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J Med Genet. 2018 Oct;55(10):669-674. doi: 10.1136/jmedgenet-2017-104962. Epub 2018 Jan 12.

Role of germline aberrations affecting CTNNA1, MAP3K6 and MYD88 in gastric cancer susceptibility.

Author information

1
Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.
2
Department of Pathology, Radboud university medical center, Nijmegen, The Netherlands.
3
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
4
Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.
5
Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
6
Expression Regulation in Cancer Group, Instituto de Investigação e Inovação em Saúde, Porto, Portugal.
7
Department of Cancer Genetics, Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal.
8
Department of Pathology and Oncology, Faculty of Medicine, University of Porto, Porto, Portugal.
9
Department of Surgical Research, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
10
Department of Biology and Biotechnology, University of Pavia, Pavia, Italy.
11
Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.
12
Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
13
Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.
14
Institute of Genomic Medicine, Catholic University of the Sacred Heart, Milan, Italy.
15
Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
16
Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
17
Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
18
Family Cancer Clinic, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
19
Department of Gastrointestinal Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek, Amsterdam, The Netherlands.
20
Department of Medical Genetics, St Olav's Hospital, Trondheim, Norway.
#
Contributed equally

Abstract

BACKGROUND:

In approximately 10% of all gastric cancer (GC) cases, a heritable cause is suspected. A subset of these cases have a causative germline CDH1 mutation; however, in most cases the cause remains unknown. Our objective was to assess to what extent these remaining cases may be explained by germline mutations in the novel candidate GC predisposing genes CTNNA1, MAP3K6 or MYD88.

METHODS:

We sequenced a large cohort of unexplained young and/or familial patients with GC (n=286) without a CDH1germline mutation for germline variants affecting CTNNA1, MAP3K6 and MYD88 using a targeted next-generation sequencing approach based on single-molecule molecular inversion probes.

RESULTS:

Predicted deleterious germline variants were not encountered in MYD88, but recurrently observed in CTNNA1 (n=2) and MAP3K6 (n=3) in our cohort of patients with GC. In contrast to deleterious variants in CTNNA1, deleterious variants in MAP3K6 also occur frequently in the general population.

CONCLUSIONS:

Based on our results MAP3K6 should no longer be considered a GC predisposition gene, whereas deleterious CTNNA1 variants are confirmed as an infrequent cause of GC susceptibility. Biallelic MYD88 germline mutations are at most a very rare cause of GC susceptibility as no additional cases were identified.

KEYWORDS:

cancer: gastric; ctnna1 – map3k6 – myd88; heritability; next generation sequencing

PMID:
29330337
PMCID:
PMC6161648
DOI:
10.1136/jmedgenet-2017-104962
[Indexed for MEDLINE]
Free PMC Article

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