AI Article Synopsis
- The study investigates genetic factors linked to hereditary breast cancer (BC) beyond the known predisposing genes, as these only account for less than half of the cases.
- Whole exome sequencing was conducted on 49 Russian patients with a clinical history of genetic BC to identify candidate mutations, leading to a list of 229 possible mutations, with further analysis suggesting 6 mutations may increase BC risk.
- The findings highlight a rare splicing variant in the USP39 gene as potentially significant for BC susceptibility, particularly associated with triple-negative breast tumors, prompting the need for additional research into these genetic variants.
Article Abstract
Purpose: Germline variants in known breast cancer (BC) predisposing genes explain less than half of hereditary BC cases. This study aimed to identify missing genetic determinants of BC.
Methods: Whole exome sequencing (WES) of lymphocyte DNA was performed for 49 Russian patients with clinical signs of genetic BC predisposition, who lacked Slavic founder mutations in BRCA1, BRCA2, CHEK2, and NBS1 genes.
Results: Bioinformatic analysis of WES data was allowed to compile a list of 229 candidate mutations. 79 of these mutations were subjected to a three-stage case-control analysis. The initial two stages, which involved up to 797 high-risk BC patients, 1504 consecutive BC cases, and 1081 healthy women, indicated a potentially BC-predisposing role for 6 candidates, i.e., USP39 c.*208G > C, PZP p.Arg680Ter, LEPREL1 p.Pro636Ser, SLIT3 p.Arg154Cys, CREB3 p.Lys157Glu, and ING1 p.Pro319Leu. USP39 c.*208G > C was strongly associated with triple-negative breast tumors (p = 0.0001). In the third replication stage, we genotyped the truncating variant of PZP (rs145240281) and the potential splice variant of USP39 (rs112653307) in three independent cohorts of Russian, Byelorussian, and German ancestry, comprising a total of 3216 cases and 2525 controls. The data obtained for USP39 rs112653307 supported the association identified in the initial stages (the combined OR 1.72, p = 0.035).
Conclusions: This study suggests the role of a rare splicing variant in BC susceptibility. USP39 encodes an ubiquitin-specific peptidase that regulates cancer-relevant tumor suppressors including CHEK2. Further epidemiological and functional studies involving these gene variants are warranted.
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| http://dx.doi.org/10.1007/s10549-019-05492-6 | DOI Listing |
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