Assessment of SLX4 Mutations in Hereditary Breast Cancers
Sohela Shah1, Yonghwan Kim, Irina Ostrovnaya
1Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
Background:
SLX4 encodes a DNA repair protein that regulates three structure-specific endonucleases and is necessary for resistance to DNA crosslinking agents, topoisomerase I and poly (ADP-ribose) polymerase (PARP) inhibitors. Recent studies have reported mutations in SLX4 in a new subtype of Fanconi anemia (FA), FA-P. Monoallelic defects in several FA genes are known to confer susceptibility to breast and ovarian cancers.
Methods And Results:
To determine if SLX4 is involved in breast cancer susceptibility, we sequenced the entire SLX4 coding region in 738 (270 Jewish and 468 non-Jewish) breast cancer patients with 2 or more family members affected by breast cancer and no known BRCA1 or BRCA2 mutations. We found a novel nonsense (c.2469G>A, p.W823*) mutation in one patient. In addition, we also found 51 missense variants [13 novel, 23 rare (MAF<0.1%), and 15 common (MAF>1%)], of which 22 (5 novel and 17 rare) were predicted to be damaging by Polyphen2 (score = 0.65-1). We performed functional complementation studies using p.W823* and 5 SLX4 variants (4 novel and 1 rare) cDNAs in a human SLX4-null fibroblast cell line, RA3331. While wild type SLX4 and all the other variants fully rescued the sensitivity to mitomycin C (MMC), campthothecin (CPT), and PARP inhibitor (Olaparib) the p.W823* SLX4 mutant failed to do so.
Conclusion:
Loss-of-function mutations in SLX4 may contribute to the development of breast cancer in very rare cases.
Insights
Loss-of-function mutations in the SLX4 gene, crucial for DNA repair, may rarely contribute to breast cancer development. This study investigated SLX4 in familial breast cancer cases, finding a novel mutation that impaired DNA repair function.
Area of Science:
- Genetics
- Molecular Biology
- Cancer Research
Background:
- SLX4 is a DNA repair protein essential for resistance to DNA crosslinking agents, topoisomerase I, and PARP inhibitors.
- Mutations in SLX4 have been identified in Fanconi anemia (FA), a disorder linked to increased cancer susceptibility.
- Defects in FA genes are known to increase the risk of breast and ovarian cancers.
Purpose of the Study:
- To investigate the potential role of SLX4 in breast cancer susceptibility.
- To identify mutations in the SLX4 gene in patients with a strong family history of breast cancer and no BRCA1/2 mutations.
Main Methods:
- Sequencing of the entire SLX4 coding region in 738 breast cancer patients.
- Identification and characterization of SLX4 variants, including novel and rare mutations.
- Functional complementation studies using a SLX4-null fibroblast cell line to assess the impact of mutations on DNA repair pathways.
Main Results:
- A novel nonsense mutation (p.W823*) in SLX4 was identified in one breast cancer patient.
- Fifty-one missense variants were found, with 22 predicted to be damaging.
- The p.W823* SLX4 mutant failed to rescue sensitivity to DNA damaging agents (MMC, CPT) and a PARP inhibitor (Olaparib) in a cellular model, unlike wild-type SLX4 and other variants.
Conclusions:
- Loss-of-function mutations in SLX4 are implicated in rare cases of breast cancer development.
- The identified SLX4 mutation impairs DNA repair mechanisms, highlighting its role in genomic stability and cancer prevention.
