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

Abstract

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.

Figure 1.

A model for partnered care integrating precision medicine tumor genomic profiling with clinical genetics care, for pathogenic germline variants incidentally detected among advanced colorectal cancer patients

Figure 2.

Flow chart of variants and patients. Initially 151 patients with 1910 distinct variants were screened for presumed pathogenic germline variants. Variants with low population frequencies (<1%) were tiered using three in silico prediction tools. Variants in Tiers 1-3 (i.e. pathogenic/probably pathogenic calls by at least 2 tools) were further characterized for pathogenicity.

Figure 3.

Presumed pathogenic germline variants. The locations of mutations and domains in the encoded protein products (shown by different colors) for the 15 presumed pathogenic variants are shown in lollipop plots. On the graph of each gene, the x axis reflects the number of amino acid residues, and the y axis represents the total number of mutations identified. Frameshift and stop gain mutations were classified in Tier 1, and were found in the following genes (as denoted by chromosomal locations): APC (5q22.2), BRCA1 (17q21.31), CDH1 (16q22.1), CHEK2 (22q12.1), MSH2(2p21-p16.3), MSH6 (2p16.3), NF2 (22q12.2), TP53 (17p13.1). Missense mutations were classified into Tiers 2 and 3, and were found in the following genes (as denoted by chromosomal locations): ATM (11q22.3), BRCA1 (17q21.31), CDH1 (16q22.1), CHEK2 (22q12.1).