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Juvenile polyposis syndrome (JPS) is an autosomal dominant cancer predisposing syndrome. It is genetically heterogenous, and is distinct from Cowden and Bayanyan-Zonana syndromes. Germline mutations in BMPR1A and SMAD4/DPC4 have been identified in patients with JPS; both are components of the TGF beta signalling pathway. Juvenile polyps from carriers of SMAD4 mutations may have a greater malignancy potential than those who do not. A 25 year old male presented with rectal bleeding. Initially twelve polyps were found, three of which were removed and were reported to be adenomatous. Subsequent investigations over several years revealed multiple juvenile polyps and review of the original polypectomy specimens led to their re-classification as juvenile polyps. He also developed numerous subcutaneous angiolipomas and severe asthma. His karyotype was found to be 46XY inv(18)(q11.2q21.1). FISH analysis using PAC probe 224-j-22 which encompasses the 11 exon SMAD4 gene, located at 18q21.1, was disrupted by this inversion. We believe this is the first repod of a visible cytogenetic rearrangement causing JPS. Further work is underway to determine whether inactivation of SMAD4 has played a role in development of his angiolipomas. [ABSTRACT FROM AUTHOR]

Background: Multiple colorectal adenoma families have been identified that do not conform to classical FAP or HNPCC. We studied the somatic mutation profile of adenomas from affected siblings in one such family to establish the nature of their inherited defect. Method: Family 'N' consisted of seven siblings, 1 with colon cancer at the age of 46, which was associated with adenomas. Screening his siblings identified two with approximately 50 adenomatous colorectal polyps at the ages of 59 and 55, respectively. 11 tumours from these 3 affected siblings were screened for somatic APC gene mutations. Results: 18 somatic inactivating APC gene mutations were identified in these 11 tumours. Remarkably, 15 of these were G:C→T:A transversions. This type of mutation was significantly over-represented when compared to somatic mutations so far described in sporadic and FAP associated adenomas/adenocarcinomas. Similar mutations had previously been reported in DNA repair deficient yeast and bacteria. In E coli a series of enzymes function synergistically to protect cells from the deleterious effects of guanine oxidation. Analysis of the human homologue of mutY (MYH) showed that the affected siblings were compound heterozygotes for the nonconservative missense variants Tyr165Cys and Gly382Asp. These occur at sub-polymorphic frequency in the general population. Assays of glycosylase activity of the mutant proteins showed their activity was reduced significantly. This provided a link between inherited variants of MYH and the pattern of somatic APC mutation found in family N and implicated defective base excision repair in adenoma formation. Since the original report of family N, we have identified over 20 further families with multiple colorecta adenomas and biallelic germline MYH mutations, confirming the role of MYH in some families with colorectal polyposis. Conclusion: Germline mutations of the base excision repair gene MYH are a cause of multiple colorectal adenomas and... [ABSTRACT FROM AUTHOR]

Background: Compound heterozygosity for missense variants of the base excision repair (BER) gene MYH has been linked to inheritance of multiple colorectal adenomas or carcinoma in a single UK family. Colorectal adenomas From affected individuals displayed an excess of somatic G:C→T:A transversions in the adenomatous polyposis coli (APC) gene, consistent with a BER defect. Methods: 157 unrelated UK patients with multiple (3 to 115) colorectal adenomas were screened for germ line mutations in MYH and subsets were screened for the related BER genes, MTH1 and OGG1. Adenomas from patients harbouring pathogenic MYH germ line mutations were tested for somatic APC mutations and loss of heterozygosity at MYH. Clinicopathological and molecular data were compared between patients with and without MYH mutations. Results: Fourteen (9%) patients harboured germ line MYH variants, with 8 (5%) having biallelic, pathogenic mutations. Both nonsense and protein truncating MYH mutations were found. Missense variants Y165C and G382D were the most frequent alterations observed. Patients with biallelic MYH mutations had more polyps than carriers of single mutations or MYH wild-type patients (medians, 55 v 3 v 7, respectively; p < 0.01). Four out of 28 (29%) patients with 15 to 115 adenomas had biallelic MYH mutations. All somatic APC mutations identified in such patients were the expected somatic G:C-→T:A transversions. No clearly pathogenic MTH1 or OGG1 germ line mutations were identified. Conclusions: The data provide strong evidence to show that individuals with two allelic MYH mutations are predisposed to a multiple adenoma phenotype. Progression to colorectal carcinoma occurs in some cases. [ABSTRACT FROM AUTHOR]