Germline PARP4 mutations in patients with primary thyroid and breast cancers
- 23 December 2015
- journal article
- research article
- Published by Bioscientifica in Endocrine-Related Cancer
- Vol. 23 (3), 171-179
- https://doi.org/10.1530/erc-15-0359
Abstract
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−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 (PP=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. Abstract 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−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 (PP=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.Keywords
This publication has 30 references indexed in Scilit:
- Comprehensive molecular portraits of human breast tumoursNature, 2012
- A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEffFly, 2012
- Incidence and Clinical Characteristics of Thyroid Cancer in Prospective Series of Individuals with Cowden and Cowden-Like Syndrome Characterized by Germline PTEN, SDH, or KLLN AlterationsJournal of Clinical Endocrinology & Metabolism, 2011
- A Clinical Scoring System for Selection of Patients for PTEN Mutation Testing Is Proposed on the Basis of a Prospective Study of 3042 ProbandsAmerican Journal of Human Genetics, 2011
- Critical Roles of Mucin 1 Glycosylation by Transactivated Polypeptide N-Acetylgalactosaminyltransferase 6 in Mammary CarcinogenesisCancer Research, 2010
- An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patientsBreast Cancer Research and Treatment, 2009
- The Sequence Alignment/Map format and SAMtoolsBioinformatics, 2009
- Fast and accurate short read alignment with Burrows–Wheeler transformBioinformatics, 2009
- Hereditary ovarian carcinoma: Heterogeneity, molecular genetics, pathology, and managementMolecular Oncology, 2009
- Germline Mutations and Variants in the Succinate Dehydrogenase Genes in Cowden and Cowden-like SyndromesAmerican Journal of Human Genetics, 2008