Sequencing of 279 cancer genes in ampullary carcinoma reveals trends relating to histologic subtypes and frequent amplification and overexpression of ERBB2 (HER2) Journal Article
| Authors: | Hechtman, J. F.; Liu, W.; Sadowska, J.; Zhen, L.; Borsu, L.; Arcila, M. E.; Won, H. H.; Shah, R. H.; Berger, M. F.; Vakiani, E.; Shia, J.; Klimstra, D. S. |
| Article 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. © 2015 USCAP, Inc All rights reserved. |
| Keywords: | immunohistochemistry; adult; clinical article; controlled study; human tissue; protein expression; aged; middle aged; gene deletion; missense mutation; phenotype; gene overexpression; gene amplification; epidermal growth factor receptor 2; gene frequency; mutational analysis; protein p53; histology; pancreas carcinoma; in situ hybridization; genome analysis; tumor suppressor gene; bile duct carcinoma; cyclin dependent kinase inhibitor 2a; oncogene k ras; point mutation; tumor gene; intestine carcinoma; indel mutation; next generation sequencing; human; male; female; priority journal; article; intestinal type ampullary carcinoma; pancreatobiliary type ampullary carcinoma |
| Journal Title: | Modern Pathology |
| Volume: | 28 |
| Issue: | 8 |
| ISSN: | 0893-3952 |
| Publisher: | Nature Research |
| Date Published: | 2015-08-01 |
| Start Page: | 1123 |
| End Page: | 1129 |
| Language: | English |
| DOI: | 10.1038/modpathol.2015.57 |
| PROVIDER: | scopus |
| PUBMED: | 25975284 |
| PMCID: | PMC4977532 |
| DOI/URL: | |
| Notes: | Export Date: 2 September 2015 -- Source: Scopus |
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