(J Clin Pathol 2001;54:484-487)

PURPOSE.Reports suggest that a subset of uveal melanoma is familial. The association of uveal melanoma with breast and ovarian cancer and the increased risk in BRCA2-linked families implicates germline BRCA2 mutations as the cause of a subset of uveal melanomas. Similarly, the association between cutaneous and uveal melanomas in some families, coupled with the high frequency of somatic deletions of the INK4A-ARF locus in uveal melanomas, strongly suggests that mutations in P16 INK4Aand P15 account for a proportion of uveal melanomas. METHODS. To examine this proposition, a systematically ascertained series of 385 patients with uveal melanoma were screened for germline mutations in BRCA2, P16INK4A , P14 ARF , and P15. RESULTS. One patient was found to harbor a Gly35Ala substitution in exon 1␣ of P16 INK4A , which has previously been reported to be pathogenic. No mutations were detected in P14 ARF or P15. None of the patients harbored germline nucleotide changes that lead to truncation or that create or disrupt consensus splice sites of BRCA2 or missense variants with clear pathogenic potential. CONCLUSIONS. These findings suggest that less than 2% of cases of uveal melanoma can be ascribed to germline mutations in BRCA2, P16INK4A , P14 ARF , or P15. It is likely that mutations in other genes contribute to an inherited predisposition to uveal melanoma. (Invest Ophthalmol Vis Sci. 2003;44:458 -462)

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...

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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