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JCO Precis Oncol. 2019;3. doi: 10.1200/PO.18.00143. Epub 2019 Apr 11.

Expanded analysis of secondary germline findings from matched tumor/normal sequencing identifies additional clinically significant mutations.

Author information

1
Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
2
Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
3
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
4
Program of Clinical Cancer Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
5
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
6
Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
7
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
8
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
9
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
10
Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
11
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Abstract

Background:

Next-generation sequencing (NGS) for tumor molecular profiling can reveal secondary germline pathogenic and likely pathogenic variants (LPV/PV). The American College of Medical Genetics (ACMG) recommends return of secondary results for a subset of 59 genes, but other genes with evidence of clinical utility are emerging. We previously reported that 4.3% of patients who underwent NGS of a targeted panel of 201 genes had LPV/PV based on the ACMG list. Here we report the frequency of additional germline cancer-related gene variants and discuss their clinical utility.

Patients and Methods:

Matched tumor and germline DNA NGS of a targeted panel of 201 genes was performed in a research laboratory on samples from 1000 patients with advanced or metastatic solid tumors enrolled in a molecular testing protocol (NCT01772771). The frequency of germline LPV/PV in 54 cancer-related genes, beyond the genes in ACMG list, were analyzed.

Results:

Among 1000 patients who underwent tumor/normal DNA sequencing, 46 (4.6%) were found to have a germline LPV/PV in the following genes: AR-(5), ATM-(4), BAP1-(1), CDH1-(1), CDKN2A-(1), CHEK1-(2), CHEK2-(10), EGFR-(1), ERCC3-(4), ERCC5-(1), HNF1B-(1), HRAS-(1), MITF-(4), MLL3-(1), NF1-(3), PKHD1-(4), PTCH1-(1), and SMARCA4-(1). Thus, a total 8.7% of patients had an LPV/PV with 2 patients having 2 concomitant germline LPV/PV. Five mutations in high-penetrance hereditary cancer predisposition genes were selected to be returned to patients or their representatives: BAP1, CDH1, CDKN2A, EGFR, and SMARCA4.

Conclusions:

Broader genomic testing is likely to identify additional secondary pathogenic germline alterations, some with potential clinical utility for return to patients and their relatives. The recommended genes for which germline results should be returned are continually changing, warranting continued study.

KEYWORDS:

NGS; hereditary cancer-related genes; matched tumor/normal DNA; next-generation sequencing; secondary germline variants

PMID:
31517177
PMCID:
PMC6741435
[Available on 2020-04-11]
DOI:
10.1200/PO.18.00143

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