A strong HLA association is seen in coeliac disease [specifically to the DQ(alpha1*0501,beta1*0201 heterodimer], but this cannot entirely account for the increased risk seen in relatives of affected cases. One or more genes at HLA-unlinked loci also predispose to coeliac disease and are probably stronger determinants of disease susceptibility than HLA. A recent study has proposed a number of candidate regions on chromosomes 6p23 (distinct from HLA), 6p12, 3q27, 5q33.3, 7q31.3, 11p11, 15q26, 19p13.3, 19q13.1, 19q13.4 and 22cen for the location of a non-HLA linked susceptibility gene. We have examined these regions in 28 coeliac disease families by linkage analysis. There was excess sharing of chromosome 6p markers, but no support for a predisposition locus telomeric to HLA. No significant evidence in favour of linkage to coeliac disease was obtained for chromosomes 3q27, 5q33.3, 7q31.3, 11p11, 19p13.3, 19q13.1, 19q13.4 or 22cen. There was, however, excess sharing close to D15S642. The maximum non-parametric linkage score was 1.99 (P = 0.03). Although the evidence for linkage of coeliac disease to chromosome 15q26 is not strong, the well established association between coeliac disease and insulin dependent diabetes mellitus, together with the mapping of an IDDM susceptibility locus (IDDM3) to chromosome 15q26, provide indirect support for this as a candidate locus conferring susceptibility to coeliac disease in some families.

B-cell chronic lymphocytic leukaemia (CLL) is the most common form of leukaemia. To gain insight into the role of inherited factors in the disease, we have conducted a survey of the family histories of 268 CLL patients and have reviewed published familial cases and epidemiological studies. The results of our survey and published studies strongly support the hypothesis that a subset of the disease can be ascribed to a genetic predisposition. The most likely genetic model for inherited predisposition appears to be dominantly acting genes with pleiotropic effects because in many families CLL appears to be associated with other lymphoproliferative disorders.

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...

Lobular carcinoma in situ (LCIS) is an unusual histological pattern of non-invasive neoplastic disease of the breast occurring predominantly in women aged between 40 and 50 years. LCIS is frequently multicentric and bilateral, and there is evidence that it is associated with an elevated familial risk of breast cancer. Although women with LCIS suffer an increased risk of invasive breast disease, this risk is moderate suggesting that LCIS may result from mutation of a gene or genes conferring a high risk of LCIS, but a lower risk of invasive breast cancer. The high frequency of somatic mutations in E-cadherin in LCIS, coupled with recent reports that germline mutations in this gene can predispose to diffuse gastric cancer, raised the possibility that constitutional E-cadherin mutations may confer susceptibility to LCIS. In order to explore this possibility we have examined a series of 65 LCIS patients for germline E-cadherin mutations. Four polymorphisms were detected but no pathogenic mutations were identified. The results indicate that E-cadherin is unlikely to act as a susceptibility gene for LCIS. © 2000 Cancer Research Campaign

14Mater Misericordiae Hospitals, South Brisbane, Australia B cell chronic lymphocytic leukaemia (CLL) shows evidence of familial aggregation, but the inherited basis is poorly understood. Mutations in the ATM gene have been demonstrated in CLL. This, coupled with a possibly increased risk of leukaemia in relatives of patients with Ataxia Telangiectasia, led us to question whether the ATM gene is involved in familial cases of CLL. To examine this proposition we typed five markers on chromosome 11q in 24 CLL families. No evidence for linkage between CLL and ATM in the 24 families studied and the best estimates of the proportion of sibling pairs that share no, one or both haplotypes at ATM were not different from their null expectations. This would imply that ATM is unlikely to make a significant contribution to the three-fold increase in risk of CLL seen in relatives of patients.