Germline alterations in the CDH1 gene in familial gastric cancer in the Japanese population

Abstract

Germline point or small frameshift mutations of the CDH1 (E‐cadherin) gene are known to cause familial gastric cancer (FGC), but the frequency of CDH1 mutations is low in Japanese patients with FGC. Because recent studies have reported germline large genomic deletions of CDH1 in European and Canadian patients with FGC, in the present study we examined DNA samples from 13 Japanese patients with FGC to determine whether similar germline changes were present in CDH1 in this population. Using a sequencing analysis, a 1‐bp deletion (c.1212delC), leading to the production of a truncated protein (p.Asn405IlefsX12), was found in an FGC family; immunohistochemical analysis revealed the loss of CDH1 protein expression in the tumors in this family. Using a combination of multiplex ligation‐dependent probe amplification (MLPA) and RT‐PCR analyses, we also found a large genomic deletion (c.164‐?_387+?del), leading to the loss of exon 3 and the production of a truncated protein (p.Val55GlyfsX38), in another FGC family. The functional effects of the detected mutations were examined using a slow aggregation assay. Significant impairment of cell–cell adhesion was detected in CHO‐K1 cells expressing Ile405fsX12‐ and Gly55fsX38‐type CDH1 compared with cells expressing wild‐type CDH1. Our results suggest that the p.Asn405IlefsX12 and p.Val55GlyfsX38 mutations of the CDH1 gene contribute to carcinogenesis in patients with FGC. This is the first report of CDH1 germline truncating mutations in Japanese patients with FGC. Screening for large germline rearrangements should be included in CDH1 genetic testing for FGC. (Cancer Sci 2011; 102: 1782–1788)

Hereditary diffuse gastric cancer in a Japanese family with a large deletion involving CDH1

“…The IGCLC determined diagnostic criteria for HDGC, but these criteria are likely to be too broad to be used in areas with high GC incidence, including Japan [2,11]. In addition, the prevalence of large deletions, as suggested by the study of Yamada et al [7] and here, might have made detection of the CDH1 mutation difficult.…”

“…On the other hand, the majority of HDGC with CDH1 mutations have been reported in the Western countries. To our knowledge, there have been only two Japanese HDCG families with germline CDH1 mutations reported so far [7]. However, it still remains unclear whether HDCG truly occurs less in Japan than in Western countries.…”

“…In contrast, in East Asian countries, including Japan, Korea, and China, with high incidences of GCs [4], HDGC has rarely been reported [5,6]. Recently, Yamada et al [7] reported two germline alterations in the CDH1 gene in two Japanese familial GCs. However, HDGC is still rarely diagnosed in East Asian countries, and it is still unknown whether HDGC is really rare or overlooked because of the high incidence of coincidental familial GC.…”

Sequence analysis of the E-cadherin (CDH1) gene in a cohort of gastric cancers seen in the western cape

“…These instabilities are commonly identified in certain genes in patients with stomach cancer (Horri et al, 1992;Richards et al, 1999;Yamada et al, 2011).…”

“…Patients who do not present with germline mutations are further analysed for large genomic deletions. These deletions have therefore been implicated as another possible contributing factor towards the pathogenesis of gastric cancer amongst the E-cadherin germline negative individuals (Oliveira et al, 2009;Pinheiro et al, 2010;Yamada et al 2011). It would therefore be interesting to explore the CDH1 large genomic deletions for future research.…”