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MAP3K6 – Gastric Cancer

Germline sequencing in a CDH1-negative kindred with familial gastric cancer identified a MAP3K6 variant p.Pro946Leu, and screening of 115 additional CDH1-negative familial cases uncovered five further MAP3K6 coding variants, with a somatic second-hit c.1516C>T (p.His506Tyr) in one tumor (PMID:25340522). Kinome deep sequencing of 14 gastric cancer cell lines and primary tumors revealed recurrent somatic MAP3K6 alterations, supporting a tumor suppressor role in gastric epithelium (PMID:21097718). However, targeted sequencing of 286 CDH1-negative hereditary or early-onset gastric cancer patients found MAP3K6 variants at population frequencies, leading to the conclusion that MAP3K6 is unlikely a gastric cancer predisposition gene (PMID:29330337).

Key Take-home: Current data dispute the clinical utility of MAP3K6 in gastric cancer predisposition testing.

References

  • PLoS genetics • 2014 • Germline mutations in MAP3K6 are associated with familial gastric cancer. PMID:25340522
  • Cancer research • 2011 • Genetic and structural variation in the gastric cancer kinome revealed through targeted deep sequencing. PMID:21097718
  • Journal of medical genetics • 2018 • Role of germline aberrations affecting CTNNA1, MAP3K6 and MYD88 in gastric cancer susceptibility. PMID:29330337

Evidence Based Scoring (AI generated)

Gene–Disease Association

Disputed

Initial familial and somatic evidence offset by lack of enrichment in a large replication cohort ([PMID:29330337]).

Genetic Evidence

Limited

Single pedigree segregation with additional 5 variants in 115 cases but no significant case enrichment in 286 patients.

Functional Evidence

Limited

Somatic mutation recurrence and mouse model support tumor suppressor role but no direct germline pathogenic mechanism demonstrated.