Low frequency of germline E-cadherin mutations in familial and nonfamilial gastric cancer

Abstract

SummaryLittle is known about the relative contributions of genetic and environmental factors to the development of gastric cancer. Mutations in the cell adhesion molecule E-cadherin are recognized to be associated with the development of undifferentiated, diffuse and invasive gastric cancers. A recent study of two gastric cancer families has shown that germline mutations in the E-cadherin gene can be causative (Guilford P et al, Nature 1998; 26: 402-405). We have examined the E-cadherin gene for constitutive mutations in a systematic series of 106 gastric cancer patients, 10 with a family history of the disease and 96 sporadic cases. No pathogenic mutations were observed in any of the 106 patients. The results indicate that germline mutations in E-cadherin will not account for more than 3% of gastric cancers. Keywords: gastric cancer; germline; E-cadherin mutations 1935British Journal of Cancer (1999) 79(11/12), 1935-1937© 1999 Cancer Research Campaign Article no. bjoc.1998 Received Family histories were obtained from all patients and 10 reported a history of gastric cancer in at least one relative. Details of these familial cases are shown in Table 3. None of the cases studied had family histories indicative of either hereditary nonpolyposis colon cancer (HNPCC) or breast-ovarian cancer syndromes. We have screened the full coding sequence and splice junctions of E-cadherin for germline mutations in these 10 familial and 96 sporadic gastric cancer patients. No clearly disease-causing mutations in the E-cadherin gene were identified in any of the 106 patients screened. Five variants were detected (Table 4). The two variants in exons 13 and 14 have been previously reported (Risinger et al, 1994;Berx et al, 1995). The polymorphism in exon 13 was a synonymous C-T substitution at position 3 of codon 692 encoding alanine, and the polymorphism in exon 14 was a synonymous C-T substitution at position 3 of codon 751 encoding aspartine. The other three variants detected were in the 5′ untranslated region of exon 1 and have not been reported previously. It is conceivable, but not likely, because none had a family history of cancer, that the mutations we detected in the 5′ untranslated region of the gene might be pathogenic by affecting the expression of Ecadherin either directly or through linkage disequilibrium with other mutations affecting promotor function.The results suggest that germline mutations in E-cadherin are rare in gastric cancer patients. We cannot exclude the possibility that a minority of mutations have been missed, but under test conditions we have found that CSGE can detect all small insertions or deletions and 90% of single base substitutions, and the technique detected a number of single base substitution polymorphisms within the gene. Based on the number of gastric cancer patients we have screened for constitutive mutations we can conclude with 95% probability that germline variation in Ecadherin will not account for more than 3% of all gastric cancers in the British population.The recent report demo...

Germline mutations in E‐cadherin do not explain association of hereditary prostate cancer, gastric cancer and breast cancer

“…Several groups have reported germline mutations in families with early onset diffuse gastric cancer. [12][13][14][15][16][17] Individuals in hereditary diffuse gastric cancer (HDGC) families have consistently demonstrated absence of loss of heterozygosity at the CDH1 locus. 13,14,16 Recently, it was shown in 2 kindreds with HDGC that they either had the promoter methylated or that they had rendered a somatic mutation in the retained wild-type allele.…”

Hereditary diffuse gastric cancer

“…6 It is estimated that cases of HDGC comprise 1% to 3% of all gastric cancers. 8,9 E-cadherin Gene Mutations in HDGC A breakthrough in understanding HDGC occurred in 1998, when inactivating germline mutations in the Ecadherin gene CDH1 were identified in 3 Maori families with multiple cases of DGC. 10 The CDH1 mutations in these families were inherited in an autosomal-dominant pattern with incomplete but high penetrance.…”

Hereditary diffuse gastric cancer (HDGC)

“…HDGC forms less than 3% of all gastric cancers (Stone et al, 1999). It often affects younger people in contrast to the other types of gastric cancer.…”