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Hereditary mixed polyposis syndrome (HMPS) is characterized by apparent autosomal dominant inheritance of multiple types of colorectal polyp, with colorectal carcinoma occurring in a high proportion of affected individuals. Here, we use genetic mapping, copy-number analysis, exclusion of mutations by high-throughput sequencing, gene expression analysis and functional assays to show that HMPS is caused by a duplication spanning the 3' end of the SCG5 gene and a region upstream of the GREM1 locus. This unusual mutation is associated with increased allele-specific GREM1 expression. Whereas GREM1 is expressed in intestinal subepithelial myofibroblasts in controls, GREM1 is predominantly expressed in the epithelium of the large bowel in individuals with HMPS. The HMPS duplication contains predicted enhancer elements; some of these interact with the GREM1 promoter and can drive gene expression in vitro. Increased GREM1 expression is predicted to cause reduced bone morphogenetic protein (BMP) pathway activity, a mechanism that also underlies tumorigenesis in juvenile polyposis of the large bowel.
Colorectal cancers that arise as a result of high-penetrance germline mutations in genes such as APC, MSH2 and MLH1 are associated with tumors of particular morphology and with variable but specific extra-colonic features. HMPS is an unusual disease, in that affected individuals can develop polyps of multiple and mixed morphologies- including serrated lesions, Peutz-Jeghers polyps, juvenile polyps, conventional adenomas and colorectal carcinoma (CRC)1-in the absence of any identifiable extra-colonic features. A single large Jewish family with HMPS (SM96) with dominantly inherited polyposis was initially identified at St Mark's Hospital, London, and germline mutations in known CRC predisposition genes were excluded over time2. Using linkage analysis in SM96 and independently in another Jewish kindred with polyposis, SM1311, we mapped the causative gene to CRAC1 (also known as HMPS) on chromosome 15q13.3 and showed that the two families shared a haplotype within this region2,3. Subsequently, we identified additional kindreds with HMPS on the basis of their clinical features and Ashkenazi descent and showed that all families shared a disease haplotype between 30.735 Mb and 31.370 Mb on chromosome 15q13.3 (ref. 4). To date, no non-Ashkenazi families with HMPS have convincingly been identified, although there is overlap between some of the clinical features of HMPS and those of juvenile polyposis syndrome (JPS)5 and hyperplastic polyposis syndrome (HPPS)6.
The possibility that...