PubMed · 12910813
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S Spoto, L De Galasso, S Costantino. [Colorectal polyps].. https://pubmed.ncbi.nlm.nih.gov/12910813/
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Base excision repair (BER) protects against damage to DNA from reactive oxygen species, methylation, deamination, hydroxylation and other by-products of cellular metabolism. Until last year, inherited deficiencies in the BER pathway had not been causally linked with any human genetic disorder. An apparent explanation was functional redundancy between proteins in this and other pathways. However, it was recently discovered that biallelic mutations in the BER DNA glycosylase MYH lead to an autosomal recessive syndrome of adenomatous colorectal polyposis and very high colorectal cancer risk. We review the molecular mechanism of tumourigenesis in MYH polyposis, the preliminary delineation of the MYH polyposis phenotype and the functional overlap of MYH with other repair proteins.
The tumor suppressor gene Smad4 (DPC4) at chromosome 18q21.1 belongs to the Smad family, which mediates the TGFbeta signaling pathway suppressing epithelial cell growth. This review summarizes the mutational events of the Smad4 gene in human cancer. The Smad4 gene is genetically responsible for familial juvenile polyposis, an autosomal dominant disease characterized by predisposition to gastrointestinal polyps and cancer. In this syndrome, polyps are formed by inactivation of the Smad4 gene through germline mutation and loss of the unaffected wild-type allele. In pancreatic and colorectal cancer, inactivation of the Smad4 gene through homozygous deletion or intragenic mutation occurs frequently in association with malignant progression. However, mutation of this gene is seen only occasionally in the rest of human cancers. The majority of Smad4 gene mutations in human cancer are missense, nonsense, and frameshift mutations at the mad homology 2 region (MH2), which interfere with the homo-oligomer formation of Smad4 protein and the hetero-oligomer formation between Smad4 and Smad2 proteins, resulting in disruption of TGFbeta signaling. Supporting evidence for the above observation was provided by genetically manipulated mice carrying either a heterozygote of the Smad4 gene or a compound heterozygote of the Smad4 and APC genes, which develop either gastrointestinal polyps/cancer mimicking familial juvenile polyposis or progressed colorectal cancer, respectively.
Familial adenomatous polyposis (FAP) and attenuated FAP are autosomal dominant disorders characterised by multiple colorectal adenomas and cancers. Both are caused by inherited mutations in the APC gene, and management includes genetic testing, colonoscopic surveillance, and prophylactic surgery for the relatives of index cases. Among 614 families recorded in six regional registers of polyposis in the UK, we identified 111 with neither dominant transmission nor evidence of APC mutation. Molecular genetic analysis showed that 25 had biallelic mutations of the MYH gene. Since our data show that MYH polyposis can be transmitted as an autosomal recessive trait, a change in genetic counselling, testing, and surveillance is needed.