RECQL and Breast Cancer Risk

TON September 2015 Vol 8 No 5 - Genetic Counseling
Cristi Radford, MS, CGC

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.

Take-Home Messages:

  • 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.

References
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.

Related Items
Addressing the Needs of Previvors Struggling to Access Screening and Recommended Interventions
Cristi Radford, MS, CGC, Lisa Schlager
TON - September 2018, Vol 11, No 4 published on September 19, 2018 in Genetic Counseling
Variants of Uncertain Significance—Frequently Asked Questions
Cristi Radford, MS, CGC, Michele Gabree, MS, CGC
TON - July 2018, Vol 11, No 3 published on July 25, 2018 in Genetic Counseling
New Criteria for Inherited Prostate Cancer Genetic Testing
Cristi Radford, MS, CGC
TON - March 2018, Vol 11, No 1 published on March 9, 2018 in Genetic Counseling, NCCN Updates
Is It Time to Reevaluate Universal Screening Strategies for Lynch Syndrome in Patients Newly Diagnosed with Colorectal Cancer?
Cristi Radford, MS, CGC, Nicole Centers, BSN, RN, OCN, CBCN, CN-BN
TON - September 2017, Vol 10, No 5 published on September 10, 2017 in Genetic Counseling
Survivorship Clinics—A Second Opportunity for Genetic Risk Stratification
Cristi Radford, MS, CGC, Nicole Centers, BSN, RN, OCN, CBCN, CN-BN
TON - July 2017, Vol 10, No 4 published on July 6, 2017 in Genetic Counseling
Therapeutic Implications—The Next Era of Genetic Diagnosis
Cristi Radford, MS, CGC
TON - May 2017, Vol 10, No 3 published on May 17, 2017 in Genetic Counseling
New Data Suggest the Benefit of Multigene Panel Testing for Patients with Early-Onset Colorectal Cancer
Cristi Radford, MS, CGC
TON - March 2017, Vol 10, No 2 published on March 7, 2017 in Genetic Counseling
Is It Time to Reconsider Testing Adolescents for Familial BRCA Mutations?
Courtney Lewis, MS, CGC , Cristi Radford, MS, CGC
TON - January 2017, Vol 10, No 1 published on January 12, 2017 in Genetic Counseling
Risk and Management Updates for Inherited Colorectal Cancer
Courtney Lewis, MS, CGC , Cristi Radford, MS, CGC
TON - November 2016, Vol 9, No 6 published on November 15, 2016 in Genetic Counseling
Increased Risk for Serous/Serous-like Endometrial Cancer Found in BRCA1 Carriers
Cristi Radford, MS, CGC
TON - September 2016, Vol 9, No 5 published on September 4, 2016 in Genetic Counseling
Last modified: September 24, 2015