutation of PTCH1 remains controversial(4)
However, the origin of UV radiation from the PTCH1 mutation is controversial, due to this
factor.
In addition to point mutations, BCC reported somatic copy number (SCNA) deviations from
PTCH1 were frequent is the SCNA most frequently identified in BCC and occurs in about 42-
70% of tumors due to the loss of part or all of the 9q chromosome arm is LOH from the PTCH1
allele

(Table1).
Table 1. on basal cell carcinoma published (BCC) Mutation frequency and loss of heterozygosity
(LOH) in cancer-related genes across a study.

Gene Nr. of Samples Analyzed Mutations (%) LOH (%) References

37 32.4 24.3 [12]
55 - 66.7 [51]
26 a 11.8 38.2 [15]
24 54.2 - [11]
15 40.0 53.3 [18]
PTCH1 31 54.8 43.5 [52]
42 66.7 52.6 [19] *
14 b 64.3 92.8 [49]
12 b 8.3 40.0 [50]
12 75.0 41.7 [48]
293 c 73.0 55.0 [22] *
14 50.0 na [57]
18 d 61.1 5.5 [51]
27 56.0 na [58]
20 35.0 na [59]
 24 45.8 na [11]
15 33.0 - [18]
TP53
50 e 66.0 na [60]
98 f 37.7 na [60]
42 40.5 7.9 [48]
30 20.0 na [61]
12 66.7 na [19]
293 61.0 17.0 [22] *
47 6.38 na [14]
SMO 42 9.5 na [48]
293 20.0 na [22] *
42 2.4 na [48]
SUFU
293 8.0 5.0 [22] *
12 50.0 na [19] *
NOTCH1
293 29.0 2.7 [22] *
12 66.7 na [19] *
NOTCH2
293 26.0 na [22] *
LATS1 293 16.0 4.0 [22] *
LATS1 293 12.0 5.0 [22] *
PPP6C 293 15.0 46.0 [22] *
STK19 293 10.0 na [22] *

Table 1. Cont.

Gene Nr. of Samples Analyzed Mutations (%) LOH (%) References

MYCN 293 30.0 na [22] *
ARID1A 293 26.0 3.0 [22] *
PTPN14 293 22.0 5.0 [22] *
CASP8 293 11.0 3.0 [22] *
CSMD1 12 91.7 na [19] *
DPP10 12 75.0 na [19] *
CSMD2 12 66.7 na [19] *
CSMD3 12 58.3 na [19] *
PREX2 12 58.3 na [19] *
DCC 12 50.0 na [19] *
GRIN2A 12 50.0 na [19] *
32 56.2 na [23]
42 g 73.8 na [24]
TERT-promoter na
196 h 38.8 na [25]
137 65.0 [26]
DPH3/OXNAD1 promoter 137 41.6 na [26]

8 BCC and 26 sporadic basal cell carinoma (BCC) and from patients with Gorin Syndrome
were from; 8 BCC and 26 sporadic basal cell carinoma (BCC) and from patients with Gorin
Syndrome were from; b 6 sporadic BCC and 6 BCC from; e BCC agresif; f BCC non-agresif
adalah d subset BCC dari area yang terpapar sinar matahari; ; pasien dengan Sindrom Gorling
adalah 23 BCC sporadis dan 19 BCC dari ; h 94 pasien non-X berasal dari h94 iradiasi dan
pasien X-iradiasi dari 102; * genes that are more than 10% have been reported with a higher
mutation frequency. heterozygous copy; na, does not apply omitted LOH(7)
found activation of SMO mutations found in 10-20% sporadic BCC and especially
missense changes affecting codon 535 representing that. Functional study on the W535L
variant mutant that is constitutively active and functionally shown in the study and basal HH
activity in the absence of the HH ligand significantly increased. Studies revealed t up to 8% of
BCCs carry loss of function SUFU variants, both missense and nonsense mutations, whose
binding to GLI can interfere with its binding, thus leading to activation of the constitutive
pathway. Urman et al reported a higher frequency of SUFU mutations, although it is considered
as a likely passenger mutation. Finally, the homologue PTCH2 gene, which shows a 57% of
similarity with PTCH1 and also serves as a receptor, has been found to carry mutations in a
small number of sporadic BCC(8)

2.2. TP53 Gene

Activation of the TP53 gene is the second most common event associated with the
pathogenesis of BCC. cell cycle arrest and programmed cell death activation involved the
tumor suppressor gene TP53. Cell cycle arrest is caused as the guardian of the genome,
TP53 is stabilized after stress by phosphorylation and alters the expression of downstream
target gene sets. pathogenesis investigated through BCC mice, loss of TP53 was shown to
increase the activity of the HH pathway thereby increasing SMO expression and forming
interfollicular keratinocytes of mice receiving X-ray-induced BCC.
in 50% of human cancers, a TP5 # genetic change that is not detected, including
all skin carcinomas, [as the earliest event which is believed if not included in the initial
event in carcinogenesis. In skin cancer, the majority of the central DNA binding core
domains (codons 102-292) and including codon 177 are located in the missense
substitution TP53, full-length proteins with converted functions resulted from 196, 245,
248, 278, and 282. in about half of sporadic cases whereas LOH has been described with a
much lower frequency in BCC compared to other tumors as colon cancer reported that
BCC, a non-synonymous mutation in the TP53 gene, lung, and bladder [57-61 (Table1).
specifically at BCC codons 177, 196, and 245 found hotspots occurring specifically at
 BCC . does not frequently mutate in other malignancies impacting Codon 177 specific for
BCC.
The codons include sequences that are slowly fixed after UV irradiation, which is
interesting to note. mutations in breast and colon cancer were found in codons 196 and
245. several types of tumors, such as lung, head and neck, ovary, stomach, and esophageal
malignancies. involves codon 245 and plays a major role in carcinogenesis
UV-induced changes suggest the majority of TP53 mutations in BCC are C to T
transitions, with a high frequency of CC to TT double base changes, it is clear. BCC from
sunscreen users identified a lower and indeed lower rate of TP53 mutation when compared
to non-sunscreen users

3. BCC Novel is related to Gen

The identification of new driver genes for BCC has led to recent improvements in
technology for lead genomic analysis, it was hypothesized previously to display a more
complex genetic network of cancer-related genes. often that there are discrepancies
regarding the list of driver genes identified in other studies, BCC with low risk or high risk
of recurrence in tumors from Gorlin syndrome patients as an example of the possible
reflection of the clinical-pathological heterogeneity of the analyzed BCC, or BCCs naïve or
resistant to target therapy.

3.1. Hippo-YAP Signaling Genes

organ size is controlled The hippopotamus pathway becomes very important in

control, and its deregulation contributes to tumorigenesis (Figure2).
This pathway was originally investigated in Drosophila, where excessive tissue
growth results mosaic mutation of the Hippo-related gene [73,74]. has been
deactivated by the Yes-related protein (YAP) transcription co-activator, so that the
Hippo axis includes a series of kinases which, through the cascade of
phosphorylation events, so that cell proliferation and apoptosis can be managed. The
YAP1 protein is the major down, the core components of the mammalian Hippo
signal are represented by the effector streams of the Hippo pathway and the MST1 /
2 and LATS1 / 2 kinases represent MST1 / 2 phosphorylating and activating the
LATS1 / 2 kinase preventing the translocation of YAP1 and its family member TAZ
(trascriptional co-activator with PDZ-binding motif) into the nucleus. Through the
activation system, YAP1 transactivation can be inhibited by the non-receptor
tyrosine phosphatase 14 (PTPN14) which promotes translocation of the nucleus to
the cytoplasm via LATS1 activation.
Massive expansion of proliferative basal epidermal cells is caused, by
BCC. Genetic studies in mouse models have shown that this pathway acts to balance
skin growth and differentiation and that elevated levels of nuclear YAP1 lead to.
The independent mechanism for activation of the Hippo-YAP line may
represent a divergent function from LATS1 and PTPN1. only one study reported an
inactive mutation in 47 of 293 (16%) BCCs, in the investigation of the ETS1 gene.
always consistent with the tumor-suppressing role of LAST V1 [22 with
24% of mutations being truncated. The most common mutation is R995C, which
occurs in the core of the kinase domain(10)
bidirectional inactivation of LATS1 in infiltrative BCC evidently brought from a
Japanese patient with Gorlin syndrome in a previous case report. reported in 12%
BCC and PTPN14 gene in 23% BCC with 61% of the truncation changes were LTS1
mutations, missense mutations in the ETS2 gene, paralog of LATS1.
that the Hippo-YAP pathway is significantly regulated in BCC can indicate in line
with i that the identification of LATS1 and PTPN14 mutations is an RNA sequencing
study.
 Figure 2. If the Hippo line is activated, the Hippo - YAP and LATS1 / 2 lines will
be active, this will phosphorylate YAP / TAZ. , MST1 / 2 kinase and SAV1 form a
complex to phosphorylate and activate LATS1 / 2 and MOB1then will be stored in
the cytoplasm or degraded. to induce expression of genes that promote tumor
development it is possible to play a role of dephosphorylation of YAP / TAZ for
translocation into the nucleus and interaction with TEAD1-4 MST, mammalian Ste2-
like kinase Hpo orthologs; SAV, Mob-as-tumor suppressor homologs; YAP, Yes
Regarding Protein Yki Ortholog; TEAD Salvador Homologous Protein 1; and LATS,
Kinase Wts Large Tumor Suppressor Orthologs; MOB1, Parent versus
decapentaplegia homologs. And transcription-enhancing association domains; TAZ,
a transcription co-activator with a PDZ-binding motif; SMAD,
4. Summary and Discussion

Several tumor suppressor genes and protocogens play important roles in the
pathogenesis of BCC, including major components of Hodgehog, such as PTCH1 and
SMO, tumor suppressor TP53, and members of the protooncogen family RAS. The
research confirmed that the Hedgehog cellular gene is associated with the development of
basal cell carcinoma. Hedgehog cellular genes are activated in the process of
organogenesis, unfortunately altered in many types of tumors (2). All this evidence
suggests a complex genetic network of tumor suppressor genes and different pathways
contribute to BCC carcinogenesis, supporting genetic heterogeneity. should, it is clear
that a more complex genetic network of cancer-related genes than previously
hypothesized is involved in BCC carcinogenesis, the gene involved is the Hodgehog
pathaway.(1).
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