Identification and prevalence of potentially therapeutic targetable variants of major cancer driver genes in ampullary cancer patients in India through deep sequencing

•The prevalence of poor prognostic factors (moderate to poor differentiation, pT-stage, PNI, LVI, LN metastasis and advance stage disease) were found to be significantly higher in pancreatobiliary (PB) subtype than intestinal (INT) subtype of AC.•This study identifies MET alterations in 16.8% cases...

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Published in:Cancer genetics 2021-11, Vol.258-259, p.41-48
Main Authors: Mishra, Shravan Kumar, Kumari, Niraj, Krishnani, Narendra, Singh, Rajneesh Kumar, Mohindra, Samir
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
Altered pathway
Ampillary cancer
Ampulla of Vater - metabolism
Ampulla of Vater - pathology
APC
Biomarkers, Tumor - genetics
Common Bile Duct Neoplasms - epidemiology
Common Bile Duct Neoplasms - genetics
Common Bile Duct Neoplasms - pathology
CTNNB1
Female
Follow-Up Studies
Genetic Predisposition to Disease
High-Throughput Nucleotide Sequencing - methods
Histological subtypes
Humans
India - epidemiology
KRAS
Male
MET
Middle Aged
Mutation
Prevalence
Prognosis
SMAD4
Targetable mutations
TP53
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Summary:•The prevalence of poor prognostic factors (moderate to poor differentiation, pT-stage, PNI, LVI, LN metastasis and advance stage disease) were found to be significantly higher in pancreatobiliary (PB) subtype than intestinal (INT) subtype of AC.•This study identifies MET alterations in 16.8% cases with predominance of most common variant (Asn375Ser) in ampullary carcinoma.•WNT pathway was found to be significantly altered in INT subtype of AC.•Strengthens the evidence of genetic similarity of INT subtype of AC with colorectal cancer. Ampulla is a complex region located at the confluence of pancreatic and common bile duct and intestinal epithelium. Tumors arising in this region are anatomically and morphologically heterogenous, however they show unique as well as overlapping molecular features. Cancers of both these anatomic sites share morphological as well as genetic profile despite having few unique differences. Targeted therapies are currently emerging as one of the demanding approaches for treatment in most cancer types especially for malignant epithelial tumors and therefore genetic profiling of cancers is the key for identification of potentially therapeutic targetable mutations to know their prevalence and prognostic impact. We studied 97 resected cases of formalin fixed paraffin-embedded AC by deep targeted sequencing using Ampliseq cancer hotspot panel comprising of 50 oncogenes and tumor suppressor genes. Potentially therapeutic targetable mutations were observed in 58/83 (70%) cases. Fourteen patients did not show any pathogenic mutation. TP53 (48.1%), KRAS (37.3%), APC (25.3%), SMAD4 (22.8%), MET (16.8%), CTNNB1 (15.6%) and PIK3CA (10.8%) were the major mutated potential therapeutic targets. KRAS mutation (43.2 Vs. 32.6%) was more prevalent in pancreatobiliary subtype, while TP53 (58.6 Vs 35.1), APC (36.9 Vs 10.8), SMAD4 (28.2 Vs 16.2), MET (21.7 Vs 10.8) and CTNNB1 (19.5 Vs 10.8) were more prevalent in intestinal subtype. WNT signaling pathway was the major altered pathway in intestinal subtype. These mutated genes and pathways may be targeted with currently available drugs and may be explored for future development of targetable agents to improve the disease course in patients of AC.
ISSN:2210-7762
2210-7770
DOI:10.1016/j.cancergen.2021.08.001