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Background: Accumulating evidence has indicated that most colorectal cancer (CRC) is initiated by the inactivation of adenomatous polyposis coli (APC) via the multi-step ‘adenomatous polyps-carcinoma’ sequence. The initiating event for the ‘mixed polyposis-carcinoma’ sequence remains unclear. Hereditary Mixed Polyposis Syndrome is characterized by colonic polyps of mixed histological types that are autosomal dominantly inherited and eventually lead to cancer. In previous study, we have identified an 11-bp deletion in exon 2 of the bone morphogenesis protein receptor 1A (BMPR1A) gene as the underlying germline defect in one such family. Methods/Results: In the present study, we screened for BMPR1A mutation by RT-PCR, long-range PCR and cDNA sequencing in six Singapore Chinese HMPS families and one sporadic CRC patient. All patients have colonic polyps of mixed hyperplastic, adenomatous, and occasional juvenile types. Five out of six of the families have patients with CRC. All cases were found to be APC and MYH mutation negative. Exon 4-5 deletion of BMPR1A was found in four out of six of the familial cases, suggesting that this could be the mutational hot spot. This germline mutation deletes the transmembrane domain that anchors the protein to the membrane and hence renders the protein non-functional. The sporadic patient was found to harbor a somatic exon 1-11 deletion in BMPR1A, effectively deleting all the functional domains of the protein, in his inflammed mucosa. Conclusion: Our results suggest that inactivating BMPR1A of the BMP pathway can initiate colorectal tumorigenesis via the ‘mixed polyposis-carcinoma’ sequence in both hereditary and sporadic CRC.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA