Abstract 3480: Germline PARP4 mutations in patients with primary thyroid and breast cancers

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Abstract Breast and thyroid cancers occur more frequently in the same individual than what is expected due to random occurrence, implying the presence of genetic susceptible factors. Germline mutations in the PTEN gene, which cause Cowden syndrome (CS), 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 attempted to identify germline variants that may be related to genetic risk of primary thyroid and breast cancers by whole-exome sequencing. Genomic DNAs extracted from peripheral blood of 14 PTEN-wild-type female research participants with primary thyroid and breast cancers were analyzed. Among them, 7 (50%) and 5 (36%) participants had a family history of thyroid or breast cancer within 3 generations of the proband, respectively. No rare variants were found in SDHx/KLLN/PIK3CA/AKT1 genes previously known to be responsible for CS. We then performed a case-control association study using the information of 406 Europeans obtained from the 1000 Genomes Project database as controls. The predicted impact of amino acid substitutions was annotated using 5 algorithms of LRT score, MutationTaster, PolyPhen-2, HumDiv, PolyPhen-2 HumVar and SIFT. Gene-based association analysis identified 34 genes, including DNA repair-related genes, possibly associated with the phenotype with P<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 6 of the 14 study participants (43%) while their frequencies were only 0.5% in controls. We subsequently performed functional analysis using HCC1143 cell line which showed the highest expression of PARP4 among 18 breast cancer cell lines examined, and found that knockdown of PARP4 with siRNA significantly enhanced the cell proliferation, compared with the cells transfected with siControl (P = 0.02). In addition, Kaplan-Meier analysis using GEO, EGA and TCGA datasets showed poor progression-free survival (P = 0.006, Hazard ratio 0.71) and overall survival (P < 0.0001, Hazard ratio 0.79) in a PARP4 low-expression group, suggesting that PARP4 may function as a tumor suppression. In conclusion, we identified PARP4 as a possible susceptibility gene of primary thyroid and breast cancer. Citation Format: Yuji Ikeda, Kazuma Kiyotani, Poh Yin Yew, Taigo Kato, Kenji Tamura, Kai Lee Yap, Jessica L. Mester, Sarah H. Nielsen, Grogan H. Raymon, Charis Eng, Yusuke Nakamura. Germline PARP4 mutations in patients with primary thyroid and breast cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3480.

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