An integrated somatic and germline approach to aid interpretation of germline variants of uncertain significance in cancer susceptibility genes.

Autor:	Schwartz A; Division of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA, United States., Manning DK; Department of Pathology, Brigham and Women's Hospital, Boston, MA, United States., Koeller DR; Division of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA, United States., Chittenden A; Division of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA, United States., Isidro RA; Department of Pathology, Brigham and Women's Hospital, Boston, MA, United States.; Harvard Medical School, Boston, MA, United States., Hayes CP; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States., Abraamyan F; Harvard Medical School, Boston, MA, United States.; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States., Manam MD; Department of Pathology, Brigham and Women's Hospital, Boston, MA, United States., Dwan M; Division of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA, United States., Barletta JA; Department of Pathology, Brigham and Women's Hospital, Boston, MA, United States.; Harvard Medical School, Boston, MA, United States., Sholl LM; Department of Pathology, Brigham and Women's Hospital, Boston, MA, United States.; Harvard Medical School, Boston, MA, United States., Yurgelun MB; Division of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA, United States.; Harvard Medical School, Boston, MA, United States.; Division of Population Sciences, Dana-Farber Cancer Institute, Boston, MA, United States., Rana HQ; Division of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA, United States.; Harvard Medical School, Boston, MA, United States.; Division of Population Sciences, Dana-Farber Cancer Institute, Boston, MA, United States., Garber JE; Division of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA, United States.; Harvard Medical School, Boston, MA, United States.; Division of Population Sciences, Dana-Farber Cancer Institute, Boston, MA, United States., Ghazani AA; Department of Pathology, Brigham and Women's Hospital, Boston, MA, United States.; Harvard Medical School, Boston, MA, United States.; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in oncology [Front Oncol] 2022 Aug 25; Vol. 12, pp. 942741. Date of Electronic Publication: 2022 Aug 25 (Print Publication: 2022).
DOI:	10.3389/fonc.2022.942741
Abstrakt:	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. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Schwartz, Manning, Koeller, Chittenden, Isidro, Hayes, Abraamyan, Manam, Dwan, Barletta, Sholl, Yurgelun, Rana, Garber and Ghazani.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu