The number of genes associated with breast cancer risk continues to increase. Recently, through whole exome sequencing, 2 groups of researchers have demonstrated that mutations in RECQL increase the risk of breast cancer.1 The first paper, by Cybulski and colleagues, was published online in Nature Genetics in April 2015 and the second, by Sun and colleagues, in PLoS Genetics in May 2015.2,3 Similar to other genes associated with breast cancer susceptibility, RECQL appears to help maintain genome stability and is involved in DNA double-strand break repair through the homologous recombination pathway.1
In the Sun and colleagues paper, the exomes of 9 individuals diagnosed with breast cancer at or under age 35 years who were previously tested for BRCA1/2 were analyzed. Two of the 9 were found to have a change in RECQL that likely impacted the RECQL protein.3 An additional 439 individuals with familial breast cancer and negative BRCA1/2 results then underwent Sanger sequencing of the coding regions of the RECQL gene. In vitro functional analysis was performed to help determine pathogenicity of variants, and a loss of heterozygosity assay was performed in 5 of the cases. Seven individuals were found to carry a pathogenic mutation. Thus, of the 448 individuals analyzed for changes in the RECQL gene, 2% were found to have a mutation in the RECQL gene. The age of probands at breast cancer diagnosis ranged from 31 years to 71 years, and the average patient age at onset of breast cancer in these families was 48 years.
Similar to Sun and colleagues, Cybulski and colleagues initially studied a limited number of families by using whole exome sequencing and then applying their findings to a larger population.2 The group that underwent whole exome analysis consisted of 144 Polish and 51 French-Canadian women with breast cancer who were selected based on their early age of diagnosis and/or strong family history. Additionally, all were negative for Polish and French-Canadian founder mutations in BRCA1, BRCA2, CHEK2, NBN, and PALB2. Of interest, whole exome sequencing did reveal nonfounder mutations in some of the individuals of Polish descent. Of the 195 patients analyzed, 2.6% were found to carry a mutation in RECQL. The coding exons of RECQL were then sequenced in a different set of 475 Polish and 475 French Canadians with familial breast cancer who were negative for BRCA1/2 founder mutations; 2 truncating and 12 missense variants were identified. The 2 truncating mutations were each seen twice, and this information prompted a second validation phase where both breast cancer cases and population controls were genotyped for the proposed founder mutation. The 2 mutations again demonstrated an association with breast cancer.
- RECQL appears to be a new breast cancer susceptibility gene.
- Similar to other inherited breast cancer genes, RECQL appears to have a role in homologous recombination.
- The breast cancer risk conferred by mutations in RECQL is not clear. Additional studies are necessary to translate this information into clinical practice.
- Given the constantly evolving landscape of inherited cancer genetics, it is important to periodically reassess at-risk families in whom an underlying genetic cause has not been identified.
1. Banerjee T, Brosh RM Jr. RECQL: a new breast cancer susceptibility gene. Cell Cycle. Published online June 30, 2015.
2. Cybulski C, Carrot-Zhang J, Kluzniak W, et al. Germline RECQL mutations are associated with breast cancer susceptibility. Nat Genet. 2015;47(6):643-646.
3. Sun J, Wang Y, Xia Y, et al. Mutations in RECQL gene are associated with predisposition to breast cancer. PLoS Genetics. 2015;11(5):e1005228.