TY - JOUR
T1 - Expanded analysis of secondary germline findings from matched tumor/normal sequencing identifies additional clinically significant mutations
AU - Dumbrava, Ecaterina Ileana
AU - Brusco, Lauren
AU - Daniels, Molly S.
AU - Wathoo, Chetna
AU - Shaw, Kenna R.
AU - Lu, Karen H.
AU - Zheng, Xiaofeng
AU - Strong, Louise C.
AU - Litton, Jennifer
AU - Arun, Banu K.
AU - Eterovic, A. Karina
AU - Routbort, Mark J.
AU - Patel, Keyur P.
AU - Qi, Yuan
AU - Piha-Paul, Sarina A.
AU - Subbiah, Vivek
AU - Hong, David S.
AU - Rodon, Jordi
AU - Kopetz, Scott
AU - Mendelsohn, John
AU - Mills, Gordon B.
AU - Chen, Ken
AU - Meric-Bernstam, Funda
N1 - Publisher Copyright:
© 2019 American Society of Clinical Oncology.
PY - 2019
Y1 - 2019
N2 - PURPOSE Next-generation sequencing (NGS) for tumor molecular profiling can reveal secondary germline likely pathogenic and pathogenic variants (LPV/PV). The American College of Medical Genetics and Genomics (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 on the basis of the ACMG list. 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 1,000 patients with advanced or metastatic solid tumors enrolled in a molecular testing protocol (ClinicalTrials.gov identifier: NCT01772771). The frequency of germline LPV/PV in 54 cancer-related genes, beyond the genes in ACMG list, were analyzed. RESULTS Among 1,000 patients who underwent tumor/normal DNA sequencing, 46 (4.6%) were found to have a germline LPV/PV in the following genes: AR (n = 5), ATM (n = 4), BAP1 (n = 1), CDH1 (n = 1), CDKN2A (n = 1), CHEK1 (n = 2), CHEK2 (n = 10), EGFR (n = 1), ERCC3 (n = 4), ERCC5 (n = 1), HNF1B (n = 1), HRAS (n = 1), MITF (n = 4), MLL3 (n = 1), NF1 (n = 3), PKHD1 (n = 4), PTCH1 (n = 1), and SMARCA4 (n = 1). Thus, 8.7% of patients had an LPV/PV, with two patients having two concomitant germline LPV/PV. Five mutations in highpenetrance hereditary cancer predisposition genes were selected to be returned to patients or their representatives: BAP1, CDH1, CDKN2A, EGFR, and SMARCA4. CONCLUSION 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, which warrants continued study.
AB - PURPOSE Next-generation sequencing (NGS) for tumor molecular profiling can reveal secondary germline likely pathogenic and pathogenic variants (LPV/PV). The American College of Medical Genetics and Genomics (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 on the basis of the ACMG list. 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 1,000 patients with advanced or metastatic solid tumors enrolled in a molecular testing protocol (ClinicalTrials.gov identifier: NCT01772771). The frequency of germline LPV/PV in 54 cancer-related genes, beyond the genes in ACMG list, were analyzed. RESULTS Among 1,000 patients who underwent tumor/normal DNA sequencing, 46 (4.6%) were found to have a germline LPV/PV in the following genes: AR (n = 5), ATM (n = 4), BAP1 (n = 1), CDH1 (n = 1), CDKN2A (n = 1), CHEK1 (n = 2), CHEK2 (n = 10), EGFR (n = 1), ERCC3 (n = 4), ERCC5 (n = 1), HNF1B (n = 1), HRAS (n = 1), MITF (n = 4), MLL3 (n = 1), NF1 (n = 3), PKHD1 (n = 4), PTCH1 (n = 1), and SMARCA4 (n = 1). Thus, 8.7% of patients had an LPV/PV, with two patients having two concomitant germline LPV/PV. Five mutations in highpenetrance hereditary cancer predisposition genes were selected to be returned to patients or their representatives: BAP1, CDH1, CDKN2A, EGFR, and SMARCA4. CONCLUSION 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, which warrants continued study.
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U2 - 10.1200/PO.18.00143
DO - 10.1200/PO.18.00143
M3 - Article
AN - SCOPUS:85077484843
SN - 2473-4284
VL - 3
SP - 1
EP - 11
JO - JCO Precision Oncology
JF - JCO Precision Oncology
ER -