Assessment of PARP4 as a candidate breast cancer susceptibility gene.

has been proposed as a candidate breast cancer susceptibility gene. However, its function and involvement in breast carcinogenesis is unclear. We sought to determine the variant frequency of in BRCA-negative women referred for genetic testing from Singapore and to perform functional analyses of sequencing of Pduanyu374 was conducted for 198 BRCA-negative cases from Singapore. Three independent case-control association analyses of Pduanyu374 were performed for (1) our Singaporean cohort, (2) three dbGaP datasets, and (3) cases from TCGA, with controls from the Exome Aggregation Consortium (ExAC). Pduanyu374 knockout cells were generated utilizing the CRISPR-Cas9 approach in MDA-MB-231 (breast cancer) and MCF10A (normal breast) cell lines, and colony formation, cell proliferation, and migration assays carried out. RESULTS:Candidate variants in Pduanyu374 were identified in 5.5% (11/198) of our Singapore cohort. Case-control association studies for our cases and the dbGaP datasets showed no significant association. However, a significant association was observed for Pduanyu374 variants when comparing 988 breast cancer cases from the TCGA provisional data and 53,105 controls from ExAC (ALL) (OR 0.249, 95% CI 0.139-0.414, P = 2.86 × 10^-11). Pduanyu374 knockout did not affect the clonogenicity, proliferation rate, and migration of normal breast cells, but appeared to decrease the proliferation rate and clonogenicity of breast cancer cells. CONCLUSIONS:Taken together, our results do not support that Pduanyu374 functions as a cancer susceptibility gene. This study highlights the importance of performing functional analyses for candidate cancer predisposition genes.

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