Recent Advances in Familial Colorectal Cancer Genetics and Diagnostics
Authors: Peh Yean Cheah, Xia Cao, Yi Hong, Yu Hui Wong, Lai Fun Thean, Carol Loi, Marian Kumarasinghe, Hui Hua Li, Yuk Ping Chau, Kong Weng Eu
Journal: Clinical Cancer Research (2007)

CN03-04  Familial adenomatous polyposis (FAP) is a heritable form of colorectal cancer (CRC) caused by autosomal dominant inheritance of the mutated adenomatous polyposis coli (APC) gene. It is characterized by the appearance of hundreds to thousands of adenomatous polyps in the colon and rectum of an affected individual by the second or third decade of his life. The risk of cancer is virtually 100 % if the polyps are not detected and removed in time.  Coupling the protein truncation test (PTT) and direct sequencing, multiplex ligation-dependent probe amplification (MLPA) and differential allelic expression techniques, our APC mutation detection rate in FAP patients has now reached 94% which is, to our knowledge, amongst the highest detection rate in the world. South East Asian patients have some features similar to and other features distinct from Caucasian patients.  The APC mutation-negative FAP variants have been screened for Axin 1, β-catenin, and MYH, three genes variously implicated in CRC tumorigenesis, and found to be mutation negative in all three genes. FAP variant patients can be classified into two groups according to the polyps and atypical clinical features. The first variant group has mixed ‘adenomatous-hyperplastic-juvenile’ polyps and the second variant group has classical polyposis (i.e. with ≥ 100 adenomatous polyps) but accelerated disease progression (statistically more CRC despite later age of diagnosis compared to FAP patients with APC mutations).  The first variant group has now been renamed as Hereditary Mixed polyposis Syndrome (HMPS) patients. We have mapped the HMPS locus to chromosome 10q23 by genomewide linkage scan in a three-generation family using the GeneChip Human Mapping 10K array and subsequently confirmed it by fine mapping with microsatellite markers in two families. Candidate gene screening in the 7 Mb critical region 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. The fully penetrant mutation resulted in a truncated protein that deleted all the functional domains of BMPR1A, including the Activin receptor domain in the 5’extracellular region. Since then, we have identified BMPR1A mutations in several other families and one sporadic case, suggesting therefore that inactivating BMPR1A of the BMP pathway can initiate colorectal tumorigenesis via the ‘mixed polyposis-carcinoma’ sequence in both hereditary and sporadic CRC.  For the second variant group, we have performed genomewide genotyping with the GeneChip Human Mapping SNP 5 array. We identified by copy number analysis an identical deleted region in all eight polyps from two affected members of the same family. We are currently verifying the region of interest in pursuit of the new tumor suppressor.  The identification of new tumour suppressors would illuminate further the tumorigenesis process and enable presymptomatic detection, better surveillance and management of patients.