Investigating the effect of 28 BRCA1 and BRCA2 mutations on their related transcribed mRNA

Breast Cancer Research and Treatment
Francisco QuilesConxi Lázaro

Abstract

Germline inactivating mutations in the BRCA1 and BRCA2 genes are responsible for hereditary breast and ovarian cancer syndrome (HBOCS). Genetic testing of these genes identifies a significant proportion of variants of uncertain significance (VUS). Elucidation of the clinical impact of these variants is an important challenge in genetic diagnostics and counseling. In this study, we assess the RNA effect of 28 BRCA1 and BRCA2 VUS identified in our set of HBOCS families with the aim of gaining insight into their clinical relevance. mRNA was extracted from VUS carriers and controls lymphocytes cultured for 5-6 days and treated with puromycin. RNA was reverse transcribed to perform transcriptional analysis for the study of splicing aberrations. In silico prediction tools were used to select those variants most likely to affect the RNA splicing process. Six out of the 28 variants analyzed showed an aberrant splicing pattern and could therefore be classified as probably pathogenic mutations. Reclassification of VUS improves the genetic counseling and clinical surveillance of carriers of these mutations and highlights the importance of RNA studies in routine diagnostic laboratories.

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Citations

Oct 27, 2016·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·You-Jin LuYing Wang
May 17, 2018·Breast Cancer Research and Treatment·Eugenia Fraile-BethencourtEladio A Velasco
Sep 29, 2018·JAMA : the Journal of the American Medical Association·Jacqueline MerschTheodora Ross
Jan 24, 2021·Medical Oncology·Maria Teresa VietriAnna Maria Molinari

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