Mutations in RECQL Gene Are Associated with Predisposition to Breast Cancer

• Published in: PLoS genetics 2015-05, Vol.11 (5), p.e1005228
• Main Authors: Sun, Jie, Wang, Yuxia, Xia, Yisui, Xu, Ye, Ouyang, Tao, Li, Jinfeng, Wang, Tianfeng, Fan, Zhaoqing, Fan, Tie, Lin, Benyao, Lou, Huiqiang, Xie, Yuntao
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Breast cancer; Breast Neoplasms - genetics; Cancer patients; Case-Control Studies; Cloning, Molecular; Computational Biology; DNA Repair; DNA sequencing; Female; Gene mutation; Genes; Genetic aspects; Genetic Predisposition to Disease; Genetic Variation; Genomic Instability; Humans; Identification and classification; Medical research; Methods; Middle Aged; Molecular Sequence Data; Mutation; Mutation, Missense; Pedigree; RecQ Helicases - genetics; RecQ Helicases - metabolism; RNA Splicing; Sequence Alignment; Sequence Analysis, DNA
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1005228

The genetic cause for approximately 80% of familial breast cancer patients is unknown. Here, by sequencing the entire exomes of nine early-onset familial breast cancer patients without BRCA1/2 mutations (diagnosed with breast cancer at or before the age of 35) we found that two index cases carried a potentially deleterious mutation in the RECQL gene (RecQ helicase-like; chr12p12). Recent studies suggested that RECQL is involved in DNA double-strand break repair and it plays an important role in the maintenance of genomic stability. Therefore, we further screened the RECQL gene in an additional 439 unrelated familial breast cancer patients. In total, we found three nonsense mutations leading to a truncated protein of RECQL (p.L128X, p.W172X, and p.Q266X), one mutation affecting mRNA splicing (c.395-2A>G), and five missense mutations disrupting the helicase activity of RECQL (p.A195S, p.R215Q, p.R455C, p.M458K, and p.T562I), as evaluated through an in vitro helicase assay. Taken together, 9 out of 448 BRCA-negative familial breast cancer patients carried a pathogenic mutation of the RECQL gene compared with one of the 1,588 controls (P = 9.14×10-6). Our findings suggest that RECQL is a potential breast cancer susceptibility gene and that mutations in this gene contribute to familial breast cancer development.