Ampullary Carcinoma – A Genetic Perspective

Jayaramayya Kaavya1,*,#, Vellingiri Balachandar2,#, Kumaran Sivanandan

Santhy1
1
Department of Zoology, Avinashilingam Institute for Home Science and Higher Education for
Women - Avinashilingam University for Women, Coimbatore-641 043, Tamil Nadu, India
2
Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and
Molecular Biology, Bharathiar University, Coimbatore 641 046, Tamil Nadu, India

*Corresponding Author

T
Jayaramayya Kaavya,
Department of Zoology, Avinashilingam Institute for Home Science and Higher

IP
Education for Women - Avinashilingam University, Coimbatore-641 043, Tamil
Nadu, India

R
Mobile: +91 9941004635; Office: +91 422 2422514; +91 422 2422222; Fax: +91 422
2422387; E-mail: Kaavyajayaramayya@gmail.com

SC
#
Authors have equal Contribution

U
N
Abstract
A
Ampulla of vater carcinoma (AVC) is a rare gastrointestinal tumour that is associated
M

clinical symptoms. Early diagnosis of this condition is essential to effectively treat

D

patients for better prognosis. A significant amount of advancement has been made in
TE

understanding the molecular nature of cancer in the past decade. A substantial number

of mutations and alterations have been detected in various tumors. Despite the
EP

occurrence of AVC across the globe, the number of studies conducted on this tumor
CC

type remains low; this is largely due to its rare occurrence. Moreover, AVC tissues

are complex and contain mutations in oncogenes, tumour suppressors, apoptotic

A

proteins, cell proliferation proteins, cell signaling proteins, transcription factors,

chromosomal abnormalities and cellular adhesion proteins. The frequently mutated

genes included KRAS, TP53 and SMAD4 and are associated with prognosis. Several

molecules of the PI3K, Wnt signaling, TGF-beta pathway and cell cycle have also
been altered in AVCs. This review comprises of all the genetic mutations, associated

pathways and related prognosis that are involved in AVCs from the year 1989 to

2017. This report can be used as a stepping-stone to establish biomarkers for early

diagnosis of AVC and to discover molecular targets for drug therapy.

Key Words: Ampulla of vater carcinoma (AVC); Mutation; Biomarker; Prognosis

T
IP
Abbreviations

R
AVC, Ampulla of vater carcinoma; KRAS, Kirsten rat sarcoma viral oncogene homolog; OS, overall
survival; RFS, recurrence free survival; HER2, human epidermal growth factor receptor 2; BRAF, B-
rapidly activated fibrosarcoma; BRCA2, breast cancer 2;TP53, tumor protein 53; SWI/SNF,

SC
SWItch/Sucrose Non-Fermentable; PTEN, Phosphatase and tensin homolog; PML, Progressive
multifocal leukoencephalopathy; DPC4, Deleted in Pancreatic Cancer-4;PIK3CA,
phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha; EGFR, epidermal growth
factor receptor; GNAS, Guanine Nucleotide Binding Protein (G Protein), Alpha Stimulating Activity

U
Polypeptide 1; PAI-1, Plasminogen activator inhibitor-1;AFP, Plasminogen activator inhibitor-1;GPC3,
glypican-3;ELF3, E74-like factor 3; HNF, Hepatocyte nuclear factors; MSI, Microsatellite instability;
N
MMR, mismatch repair;Col11A1, collagen typeX1 alpha1; ERM, ezrin, radixin and moesin; MAPK,
mitogen activated protein kinase; STAT, signal transducer and activator of transcription;
A
ERK,extracellular signal-regulated kinases;MTAP, S-methyl-5'-thioadenosine phosphorylase;EPHA3,
ephrin receptorA3;GSK-3, Glycogen synthase kinase 3; SNP, single nucleotide polymorphism; LOH,
loss of heterozygosity;XRCC1, X-ray repair cross-complementing protein 1;RECQL4,RECQ like
M

helicase 4;Hogg1,human 8-Oxoguanine glycosylase;ATM, ataxia-telangiectasia mutated;MGMT, O6-

methylguanine DNA methyltransferase;PCNA, Proliferating cell nuclear antigen;HMLH1, human
MutL homolog 1;hMSH6, human mutS homolog 6;FOX03, Forkhead box O3;ARID, AT-rich
interaction domain;PBRM1, Protein polybromo-1;KDM, lysine demethylase;ACVR1B, Activin
D

receptor type-1B;TGFBR2, transforming growth factor-beta (TGF- ) 2;ABCG8 , ATP-

binding cassette sub-family G member 8;CETP, Cholesteryl ester transfer protein;LRP1A, Low density
TE

lipoprotein receptor-related protein 1;MEP1A, Meprin A subunit alpha;IL8, Interleukin 8;CYP1A1,

Cytochrome P450, family 1, subfamily A, polypeptide 1.
EP

Introduction
CC

Ampulla of vater carcinoma (AVC) is an extremely rare malignancy that has

been associated with genetic mutations [1]. Despite the improved knowledge
A

regarding biological characteristics of other periampullary cancers, the mechanism of

ampullary carcinomas remains undetermined [2]. In the past decade, many genetic

mutations have been associated with AVC. Genetic mutations may help to establish

biomarkers for the early diagnosis of the tumor. The causes of AVC are complex and
include oncogenic mutations, alteration of tumor suppressors, apoptotic proteins, cell

proliferation proteins, cell signaling proteins, transcription factors, chromosomal

abnormalities and cellular adhesion proteins.

Oncogenic mutations in the KRAS [1], ERBB2 [3] and BRAF [4] have been

frequently associated with AVC. Alterations have also been found in apoptotic

proteins such as Livin, caspase-3 [5], and survivin [6]. Additionally, BRCA2 [7],

T
TP53 [2], SWI/SNF complex subunits [8], PTEN [9], PML [10] and DPC4 [11] are

IP
the tumor suppressors that have been frequently related to the occurrence of AVC.

R
Hypermethylation of the tumor suppressor DAP kinase-prognostic factor [12] has also

SC
been found in AVC. Moreover, cell signaling proteins like SMAD4, PIK3CA [1],

EGFR [13], 14-3-3sigma [14] and GNAS [4] have been correlated with prognosis [2]
U
[15] and tumorigenesis [16] of AVC. It has also been found that the expression of the
N
mRNAs PAI-1 [17], AFP and GPC3 have been significantly higher in AVCs as
A

compared to other pancreatic carcinomas [18]. Varied expression of transcription

M

ELF3, HNF4 4 SOX-2 [19] and other molecules like CD44 [20],
D

Ki-67 [5], apomucins [19] [22], cox-2 [6] and osteopontin [23] have been witnessed
TE

in AVCs. Similarly, the cell proliferation proteins ERM [14], Cyclin D1 [24] and the

cell adhesion protein beta-catenin [25] have also been coupled with AVC. AVC
EP

tissues also carry a considerable amount of defects in MSI (microsatellite instability)

CC

and DNA mismatch repair (MMR) [26] [27] [22] as well as kinase signaling pathways

[28] [29]. Chromosomal abnormalities in genes and loss of heterozygosity (LOH)

A

have also been interrelated with AVC [30] [31] [32] [33] [34]. Furthermore,

microRNAs have been also been studied as potential biomarkers for AVC [35].

This is a one of a kind review that emphasizes, on the identified biomarkers

and de novo mutations that have been associated with AVCs; their signaling pathways
and correlated prognosis. This review comprises of all the complete genetic

alterations that have been coupled with AVC from the year 1989 to 2017. The

literature search was conducted using the PubMED and NCBI databases. The

keywords used were ampulla of vater; carcinoma; genetics and mutation.

Genetic Mutations and Ampullary Carcinoma

Oncogenic mutations

T
KRAS is the most frequently mutated oncogene in AVCs [1] [37] [38] [39],

IP
and codes for a GTPase that is a part of several signaling pathways. It is involved with

R
signaling molecules like c-Raf and PI3-kinase and in the propagation of growth

SC
factors [40]. When tissues of AVC were inspected in Japan and Italy, KRAS

mutations were relatively more common in tumors arising from the bile duct [41]
U
[42]. Codons 12 [13] [39] [43] [37] [24] [44] and 13 [45] of the KRAS gene were
N
frequently mutated in AVCs. Substitution mutations in both codons have also been
A

reported in studies from Thailand [46] and Norway [47]. Mutations in codon 12 were
M

concomitant with shorter recurrence free survival (RFS) and overall survival (OS) in
D

Denmark [48], and appeared as early events in patients from Denmark [48] and
TE

Netherland [38]. A Glycine to Aspartic acid substitution in codon 12 (G12D) of

KRAS gene, was found in studies conducted in Japan [4], Korea [49], USA [50] [11]
EP

and Italy [51] [52]. This specific mutation was associated with shorter RFS in Korea
CC

[49] and reduced OS in USA [50]. A similar G-D substitution was found in the codon

13 (G13D) in Japanese [4] and American patients [11] [13]. Both G12D and G13D
A

variations were discovered in a Japanese report. Interestingly, glycine to valine

substitutions have been detected in codon 12(G12V) in American [11] and Japanese

[4] [53] patients and corresponded with shorter RFS in Korean patients [49].

Fascinatingly, the same mutation was also observed in NRAS, also a ras family
protein [57]. Glycine also appears to be substituted by cysteine at codon 12 in

Japanese [4] and American [11] patients. In a likewise manner, glycine to asparagine

substitutions were present in codon 12 (G12N) in investigations conducted in Japan

[53] [41] and Italy [43]. Furthermore, Glycine to serine and Glycine to Alanine were

found in codon 12 of Japanese [4] [41] and American [11] patients. Glycine has been

replaced with cysteine in codon 13 (G13C), and arginine (G13R) in codon 12 in

T
Korean patients and these alterations were linked to shorter RFS [49]. Identical G-R

IP
variations were observes in reports from Italy [51] and USA [11]. Intriguingly,

R
glutamine to histidine changes were observed in codon 61 in Korean [49] and

SC
American [13] research reports and a glutamine to arginine change was found in an

Italian study [51]. The Korean study further reported a reduced RFS [49].
U
Additionally, Howe [54] had found mutations in exon1 of the KRAS gene. KRAS
N
mutations have also been associated with a bigger tumor size and increased
A

invasiveness in Japanese patients [4]. On the contrary, Kim, found no significant link
M

between KRAS mutations and OS but associated it with reduced RFS in Korean
D

patients with AVC [15].

TE

HER2/neu or ERBB2 is the human epidermal growth factor 2, and codes for a

tyrosine kinase involved in cell signaling pathways. It is engaged in the MAPK, PI3K,
EP

STAT, phospholipase C and protein kinase C pathways. A frequent co-mutation of

CC

this gene with TP53 and overexpression of ERBB2 was found in patients from USA

[3]. Similarly, overexpression of ERBB2 was found in AVC tissues of Japanese

A

patients in a study conducted by Nakazawa [55] but not Ajiki [56]. Also, ERBB2

appeared to harbor missense mutations in an Italian study [29]. Although EGFR

(epidermal growth factor receptor), also a member of the ERBB family appears

mutated in Italian patients [29] and overexpressed along with its ligand amphiregulin
in American patients [13], a consistent overexpression of ERBB2 in AVC tissues has

not been found in studies conducted in UK [57] and Italy [29].

BRAF is a protooncogene belonging to the Raf kinase family is involved in

the MAPK/ERK signaling pathway. Schönleben [16] and Kwon [49] reported that

BRAF mutations were lesson common in American [16] and Korean [49] patients. On

the contrary, BRAF mutations were observed in Japanese patients [4]. Likewise,

T
Tahover [58] discovered a substitution of glycine with glutamic acid at position 466

IP
and Mikhitarian [13] found a V600E substitution in American patients. Interestingly,

R
the same V600E variation was observed in a study conducted in Denmark but it was

SC
not associated with RFS or OS [48].

MET is a tyrosine kinase involved with the Ras, PI3K, STAT, WNT and

.I U K 2
N
and Japanese [55] patients. These are some oncogenic genetic alterations found in
A

tissues of AVCs. Similarly, PIK3CA a kinase implicated in the PI3K pathway has
M

been altered in AVCs [59]. A substitution mutation was observed in codon 545 of
D

exon 9 in Korean [49] and American patients [13]. The American patients also had a
TE

substitution of arginine in the place of glutamine at codon 546 [13].

EP

Tumor suppressors
CC

P53 is a tumor suppressor that is mutated in many different malignancies

including AVCs [59] [60] [61]. Abnormal immune-labelling, nuclear accumulation

A

[4] and positive expression [56] of p53 were observed in Japanese patients. Abnormal

immunolabelling was further associated with shorter OS [4]. Point mutations in exons

5, 6 and 7 were also found in Japanese AVC patients [41]. Additionally, nucleotide

changes were observed in codons 146,189,166,292 and 213 [53]. The point mutations
and nucleotide changes were related to tumor progression [41] [53]. P53 exhibited an

increased expression [62] [44] and mutations [3] in studies from USA. Interestingly

p53 was methylated [52] in AVCs, and a substitution of the amino acid cysteine for

arginine was observed in the 273 position and was interlinked with tumor

advancement in Italian patients [51]. Correspondingly, missense mutations in codons

exons 4 and 8 were found in Korean cell lines [63]. Increased expression of p53 was

T
found in Singaporean studies and a positive expression in reports from France.

IP
Moreover, AGR2 a gene involved in the down regulation of p53, reduced cell

R
AVC .T

SC
implicate alterations in p53 in AVCs [64].

SMAD4/DPC4 TGF
U
cell proliferation. While examining the AVCs alterations at SMAD4 gene, mutations
N
were detected in experiments conducted in Japan and USA [59] [13]. In the same
A

way, specific substitution mutations (C449R and R361H) were seen in Italian patients
M

[51]. When expression assays were conducted, Asano observed a positive expression
D

of SMAD4 [4]. On the contrary, reduced expression [62] and gene losses [11] were
TE

reported in studies from the USA. Moreover, McCarthy discovered that the gene loss

occurred in advanced invasive carcinomas in Americans [11].

EP

P16 is a kinase dependent cyclin inhibitor that controls the progression of the
CC

cell cycle and is encoded by the CDKN2A gene. In a study conducted in USA it was

observed that the CDKN2A gene was frequently deleted in AVCs [3] and mutated
A

[59]. Interestingly, AVCs exhibited a positive expression [4], several missense

mutations and deletions [65] in the p16 gene of Japanese patients. Alternatively,

Hustinx reported a loss of p16 in American patients [34].When epigenetic

modifications were studied, de novo methylation were found in the p16 regions in
USA [66] and Italy [43]. A similar methylation profile was found on p14 [66], a gene

also involved in the cell cycle progression. The loss of MTAP gene which is

frequently deleted with p16 was also observed in AVC patients [34].Furthermore,

Cell lines of AVCs in Korea exhibited homozygous deletions in both p16 and p15

[63] genes.

BRCA2 tumor suppressor mutations are commonly present in ovarian and

T
breast cancer. BRCA2 gene insertion mutations were found in portugese patients with

IP
AVC at the frequency of 12.5% [7]. A similar BRCA2 mutation was discovered in a

R
patient with Greek and Eastern European ancestry [67]. AVC tissues of American

SC
patients consisted of loss of expression of PTEN gene, which was correlated with

reduced RFS and OS. In studies conducted in the USA, Other alterations were found
U
in the expression of Fhit and Wwox genes in patients with AVC [62]. Additionally,
N
varied expressions of the tumor suppressor PML were associated with varying
A

prognosis in Italian patients [10]. These tumor suppressors appear to be frequently

M

altered in patients with AVC.

D

Alteration in cell adhesion molecules in AVC

TE

Alterations in cell adhesion molecules can contribute greatly to tumorigenesis.

The gene encoding the EPHA3, a tyrosine kinase that regulates cell to cell adhesion
EP

was found to contain missense mutations in AVC tissues of Italian patients [29]. In
CC

Japanese AVC patients, the cell adhesion molecule APC [68] was frequently altered

and its inhibitor BUB1B consisted of a germline homozygous intronic mutation in

A

Canadian patients [30]. Abnormal immunolabelling [69] [4] and -

catenin [70] was seen in Japanese patients and an increased expression of it was

detected in American patients [28]. The gene ctnnb-1, -catenin was found

to be mutated in Japanese [24] [70] as well as Italian patients [51]. Interestingly,

GSK-3 a proteins that d -catenin consisted of an activating mutation in a

study of AVCs in USA [28]. Upregulation [28] and alterations [59] were also found in

AXIN, -catenin. Remarkably, a lack of expression of

CD44, a transmembrane glycoprotein, has been associated with metastasis and poor

prognosis in Japanese [71] and Taiwanese patients [72]. ERM proteins that localize

CD44 on actin filaments were positively expressed and related to shorter OS in

T
American patients [14]. Additionally, mRNAs of E-cadherin mRNAs [63], another

IP
cell adhesion molecule was hypermethylated in Korean cell lines. Overman had also

R
found an increased expression of these molecules in American patients [28].

SC
Chromosomal alterations in AVC

Each parental chromosome consists of single nucleotide polymorphisms

U
(SNPs), due to which alleles maintain heterozygosity. LOH is a chromosomal event
N
that results in the loss of gene on one copy of the genome. The chromosome consists
A

of the long arm q and short arm p. In studies conducted in the USA, LOH of alleles
M

was found in chromosome 5 [36]. In Italian patients with AVC, LOH was found in
D

5q,6q,9p,11p,11q,13,16p,17p, 17qand 18 [73] [36] [74] [75]. It was also found that,
TE

loss of 17p [74] [75] and 17q [74] resulted in poorer RFS and OS [76]. Similarly,

LOH in frequently mutated genes like TP53 and SMAD4 [52] were also seen in
EP

Italian patients. These LOH mutations are exhibited in (Table 1). Chromosomal gains
CC

and losses were also observed near tumor suppressors and oncogenes in Korean [77]

and Taiwanese patients [79]. In addition, Taiwanese patients also harbored an allelic
A

loss of 14q32 in synchronous tumors [79]. In experiments conducted in Japan, a high

incidence of LOH was also observed in the cell cycle regulator p16INK4 [65].

Similar, LOH was seen in the region 9p in Chinese patients as well [30]. DNA ploidy

has also implicated in AVCs [80] [81] [82]. In an Italian study, chromosomal
instability was found in AVCs, aberrations arose from chromosome 13, and a

translocation occurred between chromosome 6 and 14; a deletion occurred in

chromosome 1 and a 1p36 was associated with the reorganizations [83]. Various gene

amplifications and deletions have also been implicated in AVCs [84].

Changes in DNA repair mechanism in AVCs

Base excision repair (BER) is involved in DNA repair. Alterations were found

T
in the BER genes, XRCC1 in Chinese patients [85], RECQL4 in American patients

IP
[59] and Hogg1 in Korean patients [63]. In a study conducted in Italy, insertions were

R
found in ATM, a protein kinase that is involved in DNA repair [86]. In Chinese

SC
patients, the MGMT gene with EX5-25C>T was associated with reduced risk of AVC

[87]. In AVC tumor tissues of Japanese people, increased expression of PCNA was
U
found in advanced tumors [56] [88]. Alterations in the mismatch repair (MMR)
N
protein HMLH1 and its expression, has been observed in AVC cell lines from USA
A

[66] [89] and Korea [90]. Loss of expression of hMSH6 protein has been observed in
M

reports from Italy [91] and USA [89]. Alterations in the expression of PMS2,a
D

mismatch repair protein that forms a heterodimer with HMLH1 and interacts with
TE

MSH2were found in AVCs [59]. Achille, discovered that replication error phenotype

was associated with longer OS in Italian patients [92].

EP

Microsatellite instability (MSI) occurs due to problems in MMR proteins. This

CC

increases the probability of mutations. MSI has been observed and correlated with

increased survival [93] [59]. On the contrary, a study conducted in Korea claimed that
A

MSI was not associated with carcinogenesis in AVCs [26]

Other mutational events involved in AVCs

The transcription factors SOX2 [99], SOX9 [59], CDX-1 [28], HNF-alpha

[28], FOXO3 [28], STAT3 [28], c-myc [90] and CDX2 [100] [28] [100] were
increased in AVCs, and ELF3 [59] was frequently mutated. In contrast, CDX-2 was

negative in Japanese patients [4] and was altered according to tumor subtype in

Korean patients [49]. In addition, increased expression of miRNAs [101] [102] and

mRNAs [103] [104] were also found in AVCs. Expression of apoptosis related

proteins Livin [95], osteopontin [96], clusterin [28], caspase-3 [95] and RNASEL[97]

were associated with AVC and its prognosis, but survivin did not seem to influence

T
OS in AVC patients [98]. Mucins are glycosylated proteins that are involved in cell

IP
signaling and lubrication. MUC2 negativity was associated with poorer prognosis

R
[105] [106]. MUC5AC was related to metastasis and advancement of tumor [19].

SC
Alternatively, Sessa claimed that, MUC1, MUC5AC, MUC6 and MUC2 were

expressed in AVCs but are not prognostic factors [22].

U
The genes associated with certain hormones appear to be differently expressed
N
in AVCs. Variants of the estrogen [107] [66] Cholecystokinin [108], somatostatin and
A

motilin receptors [109] are implicated in AVCs. Cytokeratin 7(CK7) and CK20
M

biomarkers for biliary cirrhosis, as well as Alpha fetoprotein a biomarker for

D

hepatocellular carcinoma were expressed in AVC tissues [4] [110] [104]. PSTG2 or
TE

cyclooxygenase (Cox-2), is the enzyme involved in synthesis of prostaglandin, that

plays an important role in proliferation and resistance to apoptosis. Variations of this

EP

gene were found in AVCs [66] [111] and its expression was correlated with poorer
CC

survival [98] [112]. Similarly, variations of the genes APOE, APOB, ALOX5, LPL

and LDLR, belonging to the lipid metabolism pathway were involved in AVCs [113].
A

Increased expression of Cyclin D1, the gene CCDN1 that encodes it and CDK12 [3]

were found in AVCs. Cyclin D1 and CDK13 are genes involved with regulation of

the cell cycle [114] [115]. Ki-67 a molecule that is also involved in the cell cycle was

expressed in AVCs of Chinese patients [95]. Genes associated with chromosomal

remodeling like ARID2, ARID1A, PBRM1 and ones involved with demethylation of

the lysine on histones like KDM6A KDM4Chave been altered in AVCs [59].

Various cell signaling molecules belonging to many pathways have been

mutated in AVCs. Alterations were found in ACVR1B, TGFBR2 [59] genes and

GNAS gene consisted of a substitution mutation (R201C) in AVC tissues [51]. There

was an overexpression of GPC3 [104] and NOTCH-2 receptors. The genes Akt,

T
P70S6K, mTOR, MAPK and MEK kinases also had activating mutations [28] in

IP
patients with AVC. The genes of the transport proteins ABCG8 , CETP, LRP1A had

R
SNPs in these tissues [116]. Alterations were also found in MEP1A, a molecule that

SC
cleaves proteins; stratifin found in epithelial cells [14] and GPA33 a glycopreotein

[28]. SNPs were found in IL8 [97], a molecule involved in angiogenesis and CYP1A1
U
[117],a molecule implicated in metabolism of foreign particles into carcinogens in
N
Chinese patients. The various mutations involved in AVCs, their associated pathways,
A

frequency and prognosis are presented in (Table 2).

M

Signaling Pathways Involved

D

Several genes and their downstream targets have been altered in AVCs. The
TE

most frequently altered pathways include, the P13K pathway, Wnt signaling, TGF-

beta pathway, and MAPK pathway and molecules involved in the cell cycle transition
EP

from G1-S. HER2/neu/ERBB2 and MET have been found to be altered in AVCs and
CC

are associated with the RAS and PI3K pathway. Interestingly, mutations have been

found in the KRAS gene and PTEN that inhibits a downstream molecule of the PI3K
A

pathway. The molecules axin, APC, CK1,GSK3 -catenin.

W -catenin for gene expression

activities. E-cadherin present in the neighboring cell is required to maintain the

integrity of the cell and regulation of Wnt signaling. It has been discovered that APC,
 -catenin and E-cadherin were abnormal in AVCs. Furthermore, certain molecules

involved in the cell cycle progression from G1 to S seem to be distorted in AVCs.

Interactions of some molecules of these pathways are shown in (Fig 1).

Conclusion

The process of establishing biomarkers for AVC is a rather difficult task due

to the rarity of this tumor. In this review, frequently mutated genes like KRAS, TP53

T
and SMAD4 have been associated with prognosis. Additionally, frequently altered

IP
pathways have also been identified. Further studies can be done to establish these

R
genes as biomarkers for early diagnosis of AVC. The pathways identified can also be

SC
targeted for therapy in future studies. Despite the occurrence of AVCs around the

world, only limited studies have been conducted on this. The proportions of studies
U
conducted in various countries are illustrated in (Fig 2). Moreover, there have been no
N
studies conducted in India on genetic alterations in AVCs, this review can serve as a
A

stepping stone for further research on early diagnosis and drug therapy for AVC
M

patients.
D

Conflict of Interest
TE

The authors declare that there are no conflicts of interest.

EP

Acknowledgment
CC

This work was supported by the Avinashilingam University for Women and

Bharathiar University by providing the necessary facilities such as Internet to access

A

the articles and Infrastructure.

References

[1] Noguchi R, Yamaguchi K, Ikenoue T, Terakado Y, Ohta Y, Yamashita N, et

al. Genetic alterations in Japanese extrahepatic biliary tract cancer. Oncol Lett

2017;14:877 84. doi:10.3892/ol.2017.6224.

[2] Kwon MJ, Kim JW, Jeon JY, Nam ES, Cho SJ, Park H-R, et al. Concurrent

T
MET copy number gain and KRAS mutation is a poor prognostic factor in

IP
pancreatobiliary subtype ampullary cancers. Pathol - Res Pract 2017;213:381

R
8. doi:10.1016/j.prp.2017.01.004.

SC
[3] Hechtman JF, Liu W, Sadowska J, Zhen L, Borsu L, Arcila ME, et al.

Sequencing of 279 cancer genes in ampullary carcinoma reveals trends

U
relating to histologic subtypes and frequent amplification and overexpression
N
of ERBB2 (HER2). Mod Pathol Off J U S Can Acad Pathol Inc
A

2015;28:1123 9. doi:10.1038/modpathol.2015.57.
M

[4] Asano E, Okano K, Oshima M, Kagawa S, Kushida Y, Munekage M, et al.

D

Phenotypic characterization and clinical outcome in ampullary

TE

adenocarcinoma. J Surg Oncol 2016;114:119 27.

[5] Xue D, Zuo K, Li X, Zhang T, Chen H, Cheng Y, et al. Expression and

EP

prognostic significance of Livin, Caspase-3, and Ki-67 in the progression of

CC

human Ampullary Carcinoma. Appl Immunohistochem Mol Morphol

2013;21:525 31.
A

[6] Santini D, Vincenzi B, Tonini G, Scarpa S, Vasaturo F, Malacrino C, et al.

Cyclooxygenase-2 overexpression is associated with a poor outcome in

resected ampullary cancer patients. Clin Cancer Res 2005;11:3784 9.

[7] Pinto P, Peixoto A, Santos C, Rocha P, Pinto C, Pinheiro M, et al. Analysis of

Founder Mutations in Rare Tumors Associated With Hereditary

Breast/Ovarian Cancer Reveals a Novel Association of BRCA2 Mutations

with Ampulla of Vater Carcinomas. PLOS ONE 2016;11:e0161438.

doi:10.1371/journal.pone.0161438.

[8] Agaimy A, Daum O, Märkl B, Lichtmannegger I, Michal M, Hartmann A.

T
SWI/SNF complex deficient undifferentiated/rhabdoid carcinomas of the

IP
gastrointestinal tract: a series of 13 cases highlighting mutually exclusive loss

R
of SMARCA4 and SMARCA2 and frequent co-inactivation of SMARCB1

SC
and SMARCA2. Am J Surg Pathol 2016;40:544 53.

[9] Shroff S, Overman M, Rashid A, Shroff RT, Wang H, Chatterjee D, et al. The
U
expression of PTEN is associated with improved prognosis in patients with
N
ampullary adenocarcinoma after pancreaticoduodenectomy. Arch Pathol Lab
A

Med 2013;137:1619 26. doi:10.5858/arpa.2012-0418-OA.

M

[10] Vincenzi B, Santini D, Perrone G, Russo A, Adamo V, Rizzo S, et al.

D

Promyelocytic leukemia (PML) gene expression is a prognostic factor in

TE

ampullary cancer patients. Ann Oncol 2008;20:78 83.

[11] McCarthy DM, Hruban RH, Argani P, Howe JR, Conlon KC, Brennan MF, et
EP

al. Role of the DPC4 tumor suppressor gene in adenocarcinoma of the ampulla
CC

of Vater: analysis of 140 cases. Mod Pathol 2003;16:272 8.

[12] Tozawa T, Tamura G, Honda T, Nawata S, Kimura W, Makino N, et al.

A

Promoter hypermethylation of DAP‐ kinase is associated with poor survival in

primary biliary tract carcinoma patients. Cancer Sci 2004;95:736 40.

[13] Mikhitarian K, Pollen M, Zhao Z, Shyr Y, Merchant N, Parikh A, et al.

Epidermal Growth Factor Receptor Signaling Pathway is Frequently Altered

 in Ampullary Carcinoma at Protein and Genetic Levels. Mod Pathol Off J U S

Can Acad Pathol Inc 2014;27:665 74. doi:10.1038/modpathol.2013.185.

[14] Hustinx SR, Fukushima N, Zahurak ML, Riall TS, Maitra A, Brosens L, et al.

Expression and prognostic significance of 14-3-3 sigma and ERM family

protein expression in periampullary neoplasms. Cancer Biol Ther 2005;4:596

601.

T
[15] Kim BJ, Jang HJ, Kim JH, Kim HS, Lee J. KRAS mutation as a prognostic

IP
factor in ampullary adenocarcinoma: a meta-analysis and review. Oncotarget

R
2016;7:58001 6. doi:10.18632/oncotarget.11156.

SC
[16] Schönleben F, Qiu W, Allendorf JD, Chabot JA, Remotti HE, Su GH.

Molecular Analysis of PIK3CA, BRAF, and RAS Oncogenes in Periampullary

U
and Ampullary Adenomas and Carcinomas. J Gastrointest Surg Off J Soc Surg
N
Aliment Tract 2009;13:1510 6. doi:10.1007/s11605-009-0917-4.
A

[17] Warnecke-Eberz U, Prenzel KL, Baldus SE, Metzger R, Dienes HP,

M

Bollschweiler E, et al. Significant down-regulation of the plasminogen

D

activator inhibitor 1 mRNA in pancreatic cancer. Pancreas 2008;36:173 7.

TE

[18] Takahashi N, Aoyama F, Hiyoshi M, Kataoka H, Sawaguchi A. Establishment

and biological characterization of a novel cell line derived from hepatoid

EP

adenocarcinoma originated at the ampulla of Vater. Int J Oncol 2014;44:1139

CC

45.

[19] Sanada Y, Yoshida K, Konishi K, Oeda M, Ohara M, Tsutani Y. Expression

A

of gastric mucin MUC5AC and gastric transcription factor SOX2 in ampulla

of vater adenocarcinoma: comparison between expression patterns and

histologic subtypes. Oncol Rep 2006;15:1157 61.

[20] Wu C-L, Chao Y-J, Yang T-M, Chen Y-L, Chang K-C, Hsu H-P, et al. Dual

role of CD44 isoforms in ampullary adenocarcinoma: CD44s predicts poor

CD44

advanced cancer. BMC Cancer 2015;15:903. doi:10.1186/s12885-015-1924-3.

[21] KLEINERT R, PRENZEL K, STOECKLEIN N, ALAKUS H,

BOLLSCHWEILER E, HÖLSCHER A, et al. Gene expression of Col11A1 is

T
a marker not only for pancreas carcinoma but also for adenocarcinoma of the

IP
papilla of vater, discriminating between carcinoma and chronic pancreatitis.

R
Anticancer Res 2015;35:6153 8.

SC
[22] Sessa F, Furlan D, Zampatti C, Carnevali I, Franzi F, Capella C. Prognostic

factors for ampullary adenocarcinomas: tumor stage, tumor histology, tumor

U
location, immunohistochemistry and microsatellite instability. Virchows Arch
N
2007;451:649 57.
A

[23] Van Heek NT, Maitra A, Koopmann J, Fedarko N, Jain A, Rahman A, et al.
M

Gene expression profiling identifies markers of ampullary adenocarcinoma.

D

Cancer Biol Ther 2004;3:651 6.

TE

[24] Yamazaki K, Hanami K, Nagao T, Asoh A, Sugano I, Ishida Y. Increased

D1 V :
EP

catenin accumulation and k-ras gene mutation. Mol Pathol 2003;56:336 41.
CC

[25] Kawakami M, Kimura Y, Furuhata T, Zenbutsu H, Yanai Y, Mukaiya M, et

al. beta-Catenin alteration in cancer of the ampulla of Vater. J Exp Clin

A

Cancer Res CR 2002;21:23 7.

[26] Park S, Kim SW, Kim SH, Darwish NS, Kim WH. Lack of microsatellite

instability in neoplasms of ampulla of Vater. Pathol Int 2003;53:667 70.

[27] Silva VWK, Askan G, Daniel TD, Lowery M, Klimstra DS, Abou-Alfa GK, et

al. Biliary carcinomas: pathology and the role of DNA mismatch repair

deficiency. Chin Clin Oncol 2016; 5:62.

[28] Overman MJ, Zhang J, Kopetz S, Davies M, Zhi-Qin J, Stemke-Hale K, et al.

Gene Expression Profiling of Ampullary Carcinomas Classifies Ampullary

Carcinomas into Biliary-Like and Intestinal-Like Subtypes That Are

T
Prognostic of Outcome. PLoS ONE 2013;8:e65144.

IP
doi:10.1371/journal.pone.0065144.

R
[29] Corbo V, Ritelli R, Barbi S, Funel N, Campani D, Bardelli A, et al. Mutational

SC
Profiling of Kinases in Human Tumours of Pancreatic Origin Identifies

Candidate Cancer Genes in Ductal and Ampulla of Vater Carcinomas. PLoS

U
ONE 2010;5:e12653. doi:10.1371/journal.pone.0012653.
N
[30] Wang C, Lu X, Liu G, Dai L, Xu T, Chen Y, et al. Detailed deletion mapping
A

on chromosome region 9p21 in human periampullary neoplasms. Chin Med J

M

(Engl) 2001;114:588 91.

D

[31] Bernasconi B, Dossena B, Billo PR, Tibiletti MG, Sessa F. Involvement of

TE

1p36 region in two cases of adenocarcinoma of the ampulla of Vater. Cancer

Genet Cytogenet n.d.;138:133 8. doi:10.1016/S0165-4608(01)00660-4.

EP

[32] Rio Frio T, Lavoie J, Hamel N, Geyer FC, Kushner YB, Novak DJ, et al.
CC

Homozygous BUB1B mutation and susceptibility to gastrointestinal neoplasia.

N Engl J Med 2010;363:2628 37.

A

[33] Franko J, Krasinskas AM, Nikiforova MN, Zarnescu NO, Lee KK, Hughes SJ,

et al. Loss of heterozygosity predicts poor survival after resection of

pancreatic adenocarcinoma. J Gastrointest Surg 2008;12:1664 73.

[34] Hustinx SR, Hruban RH, Leoni LM, Iacobuzio-Donahue C, Cameron JL, Yeo

CJ, et al. Homozygous deletion of the MTAP gene in invasive

adenocarcinoma of the pancreas and in periampullary cancer: a potential new

target for therapy. Cancer Biol Ther 2005;4:90 3.

[35] Schultz NA, Werner J, Willenbrock H, Roslind A, Giese N, Horn T, et al.

MicroRNA expression profiles associated with pancreatic adenocarcinoma

T
and ampullary adenocarcinoma. Mod Pathol 2012;25:1609 22.

IP
[36] Motojima K, Tsunoda T, Kanematsu T, Nagata Y, Urano T, Shiku H.

R
Distinguishing pancreatic carcinoma from other periampullary carcinomas by

SC
analysis of mutations in the Kirsten-ras oncogene. Ann Surg 1991;214:657.

[37] Chung C, Wilentz R, Polak M, Ramsoekh T, Noorduyn L, Gouma D, et al.

U
Clinical significance of K-ras oncogene activation in ampullary neoplasms. J
N
Clin Pathol 1996;49:460 4.
A

[38] Roa J, Anabalon L, Tapia O, Melo A, de Aretxabala X, Roa I. Frequency of

M

K-ras mutation in biliary and pancreatic tumors. Rev Med Chil

D

2005;133:1434 40.
TE

[39] Kranenburg O. The KRAS oncogene: past, present, and future.Biochim

Biophys Acta 2005; 1756(2):81-2

EP

[40] Scarpa A, Capelli P, Zamboni G, Oda T, Mukai K, Bonetti F, et al. Neoplasia

CC

of the ampulla of Vater. Ki-ras and p53 mutations. Am J Pathol

1993;142:1163.
A

[41] Scarpa A, Zamboni G, Achille A, Capelli P, Bogina G, Iacono C, et al. ras‐

family gene mutations in neoplasia of the ampulla of vater. Int J Cancer

1994;59:39 42.
[42] Sorio C, Moore PS, Ennas MG, Tecchio C, Bonora A, Sartoris S, et al. A

novel cell line and xenograft model of ampulla of Vater adenocarcinoma.

Virchows Arch 2004;444:269 77.

[43] Agoff SN, Crispin DA, Bronner MP, Dail DH, Hawes SE, Haggitt RC.

Neoplasms of the ampulla of vater with concurrent pancreatic intraductal

neoplasia: a histological and molecular study. Mod Pathol 2001;14:139.

T
[44] Ebert MP, Hoffmann J, Schneider-Stock R, Kasper HU, Schulz HU, Lippert

IP
H, et al. Analysis of K-ras gene mutations in rare pancreatic and ampullary

R
tumours. Eur J Gastroenterol Hepatol 1998;10:1025 30.

SC
[45] Sitthideatphaiboon P, Teerapakpinyo C, Klaikaew N, Tanasanvimon S,

Vinayanuwattikun C, Parinyanitikul N, et al. Prevalence of KRAS gene

U
mutation in ampullary cancer in Thai patients. Journal of clinical oncology
N
2014;32: e15175
A

[46] Sandhu V, Bowitz Lothe I, Labori KJ, Lingjærde OC, Buanes T, Dalsgaard
M

AM, et al. Molecular signatures of mRNAs and miRNAs as prognostic

D

biomarkers in pancreatobiliary and intestinal types of periampullary

TE

adenocarcinomas. Mol Oncol 2015;9:758 71.

[47] Schultz NA, Roslind A, Christensen IJ, Horn T, Høgdall E, Pedersen LN, et
EP

al. Frequencies and prognostic role of KRAS and BRAF mutations in patients
CC

with localized pancreatic and ampullary adenocarcinomas. Pancreas

2012;41:759 66.
A

[48] Kwon MJ, Kim JW, Jung JP, Cho JW, Nam ES, Cho SJ, et al. Low incidence

of KRAS, BRAF, and PIK3CA mutations in adenocarcinomas of the ampulla

of Vater and their prognostic value. Hum Pathol 2016;50:90 100.

[49] Valsangkar NP, Ingkakul T, Correa-Gallego C, Mino-Kenudson M, Masia R,

Lillemoe KD, et al. Survival in ampullary cancer: potential role of different

KRAS mutations. Surgery 2015;157:260 8.

[50] Mafficini A, Amato E, Fassan M, Simbolo M, Antonello D, Vicentini C, et al.

Reporting tumor molecular heterogeneity in histopathological diagnosis. PloS

One 2014;9:e104979.

T
[51] Moore P, Orlandini S, Zamboni G, Capelli P, Rigaud G, Falconi M, et al.

IP
Pancreatic tumours: molecular pathways implicated in ductal cancer are

R
involved in ampullary but not in exocrine nonductal or endocrine

SC
tumorigenesis. Br J Cancer 2001;84:253 62.

[52] Imai Y, Oda H, Tsurutani N, Nakatsuru Y, Inoue T, Ishikawa T. Frequent

U
somatic mutations of the APC and p53 genes in sporadic ampullary
N
carcinomas. Cancer Sci 1997;88:846 54.
A

[53] Howe JR, Klimstra DS, Cordon-Cardo C, Paty PB, Park PY, Brennan MF. K-
M

ras mutation in adenomas and carcinomas of the ampulla of vater. Clin Cancer
D

Res 1997;3:129 33.

TE

[54] Nakazawa K, Dobashi Y, Suzuki S, Fujii H, Takeda Y, Ooi A. Amplification

and overexpression of c‐ erbB‐ 2, epidermal growth factor receptor, and c‐

EP

met in biliary tract cancers. J Pathol 2005;206:356 65.

CC

[55] Ajiki T, Kamigaki T, Hasegawa Y, Fujino Y, Suzuki Y, Takeyama Y, et al.

Proliferating cell nuclear antigen, p53, and c-erbB-2 expression in relation to

A

clinicopathological variables and prognosis in cancer of the ampulla of Vater.

Hepatogastroenterology 2001;48:1266 70.

[56] Aloysius MM, Lobo DN, Rowlands BJ, Madhusudan S, Ilyas M, Zaitoun AM.

HER‐ 2/Neu overexpression is a rare event in peri‐ ampullary cancer:

assessment using the HercepTestTM. Histopathology 2009;55:236 7.

[57] Tahover E, Shalom RB, Bogot N, Kelsen D, Gabizon A. MEK inhibitor

treatment is effective in a patient with metastatic carcinoma of the ampulla of

Vater with BRAF and NRAS mutations shown by next-generation sequencing.

T
Anticancer Drugs 2016;27:569 72.

IP
[58] Gingras M-C, Covington KR, Chang DK, Donehower LA, Gill AJ, Ittmann

R
MM, et al. Ampullary cancers harbor ELF3 tumor suppressor gene mutations

SC
and exhibit frequent WNT dysregulation. Cell Rep 2016;14:907 19.

[59] Tech M, Wee A, Raju GC. An immunohistochemical study of p53 protein in

U
gallbladder and extrahepatic bile duct/ampullary carcinomas. Cancer
N
1994;74:1542 5.
A

[60] Terris B, Muzeau F, Sauvanet A, Belghiti J, Flejou J. Gene p53 mutations and
M

53 V .G
D

Clin Biol 1998;22:495 9.

TE

[61] Bloomston M, Kneile J, Butterfield M, Dillhoff M, Muscarella P, Ellison EC,

et al. Coordinate loss of fragile gene expression in pancreatobiliary cancers:

EP

correlations among markers and clinical features. Ann Surg Oncol

CC

2009;16:2331 8.

[62] Ku J, Yoon K, Kim I, Kim W, Jang J, Suh K, et al. Establishment and

A

characterisation of six human biliary tract cancer cell lines. Br J Cancer

2002;87:187 93.
[63] Kim SJ, Jun S, Cho H-Y, Lee DC, Yeom YI, Kim JH, et al. Knockdown of

anterior gradient 2 expression extenuates tumor-associated phenotypes of

SNU-478 ampulla of Vater cancer cells. BMC Cancer 2014;14:804.

[64] Imai Y, Tsurutani N, Oda H, Nakatsuru Y, Inoue T, Ishikawa T.

P16INK4Gene Mutations Are Relatively Frequent in Ampullary Carcinomas.

Cancer Sci 1997;88:941 6.

T
[65] Kim SG, Chan AO-O, Wu T-T, Issa J-PJ, Hamilton SR, Rashid A. Epigenetic

IP
and genetic alterations in duodenal carcinomas are distinct from biliary and

R
ampullary carcinomas. Gastroenterology 2003;124:1300 10.

SC
[66] Aburjania N, Truskinovsky AM, Overman MJ, Lou E. Ampulla of vater

adenocarcinoma in a BRCA2 germline mutation carrier. J Gastrointest Cancer

2014;45:87 90. U
N
[67] Imai Y, Oda H, Tsurutani N, Nakatsuru Y, Inoue T, Ishikawa T. Frequent
A

somatic mutations of the APC and p53 genes in sporadic ampullary

M

carcinomas. Cancer Sci 1997;88:846 54.

D

[68] Asano E, Okano K, Oshima M, Kagawa S, Kushida Y, Munekage M, et al.

TE

Phenotypic characterization and clinical outcome in ampullary

adenocarcinoma. J Surg Oncol 2016;114:119 27.

EP

[69] Kawakami M, Kimura Y, Furuhata T, Zenbutsu H, Yanai Y, Mukaiya M, et

CC

al. beta-Catenin alteration in cancer of the ampulla of Vater. J Exp Clin

Cancer Res CR 2002;21:23 7.

A

[70] Yokoyama Y, Hiyama E, Murakami Y, Matsuura Y, Yokoyama T. Lack of

CD44 variant 6 expression in advanced extrahepatic bile duct/ampullary

carcinoma. Cancer 1999;86:1691 9.

[71] Wu C-L, Chao Y-J, Yang T-M, Chen Y-L, Chang K-C, Hsu H-P, et al. Dual

role of CD44 isoforms in ampullary adenocarcinoma: CD44s predicts poor

CD44

advanced cancer. BMC Cancer 2015;15:903.

[72] Michelassi F, Erroi F, Angriman I, Westbrook C. Chromosome 5 allele loss in

human gastric, ampullary and pancreatic carcinomas. Ital J Surg Sci

T
1989;19:341 4.

IP
[73] Moore PS, Missiaglia E, Beghelli S, Bragantini E, Mina MM, Zamboni G, et

R
al. Allelotype of ampulla of Vater cancer: highly frequent involvement of

SC
chromosome 11. J Cancer Res Clin Oncol 2004;130:339 45.

[74] Iacono C, Verlato G, Zamboni G, Scarpa A, Montresor E, Capelli P, et al.

U
Adenocarcinoma of the ampulla of Vater: T-stage, chromosome 17p allelic
N
loss, and extended pancreaticoduodenectomy are relevant prognostic factors. J
A

Gastrointest Surg 2007;11:578 88.

M

[75] Scarpa A, Di Pace C, Talamini G, Falconi M, Lemoine N, Iacono C, et al.

D

Cancer of the ampulla of Vater: chromosome 17p allelic loss is associated

TE

with poor prognosis. Gut 2000;46:842 8.

[76] Scarpa A, Di Pace C, Talamini G, Falconi M, Lemoine N, Iacono C, et al.

EP

Cancer of the ampulla of Vater: chromosome 17p allelic loss is associated

CC

with poor prognosis. Gut 2000;46:842 8.

[77] Park S, Whe Kim S, Hee Kim S, Lan Lee B, Ho Kim W. Loss of
A

heterozygosity in ampulla of Vater neoplasms during adenoma-carcinoma

sequence. Anticancer research 2003;23: 2955-2959.

[78] Chang M-C, Chang Y-T, Tien Y-W, Sun C-T, Wu M-S, Lin J-T. Distinct

chromosomal aberrations of ampulla of Vater and pancreatic head cancers

 detected by laser capture microdissection and comparative genomic

hybridization. Oncol Rep 2005;14:867 72.

[79] Dai Y-C, Ho C-L, Tsai Y-C, Hsu Y-H, Chang Y-C, Liu H-S, et al. Allelic loss

of 14q32 in the pathogenesis of gastrointestinal and ampullary malignancies:

mapping of the target region to a 17 cM interval. J Cancer Res Clin Oncol

2005;131:94 100.

T
[80] Baisch H, Klöppel G, Reinke B. DNA ploidy and cell-cycle analysis in

IP
pancreatic and ampullary carcinoma: flow cytometric study of formalin-fixed

R
paraffin-embedded tissue. Virchows Arch A 1990;417:145 50.

SC
[81] Shyr Y, Su C, Wu L, Li AF, Chiu J, Lui W. DNA ploidy as a major prognostic

factor in resectable ampulla of Vater cancers. J Surg Oncol 1993;53:220 5.

[82] U
Shyr Y, Su C, Wu L, Li AF, Chiu J, Lui W. DNA ploidy as a major prognostic
N
factor in resectable ampulla of Vater cancers. J Surg Oncol 1993;53:220 5.
A

[83] Bernasconi B, Dossena B, Billo PR, Tibiletti MG, Sessa F. Involvement of

M

1p36 region in two cases of adenocarcinoma of the ampulla of Vater. Cancer

D

Genet Cytogenet 2002;138:133 8.

TE

[84] Sandhu V, Wedge DC, Lothe IMB, Labori KJ, Dentro SC, Buanes T, et al.

The genomic landscape of pancreatic and periampullary adenocarcinoma.

EP

Cancer Res 2016.

CC

[85] Huang W-Y, Gao Y-T, Rashid A, Sakoda LC, Deng J, Shen M-C, et al.

Selected base excision repair gene polymorphisms and susceptibility to biliary

A

tract cancer and biliary stones: a population-based case control study in

China. Carcinogenesis 2007;29:100 5.

[86] Corbo V, Ritelli R, Barbi S, Funel N, Campani D, Bardelli A, et al. Mutational

profiling of kinases in human tumours of pancreatic origin identifies candidate

 cancer genes in ductal and ampulla of vater carcinomas. PloS One

2010;5:e12653.

[87] Zhang M, Huang W-Y, Andreotti G, Gao Y-T, Rashid A, Chen J, et al.

Variants of DNA repair genes and the risk of biliary tract cancers and stones: a

population-based study in China. Cancer Epidemiol Prev Biomark

2008;17:2123 7.

T
[88] Isozaki H, Okajima K, Ichinona T, Tanimura M, Morita S, Takada Y, et al.

IP
The significance of proliferating cell nuclear antigen (PCNA) expression in

R
cancer of the ampulla of Vater in terms of prognosis. Surg Today

SC
1994;24:494 9.

[89] Agaram NP, Shia J, Tang LH, Klimstra DS. DNA mismatch repair deficiency
U
in ampullary carcinoma: a morphologic and immunohistochemical study of 54
N
cases. Am J Clin Pathol 2010;133:772 80.
A

[90] Ku J, Yoon K, Kim I, Kim W, Jang J, Suh K, et al. Establishment and

M

characterisation of six human biliary tract cancer cell lines. Br J Cancer

D

2002;87:187 93.
TE

[91] Sessa F, Furlan D, Zampatti C, Carnevali I, Franzi F, Capella C. Prognostic

factors for ampullary adenocarcinomas: tumor stage, tumor histology, tumor

EP

location, immunohistochemistry and microsatellite instability. Virchows Arch

CC

2007;451:649 57.

[92] Achille A, Scupoli MT, Magalini AR, Zamboni G, Romanelli MG, Orlandini
A

S, et al. APC gene mutations and allelic losses in sporadic ampullary tumours:

evidence of genetic difference from tumours associated with familial

adenomatous polyposis. Int J Cancer 1996;68:305 12.

[93] Iacono C, Verlato G, Zamboni G, Scarpa A, Montresor E, Capelli P, et al.

Adenocarcinoma of the ampulla of Vater: T-stage, chromosome 17p allelic

loss, and extended pancreaticoduodenectomy are relevant prognostic factors. J

Gastrointest Surg 2007;11:578 88.

[94] Park S, Kim SW, Kim SH, Darwish NS, Kim WH. Lack of microsatellite

instability in neoplasms of ampulla of Vater. Pathol Int 2003;53:667 70.

T
[95] Xue D, Zuo K, Li X, Zhang T, Chen H, Cheng Y, et al. Expression and

IP
prognostic significance of Livin, Caspase-3, and Ki-67 in the progression of

R
human Ampullary Carcinoma. Appl Immunohistochem Mol Morphol

SC
2013;21:525 31.

[96] Van Heek NT, Maitra A, Koopmann J, Fedarko N, Jain A, Rahman A, et al.
U
Gene expression profiling identifies markers of ampullary adenocarcinoma.
N
Cancer Biol Ther 2004;3:651 6.
A

[97] Castro FA, Koshiol J, Hsing AW, Gao Y-T, Rashid A, Chu LW, et al.
M

Inflammatory gene variants and the risk of biliary tract cancers and stones: a
D

population-based study in China. BMC Cancer 2012;12:468.

TE

[98] Santini D, Vincenzi B, Tonini G, Scarpa S, Vasaturo F, Malacrino C, et al.

Cyclooxygenase-2 overexpression is associated with a poor outcome in

EP

resected ampullary cancer patients. Clin Cancer Res 2005;11:3784 9.

CC

[99] Sanada Y, Yoshida K, Konishi K, Oeda M, Ohara M, Tsutani Y. Expression

of gastric mucin MUC5AC and gastric transcription factor SOX2 in ampulla

A

of vater adenocarcinoma: comparison between expression patterns and

histologic subtypes. Oncol Rep 2006;15:1157 61.

[100] Sessa F, Furlan D, Zampatti C, Carnevali I, Franzi F, Capella C. Prognostic

factors for ampullary adenocarcinomas: tumor stage, tumor histology, tumor

 location, immunohistochemistry and microsatellite instability. Virchows Arch

2007;451:649 57.

[101] Choi DH, Park SJ, Kim HK. miR-215 overexpression distinguishes ampullary

carcinomas from pancreatic carcinomas. Hepatobiliary Pancreat Dis Int

2015;14:325 9.

[102] Schultz NA, Werner J, Willenbrock H, Roslind A, Giese N, Horn T, et al.

T
MicroRNA expression profiles associated with pancreatic adenocarcinoma

IP
and ampullary adenocarcinoma. Mod Pathol 2012;25:1609 22.

R
[103] Ehehalt F, Rümmele P, Kersting S, Lang-Schwarz C, Rückert F, Hartmann A,

SC
et al. Hepatocyte nuclea (HNF) 4

cancer subtypes and prognosis after resection. Ann Surg 2011;254:302 10.
U
[104] Takahashi N, Aoyama F, Hiyoshi M, Kataoka H, Sawaguchi A. Establishment
N
and biological characterization of a novel cell line derived from hepatoid
A

adenocarcinoma originated at the ampulla of Vater. Int J Oncol 2014;44:1139

M

45.
D

[105] Kitamura H, Yonezawa S, Tanaka S, Kim YS, Sato E. Expression of mucin

TE

carbohydrates and core proteins in carcinomas of the ampulla of Vater: their

relationship to prognosis. Cancer Sci 1996;87:631 40.

EP

[106] Schiergens TS, Reu S, Neumann J, Renz BW, Niess H, Boeck S, et al.
CC

Histomorphologic and molecular phenotypes predict gemcitabine response

and overall survival in adenocarcinoma of the ampulla of Vater. Surgery

A

2015;158:151 61.

[107] Park SK, Andreotti G, Rashid A, Chen J, Rosenberg PS, Yu K, et al.

Polymorphisms of estrogen receptors and risk of biliary tract cancers and

 gallstones: a population-based study in Shanghai, China. Carcinogenesis

2010;31:842 6.

[108] Xu H, Hsing AW, Vogtmann E, Chu LW, Cheng J, Gao J, et al. Variants in

CCK and CCKAR genes to susceptibility to biliary tract cancers and stones: A

population‐ based study in Shanghai, China. J Gastroenterol Hepatol

2013;28:1476 81.

T
[109] Xu H-L, Hsing AW, Koshiol J, Chu LW, Cheng J-R, Gao J, et al. Variants in

IP
motilin, somatostatin and their receptor genes and risk of biliary tract cancers

R
and stones in Shanghai, China. Meta Gene 2014;2:418 26.

SC
[110] Schiergens TS, Reu S, Neumann J, Renz BW, Niess H, Boeck S, et al.

Histomorphologic and molecular phenotypes predict gemcitabine response

U
and overall survival in adenocarcinoma of the ampulla of Vater. Surgery
N
2015;158:151 61.
A

[111] Sakoda LC, Gao Y-T, Chen BE, Chen J, Rosenberg PS, Rashid A, et al.
M

Prostaglandin-endoperoxide synthase 2 (PTGS2) gene polymorphisms and

D

risk of biliary tract cancer and gallstones: a population-based study in

TE

Shanghai, China. Carcinogenesis 2005;27:1251 6.

[112] Santini D, Vincenzi B, Tonini G, Scarpa S, Vasaturo F, Malacrino C, et al.

EP

Cyclooxygenase-2 overexpression is associated with a poor outcome in

CC

resected ampullary cancer patients. Clin Cancer Res 2005;11:3784 9.

[113] Andreotti G, Chen J, Gao Y-T, Rashid A, Chen BE, Rosenberg P, et al.
A

Polymorphisms of genes in the lipid metabolism pathway and risk of biliary

tract cancers and stones: a population-based case-control study in Shanghai,

China. Cancer Epidemiol Prev Biomark 2008;17:525 34.

[114] Yamazaki K, Hanami K, Nagao T, Asoh A, Sugano I, Ishida Y. Increased

D1 V :

catenin accumulation and k-ras gene mutation. Mol Pathol 2003;56:336.

[115] Baumhoer D, Zlobec I, Tornillo L, Dietmaier W, Wuensch PH, Hartmann A,

et al. Immunophenotyping and oncogene amplifications in tumors of the

papilla of Vater. Virchows Arch 2008;453:579.

T
[116] Xu H-L, Cheng J-R, Andreotti G, Gao Y-T, Rashid A, Wang B-S, et al.

IP
Cholesterol metabolism gene polymorphisms and the risk of biliary tract

R
cancers and stones: a population-based case-control study in Shanghai, China.

SC
Carcinogenesis 2010;32:58 62.

[117] Park SK, Andreotti G, Sakoda LC, Gao Y-T, Rashid A, Chen J, et al. Variants
U
in hormone-related genes and the risk of biliary tract cancers and stones: a
N
population-based study in China. Carcinogenesis 2009;30:606 14.
A
M

Table 1: Karyotype terminology exhibited by AVC

D
TE

S.No Chromosomal location Sample size Frequency Country Ref

[64
EP

1 9p21-22 (D9S162)* 17 17.6% Japan ]

[67
2 17p13 17 62.5% Japan ]
[67
CC

3 5q22 (Exon 11) 17 17.6% Japan ]

[67
4 5q22 (Exon 15) 17 17.6% Japan ]
A

[79
5 14q32 10 10% Taiwan ]
[74
6 17p 42 55% (Shorter OS)** Italy ]
[77
32 >50% Korea ]
[73
8 >50% Italy ]
 [75
53 53% (Shorter OS)** Italy ]
[74
7 17Q 42 36% (Shorter OS)** Italy ]
[77
32 Korea ]
[73
8 11p 8 44.4% Italy ]
[73
9 11q 8 41.3% Italy ]
[77

T
10 9p 32 >50% Korea ]
[29

IP
8 37.5% China ]
[73

R
8 >50% Italy ]
[36

SC
11 5q13.3-q14; 5q23-q31 27 70% Italy ]
[35
12 5 2 USA ]
[77
13 18q (D18S34)* 32
U Korea ]
[77
N
14 13q (D13S118)* 32 Korea ]
[77
A
15 8p (D8S261)* 32 40% Korea ]
M

[73
16 5q 8 >50% Italy ]
[73
17 6q 8 >50% Italy ]
D

[73
18 13 8 >50% Italy ]
TE

[73
19 16p 8 >50% Italy ]
[73
EP

20 18p 8 >50% Italy ]

CC

* Marker used
** Prognosis
A
 R I
SC
Table 1: Gene specific mutations in Ampullary carcinoma

U
N
S.No Gene Associated No of samples Type of alteration Location of Freque Prognosis Country Ref
pathway mutation ncy of

A
mutatio
n [59

M
1 PMS2 MMR 98 N.A N.A N.A N.A USA, UK , Australia, ]
Germany,Thailand
ED [59
2 Elf3 Transcription 98 Frameshift or N.A N.A N.A USA, UK , Australia, ]
factor nonsense Germany,Thailand
[59
3 KRAS MAPK 98 N.A N.A N.A N.A USA, UK , Australia, ]
PT

Germany,Thailand
27 BTC, 2AVC N.A N.A 50% N.A Japan [1]
66 Substitution G12D 16.7% N.A Japan [4]
E

[49
CC

62 12.9% Shorter RFS Korea ]

[50
75 12% Poorer survival USA ]
[11
A

140 14% N.A USA ]

[51
35BTC, 5AVC 18% N.A Italy ]
[52
16 31.2% Italy ]
66 substitution G12V 12.1% N.A Japan [4]
[49
62 9.7% Shorter RFS Korea ]
 R I
[11

SC
140 9% N.A USA ]
[53
17 5.8% Japan ]

U
66 substitution G13D 4.5% N.A Japan [4]
[13

N
52 2% USA ]
[11

A
140 5% USA ]

M
66 substitution G12C 1.5% N.A Japan [4]
[11
ED140 4% USA ]
[53
17 G12N 17.6% Japan ]
[42
PT
17 29.4% Italy ]
[41
11 9% Japan ]
66 substitution G12S 1.5% N.A Japan [4]
E

[11
CC

140 1% USA ]
66 substitution G12A 1.5% N.A Japan [4]
[11
140 2% USA ]
A

[41
11 9% Japan ]
66 substitution G12D+G13D 1.5% N.A Japan [4]
[49
62 Substitution G13C 1.6% Shorter RFS Korea ]
[49
62 G12R 3.2% Shorter RFS Korea ]
35 BTC. 5 AVC 84% Italy [51
 R I
SC
]
[11
140 4% USA ]

U
[49
62 Q61H 3.2% Shorter RFS Korea ]

N
[13
52 6% N.A USA ]

A
[51
35 BTC, 5AVC Q61R 31% Italy ]

M
[54
92 Exon 1 37% USA ]
ED [45
5 AVC Point mutation Codon 13 40% Germany ]
GGC-->GGG
and
GGC-->GGT [47
PT

85periampullary Substitution Codon 12 53.3% Norway ]

, 15 AVC &13 [46
63 Codon 12 46% Thailand ]
E

&13
[13
CC

52 Codon 12 40% USA ]

[48
A

107 54% Shorter RFS Denmark ]

and OS
[39
15 80% N.A Chile ]
[43
Cell line N.A Italy ]
[37
16 13.3% Japan ]
 R I
SC
[24
30 40% Japan ]
[44

U
2 100% USA ]
[38

N
17 41% Netherland ]
4 SMAD4 TGF-beta 98 N.A N.A N.A N.A USA, UK , Australia,

A
[59
Germany,Thailand ]

M
27 BTC, 2AVC N.A N.A 50% N.A Japan [1]
68 positive N.A 75% N.A Japan [4]
ED [51
35BTC, 5AVC Substitution C449R 13% N.A Italy ]
[51
35BTC, 5AVC Substitution R361H 24% N.A Italy ]
[13
PT

52 6% N.A USA ]
[62
49 Reduced N.A 60% N.A USA ]
E

expression
[11
CC

140 loss N.A 34% N.A USA ]

[59
5 TP53 Cell cycle 98 N.A N.A USA, UK , Australia, ]
Germany,Thailand
A

68 Abnormal N.A 82.4% Shorter OS Japan [4]

immunolabelling
68 Loss of labeling N.A 41.2% N.A Japan [4]
68 Nuclear N.A 41.2% N.A Japan [4]
accumulation
106 Mutated N.A N.A USA [3]
[51
35BTC, 5AVC Substitution R273C 40% N.A Italy ]
 R I
SC
[62
49 Increased N.A 43% N.A USA ]
expression

U
N
[60
35 66% Singapore ]

A
[90
Cell line Adenine insertion Codon 266, N.A Korea ]

M
resulting in stop exon 8
codon
ED [90
Cell line Missense Codon 48 of N.A Korea ]
mutation exon 4 [90
Cell line Missense Codon 273, N.A Korea ]
mutation exon 8
PT

[56
30 Positive N.A 53% Japan ]
[44
E

5 60% USA ]
[61
CC

29 55% France ]
[52
16 Methylation 25% Italy ]
[42
A

11 Point mutation Exon 5 9% Japan ]

Exon 6 27.2%
Exon 7 18.1%
[53
17 Nucleotide Codon 146 5.9% Japan ]
change Codon 189 35.3%
Codon 166 17.6%
Codon 292 5.9%
 R I
SC
Codon 213 5.9% [59
6 CDKN2A Cell cycle 98 N.A N.A N.A N.A USA, UK , Australia, ]
Germany,Thailand

U
106 deleted USA [3]
[59

N
7 APC Wnt 98 N.A N.A N.A N.A USA, UK , Australia, ]
Germany,Thailand

A
[53
17 Insertion codon 1554 11.7% Japan ]

M
(A)

ED Nucleotide Codons 1314, 35.9%

change 1306, 1375,
1374,
149
[59
PT

8 PIK3CA PI3K 98 N.A N.A N.A N.A USA, UK , Australia, ]

Germany, Thailand [49
62 Substitution Exon 9 1.6% Korea ]
E

Codon 545 [13

CC

52 9.6% USA ]
[13
52 p.Q546R 1.9% USA ]
[59
A

9 CTNNB1 Wnt 98 N.A N.A N.A N.A USA, UK , Australia, ]

Germany, Thailand
[79
21 deletion Codon 32 4.6% Japan ]
[51
35 BTC, 5AVC Substitution S45F 43% Italy ]
[24
30 S37F 3.3% Japan ]
 R I
SC
S37C
T41A
S45P [59

U
10 ARID2 Chromatin 98 N.A N.A N.A N.A USA, UK , Australia, ]
Remodeling Germany,Thailand [59

N
11 SOX9 Transcription 98 N.A N.A N.A N.A USA, UK , Australia, ]
factor Germany,Thailand [59

A
12 ACVR1B TGF-beta 98 N.A N.A N.A N.A USA, UK , Australia, ]

M
Germany,Thailand [59
13 PTEN PI3K 98 N.A N.A N.A N.A USA, UK , Australia, ]
ED Germany,Thailand
92 Loss 25% Shorter RFS USA [9]
and OS

14 TGFBR2 TGF-beta 98 N.A N.A N.A N.A USA, UK , Australia, [59]

PT

Germany,Thailand
15 ARID1A Chromatin 98 N.A N.A N.A N.A USA, UK , Australia, [59]
Remodeling Germany,Thailand
E

16 ATM Cell cycle 98 Missense p.R823C N.A N.A USA, UK , Australia, [59]
CC

c.2879 C>T Germany,Thailand

36PDAC,16AV Italy [86]

C
A

17 AXIN Wnt 98 N.A N.A N.A N.A USA, UK , Australia, [59]

Germany, Thailand
32 Upregulation USA [27]
periampullary.
16AVC
18 PBRM1 Chromatin 98 N.A N.A N.A N.A USA, UK , Australia, [59]
remodeling Germany,Thailand
19 RECQL4 Homologous 98 N.A N.A N.A N.A USA, UK , Australia, [59]
 R I
SC
recombination Germany,Thailand
20 KDM6A Histone 98 N.A N.A N.A N.A USA, UK , Australia, [59]
demethylation Germany,Thailand

U
21 KDM4C Histone 98 Deletion Chromosome N.A N.A USA, UK , Australia, [59]
demethylation Decreased 9 Germany,Thailand

N
expression

A
22 CD44 N.A Altered N.A N.A N.A Taiwan [94]
expression

M
CD44ν3 -10 N.A Increased N.A Increased
expression recurrence
CD44ν -10 ED N.A N.A

36 Lack of 36.1% Poor OS and Japan [71]

expression RFS
PT

23 MET RAS , PI3K, 62 Increased N.A 38.7% N.A Korea [2]

JAK/STAT, Wnt, expression
NOTCH
E

pathways
24 HGF RAS , PI3K, 62 Increased N.A 24.2% N.A Korea [2]
CC

JAK/STAT, Wnt, expression

NOTCH
pathways
25 BRCA2 DNA repair 1 Insertion c.156_157ins 12.5% N.A Portugal [7]
A

Alu
1 N.A N.A N.A USA [67]
26 CDX-2 Transcription 68 Negative N.A 38.2% N.A Japan [4]
factor 62 positive intestinal 87.9% Korea [49]
62 Negative Pancreatobili 75.9% Korea [49]
ary
32 Positive N.A 71.4% USA [27]
 R I
SC
periampullary,
16AVC
53 60% Italy [22]

U
27 MUC1 68 Negative N.A 58.8% N.A Japan [4]
53

N
Positive 75% N.A Italy [22]
38 Increased 61% Shorter OS Japan [105

A
expression ]
28 MUC2 68 Negative N.A 83.8% Japan [4]

M
38 73.7% Shorter OS Japan [105
]
ED 95 Negative N.A Decreased OS Germany [110

]
53 positive 28% N.A Italy [22]
29 CK20 68 positive N.A 76.5% N.A Japan [4]
PT

30 CK7 68 Positive N.A 86.8% N.A Japan [4]

95 Positive N.A Decreased OS Germany [110
]
E

31 Β-catenin Wnt 67 Loss of labeling N.A 41.8% N.A Japan [4]

32 Increased USA [27]
CC

periampullary, expression
16AVC
30 30% Japan [24]
A

32 P16 Cell cycle 68 Positive N.A 55.9% N.A Japan [4]

54 Loss 67% USA [41]
Cell line Promoter N.A Italy [43]
methylation
9 Methylation 22.2% USA [66]
17 Missense G35R 41.2% Japan [65]
Deletion Codon 76
Missense R99Q
 R I
SC
Missense P70S
Missense S56N
Missense A30V

U
Nonsense 110 –Trp to
stop

N
33 BRAF MAPK 67 N.A N.A 3% N.A Japan [4]
1 Substitution G466E N.A N.A USA [57]

A
52 p.V600E 1.9% [13]
107 N.A 12% Denmark [48]

M
34 NRAS MAPK 1 substitution G12V N.A N.A USA [58]

35 miRNA
ED 4 overexpression miR-215
miR141
N.A N.A Korea [101
]
miR422
miR622
PT

miR650
miR513
miR378
E

miR383
miR93
CC

miR663b
107 miR-187 Denmark [102
miR-194 ]
A

miR-205
miR-552
miR-654-5p
36 ERBB2 MAPK, PI3K, 106 Amplification N.A 13% N.A USA [3]
STAT, Missense pD639V 5%
phospholipase C p. R678Q N.A
and PKC R103L N.A
R784C N.A
 R I
SC
36PDAC, p.V777L N.A Italy [86]
16AVC
221 BTC, 26 Overexpression N.A 11.5% Japan [55]

U
AVC
30 Positive 23% [56]

N
37 CDK12 Cell cycle 106 Amplification N.A N.A N.A USA [3]
38 CCND 1 Cell cycle 106 Amplification N.A N.A N.A USA

A
39 AGR2 Cell cycle 1 cell line Overexpression N.A N.A Increased Korea [90]

M
invasiveness

ED and
proliferation
40 GNAS GPCR pathway 35BTC, 5AVC Substitution R201C 46% N.A Italy [51]
41 MLN GPCR pathway 439 BTC, 53 SNP RS2281820 N.A N.A China [109
AVC Rs379307 ]
PT

RS2281819
42 MLNR GPCR pathway 439 BTC, 53 SNP RS9568 N.A N.A China [109
AVC ]
E

43 SSTR2 GPCR pathway 439 BTC, 53 SNP RS7210080 N.A N.A China [109
AVC Rs1466113 ]
CC

RS2236738
RS2236750
44 SSTR5 GPCR pathway 439 BTC, 53 SNP RS169068 N.A N.A China [109
A

AVC ]
45 AFP Cell line Overexpression N.A N.A N.A Japan [18]
46 GPC3 Wnt and Cell line Overexpression N.A N.A N.A Japan [18]
Hedgehog
signaling
47 amphireguli MAPK. PI3K, 52 overexpression N.A 82.7% USA [13]
n JNK
48 EGFR MAPK. PI3K 52 Overexpression N.A 25% N.A USA [13]
 R I
SC
JNK
36PDAC,16AV Insertion 892fs896stop N.A Italy [86]
C

U
49 BUB1B Spindle 1 Germline, 2386- N.A N.A Canada [32
checkpoint, homozygous, 11A G

N
Chromosome Intronic mutation

A
seggregation
50 ABCG8 439 BTC, SNP Rs4148217 N.A N.A China [116

M
53AVC Rs11887534 ]
51 CETP Lipid metabolism
ED Rs708272
Rs1800775
52 LRPAP1 Lipid metabolism Rs11267919 [86
53 EPHA3 VEGF pathway 36PDAC,16AV Missense p.K207N N.A N.A Italy ]
C
PT

[27
54 MEP1A 32 upregulation N.A N.A N.A USA ]
GUCY2C G- protein periampullary.
E

pathway 16AVC
* GPA33
CC

* CDX-1 Transcription
factor
57 Clusterin apoptosis
A

58 NOTCH-2 Notch signaling

59 HNF- alpha Transcription
factor
60 AKT PI3K Activating marker Ser473
61 GSK-3 Wnt (phosphorylation) Ser21
62 P70S6K PI3K T389
63 mTOR PI3K S2448
64 FOX03 PI3K N.A
 R I
SC
65 MAPK MAPK N.A
66 MEK MAPK N.A
67 STAT3 JAK/STAT S727

U
68 E-Cadherin Wnt 32 Increased N.A USA [27]
periampullary. expression

N
16AVC
Cell line hypermethylation Korea [90]

A
69 CCK 439 BTC, SNP Rs747455N.A N.A China [108

M
53AVC rs8192473 ]
ED rs1799923
rs3774396
rs10865918
70 CCKAR rs2071011 N.A N.A
rs915889
PT

rs3822222
rs1800855
71 Livin Apoptosis 71 Positive 46.5% Shorter OS China [5]
E

72 Caspase 3 Apoptosis expression 54.9% N.A

CC

73 Ki-67 56.3% N.A

74 IL8 G-Protein 456 BTC, SNP rs10805066 N.A N.A China [97]
pathway 53AVC
75 RNASEL Apoptosis rs672527 N.A N.A
A

76 MSH6 MMR Loss of protein N.A 3.7% N.A USA [89]

53 MSI and loss of Italy [22]
expression
77 MLH1/PMS MMR Loss of protein 1.8% N.A USA [89]
2 53 Positive N.A Italy [22]
expression
9 Methylation 11.1% USA [66]
 R I
SC
Cell line Missense Codon 384
exon 12
78 ESR1 GPCR pathway 411 BTC, SNP rs1801132 N.A N.A China [107

U
47AVC (P325P) G ]

N
9 Methylation 66.7% USA [66]
79 ESR2 GPCR pathway 411 BTC, SNP rs4986938 N.A N.A China [107

A
47AVC (3 ofbp 3 ]

M
STP)
80 Fhit Tumour 49 Reduced /loss of N.A 98% N.A USA [62]
suppressor
ED expression
81 Wwox Tumour 49 Reduced /loss of N.A 80% N.A USA [62]
suppressor expression
82 CYP1A1 SNP Ex7 + 131 N.A N.A China [117
PT
(rs1048943) ]
G allele
83 PML Transcriptional 62 Expression is N.A 38.7% Shortest OS Italy [10]
E

regulation absent and RFS

Focal expression 25.8% Medium OS
CC

and RFS
Diffused 35.5% Longest OS
expression and RFS
84 APOB Fat metabolism 627 BTC, SNP IVS6+360C> N.A N.A China [113
A

68AVC T ]
EX4+56C>T
EX26-
3573T>C
85 APOE Fat metabolism IVS1+69C> N.A N.A
G
86 LDLR EX18+88G> N.A N.A
 R I
SC
A
EX10+55G>
A

U
IVS17-
42A>G

N
87 LPL IVS5- N.A N.A

A
540C>T

M
88 ALOX5 IVS3+100G N.A N.A
>A
89 SOX2 Transcription
ED 6 Positive Pancreatobili N.A N.A Japan [19]
factor expression ary subtype
90 MUC5AC 6 Pancreatobili N.A Japan [19]
ary subtype
53 43% Italy [22]
PT

91 PTGS2/ Prostaglandin 627 BTC, SNP Ex10þ837T - N.A N.A China [111
COX-2 synthesis 68AVC C ]
39 Positive N.A 61.5% Shorter OS Italy [6]
E

expression
CC

9 Methylation 11.1% N.A USA [66]

5 40% [44]
92 stratifin Positive N.A 85% Shorter OS USA [14]
93 ERM Mitosis expression N.A 57%
A

protein
94 survivin apoptosis No expression N.A 92.3% N.A Italy [6]
95 MTAP Polyamine 54 loss N.A 17% N.A USA [33]
metabolism
96 XRCC1 DNA repair 411 BTC, SNP R280H, N.A China [85]
47AVC Ex9þ16G.A,
(280HH)
97 MUC6 53 Positive N.A 39% N.A Italy [22]
 R I
SC
98 osteopontin 28 Overexpression N.A N.A USA [34]
99 cyclinD1 Cell cycle 30 Increased N.A 56.65 Shorter RFS Japan [24]
expression

U
100 IFNA 9 Loss N.A 12.5% N.A USA [66]
101 P14 Cell cycle 9 methylation N.A 11.1% N.A USA [66]

N
A
102 MGMT DNA repair N.A 11.1% N.A
103 RAR-Beta Transcriptional N.A 33.3% N.A

M
regulation
104 HOGG1 DNA repair Cell line C-G nucleotide Exon 5 N.A N.A Korea [90]
ED change
105 D9S942 N.A 8 loss N.A 42.9% N.A China [30]
106 D9S171 N.A 8 loss N.A 37.5% N.A China [30]
107 PCNA DNA repair 30 positive N.A 39.1% Shorter RFS Japan [56]
17 43% Shorter OS Japan [65]
PT

108 RER Replication error 25 positive N.A 20% Longer OS Italy [73]
phenotype
109 63 DNA ploidy* diploidy 49.2% Shorter OS China [81]
E

Aneuploidy 50.8% Longer OS

CC

5 Aneuploidy 15% Germany [80]

110 60 Gene deletion* 18q21.2 and N.A N.A Norway [84]
periampullary 9p21.3, 4q,
carcinoma 5q
A

13 AVC
111 60 Gene 3q26.2 and N.A N.A Norway [84]
periampullary amplification* 8q24.21, 13q,
carcinoma 5p, 13p
AVC
 R I
SC
** Gene name not included in article reviewed

U
BTC- Biliary tract cancer; AVC- ampulla of vater carcinoma; PDAC- pancreatic ductal adenocarcinoma; N.A- not
applicable; OS-overall survival; RFS- recurrence free survival; SNP- single nucleotide polymorphisms; ins- insertion;

N
A
Fig 1: Signaling pathways involved in AVC

M
*Mutations observed
p120- catenin delta-1; PP2A-protein phosphatase 2A; WTX- Wilms tumor gene; AXIN- axis inhibition protein 1 ; APC- Adenomatous polyposis coli; CSK1- C-terminal src kinase; GSK-3-Glycogen
synthase kinase 3; CDK- cyclin dependent kinase; HER2- human epidermal growth factor 2; RAS- rat sarcoma; MEK- Mitogen-activated protein kinase kinase; ERK- extracellular signal-regulated
kinases; MET- MET Proto-Oncogene; PI3K- Phosphoinositide-3-Kinase; Akt- protein kinase B; Fox01/3-PTEN- Phosphatase and tensin homolog; Fox01- forkhead box O1; TGF- tumor growth
ED
factor; SMAD- homologues of the Drosophila protein, mothers against decapentaplegic (Mad) and the Caenorhabditis elegans protein Sma; AGR2- anterior grade 2.
E PT
CC
A
 R I
SC
Fig2 : Proportion of studies conducted in different countries

U
N
A
M
ED
EPT
CC
A