AUTHOR=Schwartz Alison , Manning Danielle K. , Koeller Diane R. , Chittenden Anu , Isidro Raymond A. , Hayes Connor P. , Abraamyan Feruza , Manam Monica Devi , Dwan Meaghan , Barletta Justine A. , Sholl Lynette M. , Yurgelun Matthew B. , Rana Huma Q. , Garber Judy E. , Ghazani Arezou A. TITLE=An integrated somatic and germline approach to aid interpretation of germline variants of uncertain significance in cancer susceptibility genes JOURNAL=Frontiers in Oncology VOLUME=12 YEAR=2022 URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.942741 DOI=10.3389/fonc.2022.942741 ISSN=2234-943X ABSTRACT=

Genomic profiles of tumors are often unique and represent characteristic mutational signatures defined by DNA damage or DNA repair response processes. The tumor-derived somatic information has been widely used in therapeutic applications, but it is grossly underutilized in the assessment of germline genetic variants. Here, we present a comprehensive approach for evaluating the pathogenicity of germline variants in cancer using an integrated interpretation of somatic and germline genomic data. We have previously demonstrated the utility of this integrated approach in the reassessment of pathogenic germline variants in selected cancer patients with unexpected or non-syndromic phenotypes. The application of this approach is presented in the assessment of rare variants of uncertain significance (VUS) in Lynch-related colon cancer, hereditary paraganglioma-pheochromocytoma syndrome, and Li-Fraumeni syndrome. Using this integrated method, germline VUS in PMS2, MSH6, SDHC, SHDA, and TP53 were assessed in 16 cancer patients after genetic evaluation. Comprehensive clinical criteria, somatic signature profiles, and tumor immunohistochemistry were used to re-classify VUS by upgrading or downgrading the variants to likely or unlikely actionable categories, respectively. Going forward, collation of such germline variants and creation of cross-institutional knowledgebase datasets that include integrated somatic and germline data will be crucial for the assessment of these variants in a larger cancer cohort.