Germline CDH1 mutations are a significant contributor to the high frequency of early-onset diffuse gastric cancer cases in New Zealand Māori

Abstract

New Zealand Māori have a considerably higher incidence of gastric cancer compared to non-Māori, and are one of the few populations worldwide with a higher prevalence of diffuse-type disease. Pathogenic germline CDH1 mutations are causative of hereditary diffuse gastric cancer, a cancer predisposition syndrome primarily characterised by an extreme lifetime risk of developing diffuse gastric cancer. Pathogenic CDH1 mutations are well described in Māori families in New Zealand. However, the contribution of these mutations to the high incidence of gastric cancer is unknown. We have used next-generation sequencing, Sanger sequencing, and Multiplex Ligation-dependent Probe Amplification to examine germline CDH1 in an unselected series of 94 Māori gastric cancer patients and 200 healthy matched controls. Overall, 18% of all cases, 34% of cases diagnosed with diffuse-type gastric cancer, and 67% of cases diagnosed aged less than 45 years carried pathogenic CDH1 mutations. After adjusting for the effect of screening known HDGC families, we estimate that 6% of all advanced gastric cancers and 13% of all advanced diffuse-type gastric cancers would carry germline CDH1 mutations. Our results demonstrate that germline CDH1 mutations are a significant contributor to the high frequency of diffuse gastric cancer in New Zealand Māori.

An integrated classifier improves prognostic accuracy in non-metastatic gastric cancer

“…It has also been reported as a susceptible gene in hereditary diffuse GC. [28][29][30][31][32] The other validated immune classifier genes were CD3, CD4, CD274, GZMB, and PAX5. Tumor-infiltrating immune cells have diverse effects on tumor progression depending on the cancer type.…”

Diffuse Gastric Cancer: A Summary of Analogous Contributing Factors for Its Molecular Pathogenicity

“…In 1998, Guilford et al found multiple cases of early-onset DGC in Maori ethnic peoples of New Zealand that were carriers of a three germline truncating mutation in the E-cadherin ( CDH1 ) gene [23]. Several other publications emerged confirming the association of autosomal-dominant pattern of inheritance with germline mutations of the CDH1 gene in the following years [26,71,90,107,140,141,142,143,144,145]. Sporadic DGC has shown germline mutations for CDH1 in a hot spot region between exons 7 and 9, whereas genetic alterations scattered over the entire gene length have been observed for HDGC [146].…”

Hereditary gastric cancer. Indications of genetic study. When and to whom?

“…En Japón y Corea, países con altas tasas de incidencia de CG, incluso mayores que nuestro país, el CG hereditario y sus alteraciones genéticas presentan una baja frecuencia. La mayoría de las familias descritas provienen de países europeos, norteamérica y Nueva Zelandia [7][8][9][10] . No existen datos nacionales a gran escala sobre la frecuencia del CG hereditario.…”