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

Ecaterina Ileana Dumbrava, Lauren Brusco, Molly S. Daniels, Chetna Wathoo, Kenna R. Shaw, Karen H. Lu, Xiaofeng Zheng, Louise C. Strong, Jennifer Litton, Banu K. Arun, A. Karina Eterovic, Mark J. Routbort, Keyur P. Patel, Yuan Qi, Sarina A. Piha-Paul, Vivek Subbiah, David S. Hong, Jordi Rodon, Scott Kopetz, John MendelsohnGordon B. Mills, Ken Chen, Funda Meric-Bernstam

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    3 Scopus citations

    Abstract

    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.

    Original languageEnglish (US)
    JournalJCO Precision Oncology
    Volume3
    DOIs
    StatePublished - 2019

    ASJC Scopus subject areas

    • Cancer Research
    • Oncology

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    Dumbrava, E. I., Brusco, L., Daniels, M. S., Wathoo, C., Shaw, K. R., Lu, K. H., Zheng, X., Strong, L. C., Litton, J., Arun, B. K., Eterovic, A. K., Routbort, M. J., Patel, K. P., Qi, Y., Piha-Paul, S. A., Subbiah, V., Hong, D. S., Rodon, J., Kopetz, S., ... Meric-Bernstam, F. (2019). Expanded analysis of secondary germline findings from matched tumor/normal sequencing identifies additional clinically significant mutations. JCO Precision Oncology, 3. https://doi.org/10.1200/PO.18.00143