Germline Mutations in MAP3K6 Are Associated with Familial Gastric Cancer

Autores e Afiliações:

Daniel Gaston¹*, Samantha Hansford²*, Carla Oliveira³, Mathew Nightingale¹, Hugo Pinheiro³, Christine Macgillivray⁴, Pardeep Kaurah², Andrea L. Rideout⁵, Patricia Steele⁵, Gabriela Soares⁶, Weei-Yuarn Huang⁷, Scott Whitehouse¹, Sarah Blowers⁸, Marissa A. LeBlanc¹, Haiyan Jiang⁹, Wenda Greer¹, Mark E. Samuels¹,¹⁰, Andrew Orr¹,⁴, Conrad V. Fernandez¹¹, Jacek Majewski¹², Mark Ludman⁵,¹³, Sarah Dyack5,¹¹, Lynette S. Penney⁵,¹¹, Christopher R. McMaster¹⁴, David Huntsman², Karen Bedard¹

¹ Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada,

² Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada,

³ Expression Regulation in Cancer Group, IPATIMUP, Institute of Molecular Pathology and Immunology of the University of Porto & Medical Faculty of the University of Porto, Porto, Portugal,

⁴ Department of Ophthalmology and Visual Sciences, Dalhousie University, Halifax, Nova Scotia, Canada,

⁵ Medical Genetics, IWK Health Centre, Halifax, Nova Scotia, Canada,

⁶ Center of Medical Genetics Jacinto de Magalhães, Porto Hospital Center, Porto, Portugal,

⁷ Division of Anatomical Pathology, Department of Pathology, Queen Elizabeth II Health Science Center and Dalhousie University, Halifax, Nova Scotia, Canada,

⁸ Queen’s Family Health Team, Kingston, Ontario, Canada,

⁹ Department of Biostatistics, Princess Margaret Cancer Centre, Toronto, Ontario, Canada,

¹⁰ Centre de Recherche du CHU Ste-Justine and Department of Medicine, University of Montreal, Montreal, Quebec, Canada,

¹¹ Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada,

¹² Department of Human Genetics, McGill University, Montreal, Que´bec, Canada,

¹³ Oncogenetics Service, Institute of Medical Genetics, Meir Medical Center, Kfar Saba, Israel,

¹⁴ Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada

* These authors contributed equally to this work.

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.

Revista: Plos Genetics

Link: http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1004669