Sequencing of 279 cancer genes in ampullary carcinoma reveals trends relating to histologic subtypes and frequent amplification and overexpression of ERBB2 (HER2).

Mod Pathol 2015 Aug 15;28(8):1123-9. Epub 2015 May 15.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

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.

Download full-text PDF

Source
http://dx.doi.org/10.1038/modpathol.2015.57DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4977532PMC
August 2015
71 Reads

Publication Analysis

Top Keywords

ampullary carcinomas
20
ampullary carcinoma
16
ampullary
9
overexpression erbb2
8
amplification immunohistochemical
8
pancreatobiliary-type ampullary
8
intestinal-type ampullary
8
erbb2 amplification
8
erbb2
6
amplification
5
carcinomas
5
tumors
5
tumors harbored
4
frequent kras
4
kras alterations
4
including frequent
4
trends including
4
alterations subtypes
4
subtypes trends
4
tumors amplification
4

References

(Supplied by CrossRef)

DC Ang et al.
Am J Surg Pathol 2014

V Adsay et al.
Am J Surg Pathol 2012

MJ Overman et al.
PLoS One 2013

P Bronsert et al.
BMC Cancer 2013

H Zhou et al.
Am J Surg Pathol 2004

H Li et al.
Bioinformatics 2010

K Cibulskis et al.
Nat Biotechnol 2013

JT Robinson et al.
Nat Biotechnol 2011

P Jelinic et al.
Nat Genet 2014

M Arcila et al.
J Mol Diagn 2011

Similar Publications