Targeted sequencing for hereditary breast and ovarian cancer in BRCA1/2-negative families reveals complex genetic architecture and phenocopies.

Autor:	Plowman JN; Department of Pharmacology and Neuroscience, Creighton University, Omaha, NE 68178, USA., Matoy EJ; Department of Pharmacology and Neuroscience, Creighton University, Omaha, NE 68178, USA., Uppala LV; Department of Pharmacology and Neuroscience, Creighton University, Omaha, NE 68178, USA., Draves SB; Department of Pharmacology and Neuroscience, Creighton University, Omaha, NE 68178, USA., Watson CJ; Creighton University Core Facilities, Creighton University, Omaha, NE 68178, USA., Sefranek BA; Creighton University Core Facilities, Creighton University, Omaha, NE 68178, USA., Stacey ML; Creighton University Core Facilities, Creighton University, Omaha, NE 68178, USA., Anderson SP; Creighton University Core Facilities, Creighton University, Omaha, NE 68178, USA., Belshan MA; Department of Medical Microbiology and Immunology, Creighton University, Omaha, NE 68178, USA., Blue EE; Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA 98195, USA; Institute for Public Health Genetics, University of Washington, Seattle, WA 98195, USA; Brotman Baty Institute, Seattle, WA 98195, USA., Huff CD; Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Fu Y; Department of Biomedical Sciences, Creighton University, Omaha, NE 68178, USA., Stessman HAF; Department of Pharmacology and Neuroscience, Creighton University, Omaha, NE 68178, USA; Creighton University Core Facilities, Creighton University, Omaha, NE 68178, USA. Electronic address: hollystessman@creighton.edu.
Jazyk:	angličtina
Zdroj:	HGG advances [HGG Adv] 2024 Jul 18; Vol. 5 (3), pp. 100306. Date of Electronic Publication: 2024 May 10.
DOI:	10.1016/j.xhgg.2024.100306
Abstrakt:	Approximately 20% of breast cancer cases are attributed to increased family risk, yet variation in BRCA1/2 can only explain 20%-25% of cases. Historically, only single gene or single variant testing were common in at-risk family members, and further sequencing studies were rarely offered after negative results. In this study, we applied an efficient and inexpensive targeted sequencing approach to provide molecular diagnoses in 245 human samples representing 134 BRCA mutation-negative (BRCAX) hereditary breast and ovarian cancer (HBOC) families recruited from 1973 to 2019 by Dr. Henry Lynch. Sequencing identified 391 variants, which were functionally annotated and ranked based on their predicted clinical impact. Known pathogenic CHEK2 breast cancer variants were identified in five BRCAX families in this study. While BRCAX was an inclusion criterion for this study, we still identified a pathogenic BRCA2 variant (p.Met192ValfsTer13) in one family. A portion of BRCAX families could be explained by other hereditary cancer syndromes that increase HBOC risk: Li-Fraumeni syndrome (gene: TP53) and Lynch syndrome (gene: MSH6). Interestingly, many families carried additional variants of undetermined significance (VOUSs) that may further modify phenotypes of syndromic family members. Ten families carried more than one potential VOUS, suggesting the presence of complex multi-variant families. Overall, nine BRCAX HBOC families in our study may be explained by known likely pathogenic/pathogenic variants, and six families carried potential VOUSs, which require further functional testing. To address this, we developed a functional assay where we successfully re-classified one family's PMS2 VOUS as benign. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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