首页 | 本学科首页   官方微博 | 高级检索  
   检索      


Germline Mutations in MAP3K6 Are Associated with Familial Gastric Cancer
Authors:Daniel Gaston  Samantha Hansford  Carla Oliveira  Mathew Nightingale  Hugo Pinheiro  Christine Macgillivray  Pardeep Kaurah  Andrea L Rideout  Patricia Steele  Gabriela Soares  Weei-Yuarn Huang  Scott Whitehouse  Sarah Blowers  Marissa A LeBlanc  Haiyan Jiang  Wenda Greer  Mark E Samuels  Andrew Orr  Conrad V Fernandez  Jacek Majewski  Mark Ludman  Sarah Dyack  Lynette S Penney  Christopher R McMaster  David Huntsman  Karen Bedard
Abstract:Gastric cancer is among the leading causes of cancer-related deaths worldwide. While heritable forms of gastric cancer are relatively rare, identifying the genes responsible for such cases can inform diagnosis and treatment for both hereditary and sporadic cases of gastric cancer. Mutations in the E-cadherin gene, CDH1, account for 40% of the most common form of familial gastric cancer (FGC), hereditary diffuse gastric cancer (HDGC). The genes responsible for the remaining forms of FGC are currently unknown. Here we examined a large family from Maritime Canada with FGC without CDH1 mutations, and identified a germline coding variant (p.P946L) in mitogen-activated protein kinase kinase kinase 6 (MAP3K6). Based on conservation, predicted pathogenicity and a known role of the gene in cancer predisposition, MAP3K6 was considered a strong candidate and was investigated further. Screening of an additional 115 unrelated individuals with non-CDH1 FGC identified the p.P946L MAP3K6 variant, as well as four additional coding variants in MAP3K6 (p.F849Sfs*142, p.P958T, p.D200Y and p.V207G). A somatic second-hit variant (p.H506Y) was present in DNA obtained from one of the tumor specimens, and evidence of DNA hypermethylation within the MAP3K6 gene was observed in DNA from the tumor of another affected individual. These findings, together with previous evidence from mouse models that MAP3K6 acts as a tumor suppressor, and studies showing the presence of somatic mutations in MAP3K6 in non-hereditary gastric cancers and gastric cancer cell lines, point towards MAP3K6 variants as a predisposing factor for FGC.
Keywords:
设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司  京ICP备09084417号