Germline mutations in the LKB1/STK11 tumour suppressor gene cause Peutz -Jeghers syndrome (PJS), a rare dominant disorder. In addition to typical hamartomatous gastrointestinal polyps and pigmented perioral lesions, PJS is associated with an increased risk of tumours at multiple sites. Follow-up information on carriers is limited and genetic heterogeneity makes counselling and management in PJS difficult. Here we report the analysis of the LKB1/STK11 locus in a series of 33 PJS families, and estimation of cancer risks in carriers and noncarriers. Germline mutations of LKB1/STK11 were identified in 52% of cases. This observation reinforces the hypothesis of a second PJS locus. In carriers of LKB1/STK11 mutations, the risk of cancer was markedly elevated. The risk of developing any cancer in carriers by age 65 years was 47% (95% CI: 27 -73%) with elevated risks of both gastrointestinal and breast cancer. PJS with germline mutations in LKB1/STK11 are at a very high relative and absolute risk of multiple gastrointestinal and nongastrointestinal cancers. To obtain precise estimates of risk associated with PJS requires further studies of genotype -phenotype especially with respect to LKB1/STK11 negative cases, as this group is likely to be heterogeneous.

Mutations in the base excision repair gene MYH have recently been shown to confer recessive susceptibility to colorectal adenomas and carcinomas. To evaluate the contribution of germline MYH mutations to early-onset colorectal cancer, we screened a series of 358 unselected early-onset cases for germline changes in the coding sequence of the gene. Two cases harbored biallelic germline mutations (0.6%; 95% CI ‫؍‬ 0.06 -2.0) and 8 single MYH mutations (2.2%; 95% CI ‫؍‬ 0.9 -4.4). Both cases harboring biallelic MYH mutations had multiple polyps but not profuse polyposis. All cases had distally sited tumors. No biallelic mutations were detected among 354 controls. These results confirm that biallelic MYH mutations confer susceptibility to colorectal cancer but are unlikely to account for more than 3% of early-onset colorectal cancer. © 2004 Wiley-Liss, Inc. Key words: MYH; mutation; colorectal cancerGenetic susceptibility to colorectal cancer is well recognized. A recent twin study suggests that ϳ 35% of all colorectal cancer can be ascribed to inherited genetic susceptibility 1 and epidemiologic studies have identified a 2-to 3-fold increase in risk associated with having a first-degree relative with the disease. 2 Existing data, however, suggest that less than 5% can be attributed to dominant syndromes for which mutations in genes including APC and DNA mismatch repair genes SMAD4 and STK11 have been shown to be causative. 3,4 On the basis that familial colorectal cancer risks in relatives of adenoma cases parallel those seen in relatives of cancer cases, there is strong a priori evidence that a significant proportion of the residual inherited predisposition is mediated through susceptibility to adenoma formation. 2 Inherited biallelic mutations in the human homologue of the base excision repair (BER) gene mutY (MYH) have recently been shown to predispose to multiple colorectal adenomas and carcinoma. [5][6][7][8] The BER pathway plays a significant role in the repair of mutations caused by reactive oxygen species that are generated during aerobic metabolism. 9 In Escherichia coli, the mutY protein along with mutM and mutT is involved in defending against the mutagenic effects of 7,8-dihydro-8-oxo-guanine (8-oxoG), the most stable product of oxidative damage to DNA. 10 8-oxoG is highly mutagenic because it mispairs readily with adenine residues, 11 which leads to an increased frequency of spontaneous G:C3 T:A transversion mutations in repair deficient bacteria and yeast cells. 12 The DNA glycosylase mutM removes the oxidized base from 8-oxoG:C base pairs in duplex DNA, the DNA glycosylase mutY excises adenine misincorporated opposite unrepaired 8-oxoG during replication, whereas the 8-oxo-dGTPase mutT prevents incorporation of 8-oxo-dGMP into nascent DNA. Homologues of mutM, mutY and mutT have been identified in human cells and termed OGG1, 13 MYH 14 and MTH, 15 respectively. The functionally compromised missense mutations Y165C and G382D appear to be the most frequent MYH mutations in Caucasians. 6 -8 As predicte...

The base excision repair gene MYH protects against damage to DNA from reactive oxygen species, which are commonly found in cigarette smoke. Inherited mutations in MYH predispose to colorectal adenomas and carcinomas that show a characteristic pattern of somatic G:C-->T:A mutations in the APC gene. A similar pattern of somatic mutations in the TP53 gene is reported in smoking-related lung cancers. We therefore tested whether germline changes in MYH may also contribute to the development of lung cancer by screening for variants in 276 patients with lung carcinoma and 106 normal controls. No patients harboured truncating mutations in MYH and only a single patient was a carrier for the G382D missense mutation. We identified three common coding region (V22M, Q324H and S501F) and intronic (157+30A>G, 462+35G>A and 1435-40G>C) variants, but none were over-represented in the patient samples, indicating that MYH variants are unlikely to predispose significantly to the risk of lung cancer.

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