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Germline mutations in the  PTEN  gene, which cause Cowden syndrome, are known to be one of the genetic factors for primary thyroid and breast cancers; however,  PTEN  mutations are found in only a small subset of research participants with non-syndrome breast and thyroid cancers. In this study, we aimed to identify germline variants that may be related to genetic risk of primary thyroid and breast cancers. Genomic DNAs extracted from peripheral blood of 14  PTEN  WT female research participants with primary thyroid and breast cancers were analyzed by whole-exome sequencing. Gene-based case-control association analysis using the information of 406 Europeans obtained from the 1000 Genomes Project database identified 34 genes possibly associated with the phenotype with  P &lt;1.0×10 −3 . Among them, rare variants in the  PARP4  gene were detected at significant high frequency (odds ratio=5.2;  P =1.0×10 −5 ). The variants, G496V and T1170I, were found in six of the 14 study participants (43%) while their frequencies were only 0.5% in controls. Functional analysis using HCC1143 cell line showed that knockdown of  PARP4  with siRNA significantly enhanced the cell proliferation, compared with the cells transfected with siControl ( P =0.02). Kaplan–Meier analysis using Gene Expression Omnibus (GEO), European Genome-phenome Archive (EGA) and The Cancer Genome Atlas (TCGA) datasets showed poor relapse-free survival ( P &lt;0.001, Hazard ratio 1.27) and overall survival ( P =0.006, Hazard ratio 1.41) in a  PARP4  low-expression group, suggesting that PARP4 may function as a tumor suppressor. In conclusion, we identified  PARP4  as a possible susceptibility gene of primary thyroid and breast cancer.

Germline PARP4 mutations in patients with primary thyroid and breast cancers