Ikeda Yuji, Kiyotani Kazuma, Yew Poh Yin, Kato Taigo, Tamura Kenji, Yap Kai Lee, Nielsen Sarah M, Mester Jessica L, Eng Charis, Nakamura Yusuke, Grogan Raymon H
Section of Hematology/OncologyDepartment of Medicine, The University of Chicago, Chicago, Illinois 60637, USAGenomic Medicine InstituteCleveland Clinic, Cleveland, Ohio 44195, USADepartment of Genetics and Genome SciencesComprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USAEndocrine Surgery Research ProgramSection of General Surgery, Department of Surgery, The University of Chicago, 5841 S Maryland Avenue, Chicago, Illinois 60637, USA.
Section of Hematology/OncologyDepartment of Medicine, The University of Chicago, Chicago, Illinois 60637, USAGenomic Medicine InstituteCleveland Clinic, Cleveland, Ohio 44195, USADepartment of Genetics and Genome SciencesComprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USAEndocrine Surgery Research ProgramSection of General Surgery, Department of Surgery, The University of Chicago, 5841 S Maryland Avenue, Chicago, Illinois 60637, USA Section of Hematology/OncologyDepartment of Medicine, The University of Chicago, Chicago, Illinois 60637, USAGenomic Medicine InstituteCleveland Clinic, Cleveland, Ohio 44195, USADepartment of Genetics and Genome SciencesComprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USAEndocrine Surgery Research ProgramSection of General Surgery, Department of Surgery, The University of Chicago, 5841 S Maryland Avenue, Chicago, Illinois 60637, USA.
Endocr Relat Cancer. 2016 Mar;23(3):171-9. doi: 10.1530/ERC-15-0359. Epub 2015 Dec 23.
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 < 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 < 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.
已知导致考登综合征的PTEN基因种系突变是原发性甲状腺癌和乳腺癌的遗传因素之一；然而，仅在一小部分非综合征性乳腺癌和甲状腺癌研究参与者中发现了PTEN突变。在本研究中，我们旨在鉴定可能与原发性甲状腺癌和乳腺癌遗传风险相关的种系变异。通过全外显子测序分析了从14名患有原发性甲状腺癌和乳腺癌的PTEN野生型女性研究参与者外周血中提取的基因组DNA。利用从千人基因组计划数据库获得的406名欧洲人的信息进行基于基因的病例对照关联分析，确定了34个可能与该表型相关的基因，P<1.0×10^(-3)。其中，PARP4基因中的罕见变异以显著高频率被检测到（优势比=5.2；P=1.0×10^(-5)）。在14名研究参与者中有6名（43%）发现了G496V和T1170I变异，而其在对照组中的频率仅为0.5%。使用HCC1143细胞系进行的功能分析表明，与转染siControl的细胞相比，用siRNA敲低PARP4可显著增强细胞增殖（P=0.02）。使用基因表达综合数据库（GEO）、欧洲基因组-表型档案库（EGA）和癌症基因组图谱（TCGA）数据集进行的Kaplan-Meier分析显示，PARP4低表达组的无复发生存期较差（P<0.001，风险比1.27）和总生存期较差（P=0.006，风险比1.41），表明PARP4可能作为一种肿瘤抑制因子发挥作用。总之，我们确定PARP4是原发性甲状腺癌和乳腺癌的一个可能的易感基因。
