2017 ASCO Annual Meeting!
Session: Cancer Prevention, Genetics, and Epidemiology
Type: Poster Session
Time: Monday June 5, 1:15 PM to 4:45 PM
Location: Hall A
Prevalence of incidental germline pathogenic (PV) and likely pathogenic (LPV) variants in hereditary cancer-related genes identified in matched tumor/normal sequencing of advanced solid tumors.
Cancer Prevention, Hereditary Genetics, and Epidemiology
2017 ASCO Annual Meeting
Poster Board Number:
Poster Session (Board #182)
J Clin Oncol 35, 2017 (suppl; abstr 1524)
Author(s): Ecaterina Elena Ileana Dumbrava, Lauren Brusco, Molly S Daniels, Chetna Wathoo, Kenna Rael Shaw, Karen H. Lu, Xiaofeng Zheng, Louise C. Strong, Jennifer Keating Litton, Banu Arun, Agda Karina Eterovic, Mark Routbort, Sarina Anne Piha-Paul, Vivek Subbiah, David S. Hong, Scott Kopetz, John Mendelsohn, Gordon B. Mills, Ken Chen, Funda Meric-Bernstam; The University of Texas MD Anderson Cancer Center, Houston, TX; Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX; MD Anderson Cancer Center, Houston, TX; Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center, Houston, TX
Background: Next-generation sequencing (NGS) for tumor molecular profiling can reveal germline incidental mutations in hereditary cancer-related genes. The American College of Medical Genetics and Genomics (ACMG) has recommended that laboratories performing clinical sequencing seek and report PV and LPV in 56 genes. We assessed the prevalence of incidental germline LPV and PV in other cancer-related genes among patients undergoing hybrid capture sequencing of 201 cancer-related genes. Methods: Matched tumor and germline DNA NGS of a targeted panel of 201 genes was performed in 1000 patients (pts) with advanced or metastatic solid tumors enrolled in a molecular testing protocol (NCT01772771) in a research laboratory. We previously reported germline alterations in the putative most actionable genes as designated by ACMG (PMID: 26787237). We assessed the germline LPV and PV in 54 additional cancer-related genes. Results: Among the 1000 patients who underwent tumor and normal DNA sequencing, 37 patients (3.7%) were found to have a germline PV or LPV in the following genes: ATM (4); BAP1 (1); CDH1 (1); CDKN2A (1); CHEK1 (2); CHEK2 (10); EGFR (1); ERCC3 (4); ERCC5 (1); HNF1B (1); HRAS (1); MLL3 (1); NF1 (3); PKHD1 (4); PTCH1 (1) and SMARCA4 (1). Eight pts (22%) had previous genetic counseling and testing for various reasons, but only 3 pts (8%) had previously identified alterations (all with NF1 mutations). After discussion in our return of germline results board, it was decided to return the findings in established hereditary cancer predisposition genes with high penetrance: BAP1 (p.Y401X), CDH1 (p.C688X), CDKN2A (p.G101W), EGFR (p.T790M) and SMARCA4 (p.S332FfsX55) after validation in a CLIA laboratory. Conclusions: Return of the previously unrecognized germline LPV or PV in patients with advanced or metastatic cancers who undergo somatic profiling is of great interest. The exact genes for which the germline results should be returned is controversial. Broader genomic testing is likely to identify additional incidental germline alterations with potential clinical utility to patients and their relatives.