title: Sequencing of 279 cancer genes in ampullary carcinoma reveals trends relating to histologic subtypes and frequent amplification and overexpression of ERBB2 (HER2).
abstract: The biological relevance of histological subtyping of ampullary carcinoma into intestinal vs pancreaticobiliary types remains to be determined. In an effort to molecularly profile these subtypes of ampullary carcinomas, we conducted a two-phase study. In the discovery phase, we identified 18 pancreatobiliary-type ampullary carcinomas and 14 intestinal-type ampullary carcinomas using stringent pathologic criteria and performed next-generation sequencing targeting 279 cancer-associated genes on these tumors. Although the results showed overlapping of genomic alterations between the two subtypes, trends including more frequent KRAS alterations in pancreatobiliary-type ampullary carcinoma (61 vs 29%) and more frequent mutations in APC in intestinal-type ampullary carcinoma (43 vs 17%) were observed. Of the entire cohort of 32 tumors, the most frequently mutated gene was TP53 (n=17); the most frequently amplified gene was ERBB2 (n=5); and the most frequently deleted gene was CDKN2A (n=6). In the second phase of the study, we aimed at validating our observation on ERBB2 and assessed ERBB2 amplification and protein overexpression in a series of 100 ampullary carcinomas. We found that (1) gene amplification and immunohistochemical overexpression of ERBB2 occurred in 13% of all ampullary carcinomas, therefore providing a potential target for anti-HER2 therapy in these tumors; (2) amplification and immunohistochemical expression correlated in all cases, thus indicating that immunohistochemistry could be used to screen tumors; and (3) none of the 14 ERBB2-amplified tumors harbored any downstream driver mutations in KRAS/NRAS, whereas 56% of the cases negative for ERBB2 amplification did, an observation clinically pertinent as downstream mutations may cause primary resistance to inhibition of EGFR family members.
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Jaclyn F
authors.initials: JF
authors.lastname: Hechtman
authors.affiliation: Department of Pathology, University of Buffalo, Buffalo, NY, USA.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Justyna
authors.initials: J
authors.lastname: Sadowska
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Zhen
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Borsu
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Arcila
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Helen H
authors.initials: HH
authors.lastname: Won
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Ronak H
authors.identifier: 0000000190426213
authors.initials: RH
authors.lastname: Shah
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Berger
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Efsevia
authors.initials: E
authors.lastname: Vakiani
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Jinru
authors.initials: J
authors.lastname: Shia
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Klimstra
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014670:Ampulla of Vater / Q000737:chemistry / Q000473:pathology; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D002277:Carcinoma / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D003138:Common Bile Duct Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics; D005784:Gene Amplification; D017353:Gene Deletion; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011237:Predictive Value of Tests; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D020558:GTP Phosphohydrolases; D008565:Membrane Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018719:Erb-b2 Receptor Tyrosine Kinases; D016159:Tumor Suppressor Protein p53; C117307:KRAS protein, human; C495901:TP53 protein, human; C508053:ERBB2 protein, human; C579846:NRAS protein, human