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.
Highlights
The worldwide incidence of gastric cancer has declined steadily over the past 4–5 decades, it remains the 5th most common cancer type worldwide [1]
Germline CDH1 was sequenced for 94 Māori gastric cancer patients and 200 healthy matched controls
Personal communication) and using a lifetime penetrance estimate of 70%, we estimate that in the absence of familial Hereditary Diffuse Gastric Cancer (HDGC) screening, germline CDH1 mutations would account for 6% of all advanced Māori gastric cancers and 13% of all diffuse-type gastric cancers. This is the first study that has examined the frequency of gastric cancers that are attributable to germline CDH1 mutations in a specific ethnic group
Summary
The worldwide incidence of gastric cancer has declined steadily over the past 4–5 decades, it remains the 5th most common cancer type worldwide [1]. The vast majority of gastric cancers are adenocarcinomas, which can be further subdivided into intestinal and diffuse type according to the Lauren classification [2]. Intestinal-type tumours predominate high-incidence geographic areas and account for much of the variation in gastric cancer incidence between groups [3]. New Zealand is a country with a low incidence of gastric cancer [1]. Māori, the indigenous people of New Zealand (who comprise almost 15% of the total 4.5 million population) [4], experience disproportionate rates of gastric cancer compared to non-Māori [5].
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