Germline PARP4 mutations in patients with primary thyroid and breast cancers

Abstract

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 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-wild-type 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<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. 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 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.

Comparison of algorithms for the detection of cancer drivers at subgene resolution

“…3). Recent reports suggest that germline mutations in PARP4 might increase the risk to thyroid cancer and breast adenocarcinoma 40 , thus we believe that this gene could play an important role in this type of cancer.…”

Protein Synthesis by Day 16 Bovine Conceptuses during the Time of Maternal Recognition of Pregnancy

“…This is a similar signaling pathway that can be activated by a Type I interferon, and conceptus-derived MERTK may play a role in enhancing IFN-mediated signaling in the endometrium. The absence of PARP4, or the downregulation of its coding gene, is related to cancer [46][47][48]. This gene family is related to apoptosis [49] and a potential role for this in Day 16 conceptuses could be regulating cell proliferation.…”

Intratumoral Genetic and Functional Heterogeneity in Pediatric Glioblastoma

“…1G). Among these genes, RASAL2 encodes a RasGAP and is a tumor suppressor (21); PARP4 encodes a member of the poly (ADP)-ribose family and was recently shown to be mutated in the germlines of patients with thyroid and breast cancer (22); HUWE1 encodes an E3 ubiquitin ligase that was shown to be a tumor suppressor in mouse models of skin cancer (23) and colorectal cancer (24). Similarly, we called 4 de novo nsSNVs in the germline of patient 3 (Fig.…”