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Detection of Pathogenic Germline Variants Among Patients With Advanced Colorectal Cancer Undergoing Tumor Genomic Profiling for Precision Medicine

You, Y. Nancy, M.D., M.H.Sc.1,2; Borras, Ester, Ph.D.2; Chang, Kyle, Ph.D.2; Price, Brandee A., Ph.D.1; Mork, Maureen, M.S., C.G.C.1; Chang, George J., M.D., M.S.1,3; Rodriguez-Bigas, Miguel A., M.D.1; Bednarski, Brian K., M.D.1; Meric-Bernstam, Funda, M.D.1,4; Vilar, Eduardo, M.D., Ph.D.2,5

Diseases of the Colon & Rectum: April 2019 - Volume 62 - Issue 4 - p 429–437
doi: 10.1097/DCR.0000000000001322
Original Contributions: Colorectal Cancer
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BACKGROUND: Genomic profiling of colorectal cancer aims to identify actionable somatic mutations but can also discover incidental germline findings.

OBJECTIVE: The purpose of this study was to report the detection of pathogenic germline variants that confer heritable cancer predisposition.

DESIGN: This was a retrospective study.

SETTINGS: The study was conducted at a tertiary-referral institution.

PATIENTS: Between 2012 and 2015, 1000 patients with advanced cancer underwent targeted exome sequencing of a 202-gene panel. The subgroup of 151 patients with advanced colorectal cancer who underwent matched tumor-normal (blood) sequencing formed our study cohort.

INTERVENTIONS: Germline variants in 46 genes associated with hereditary cancer predisposition were classified according to a defined algorithm based on in silico predictions of pathogenicity. Patients with presumed pathogenic variants were examined for type of mutation, as well as clinical, pedigree, and clinical genetic testing data.

MAIN OUTCOME MEASURES: We measured detection of pathogenic germline variants.

RESULTS: A total of 1910 distinct germline variants were observed in 151 patients. After filtering, 15 pathogenic germline variants (9.9%) were found in 15 patients, arising from 9 genes of varying penetrance for colorectal cancer (APC (n = 2; 13%), ATM (n = 1; 6%), BRCA1 (n = 2; 13%), CDH1 (n = 2; 13%), CHEK2 (n = 4; 27%), MSH2 (n = 1; 7%), MSH6 (n = 1; 7%), NF2 (n = 1; 7%), and TP53 (n = 1; 7%)). Patients with pathogenic variants were diagnosed at a younger age than those without (median, 45 vs 52 y; p = 0.03). Of the 15 patients, 7 patients (46.7%) with variants in low/moderate- penetrant genes for colorectal cancer would likely have not been tested based on clinical and pedigree criteria, where 2 harbored clinically actionable variants (CDH1 and NF2, 28.5% of 7).

LIMITATIONS: This study was limited by its small sample size and advanced-stage patients.

CONCLUSIONS: Tumor-normal sequencing can incidentally discover clinically unsuspected germline variants that confer cancer predisposition in 9.9% of patients with advanced colorectal cancer. Precision medicine should integrate clinical cancer genetics to inform and interpret the actionability of germline variants and to provide follow-up care to mutation carriers. See Video Abstract at http://links.lww.com/DCR/A906.

1 Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas

2 Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, Texas

3 Department of Health Services Research, University of Texas MD Anderson Cancer Center, Houston, Texas

4 Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas

5 Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas

Funding/Support: This study was supported in part by the University of Texas MD Anderson Cancer Center Clinical Innovator Award (to Dr You), the Cancer Prevention Education Award (to Dr Chang, R25T CA057730), the Cancer Prevention and Research Institute of Texas (RP1100584), the Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, and the MD Anderson Cancer Center Support Grant (P30 CA016672).

Financial Disclosure: None reported.

Podium presentation at the meeting of The American Society of Colon and Rectal Surgeons, Nashville, TN, May 19 to 23, 2018.

Correspondence: Y. Nancy You, M.D., M.H.Sc., Departments of Surgical Oncology and Clinical Cancer Prevention, Clinical Cancer Genetics Program, University of Texas MD Anderson Cancer Center, 1400 Pressler St, Houston, TX 77030. E-mail: ynyou@mdanderson.org or Eduardo Vilar, M.D., Ph.D., Departments of Clinical Cancer Prevention and Medical Oncology, University of Texas MD Anderson Cancer Center, Dan L. Duncan Building, 1155 Pressler St, Houston, TX 77030. E-mail: evilar@mdanderson.org

© 2019 The American Society of Colon and Rectal Surgeons