Hereditary non-polyposis colorectal cancer is predicted to contribute towards colorectal cancer in young South African blacks

Introduction Colorectal carcinogenesis involves the stepwise accumulation of mutations and/or epigenetic alterations, leading to the transformation of normal colonic epithelia. This process may develop and progress over a period of 10 to 15 years. Comprehensive studies have examined both morphological and molecular changes associated with the initiation and progression of colorectal cancer. A wealth of knowledge has thus far been accumulated and has led to the detailed classification of four distinct molecular pathways. The classical pathway, somewhat involved in all of the pathways described, involves the somatic mutational inactivation of the adenomatous polyposis coli (APC) gene in colorectal epithelial cells. This leads to a cascade of events including, amongst others, degradation of β-catenin binding sites and interference with E-cadherin homeostasis during tumour initiation, and ultimately to p53 gene mutations during tumour progression. The familial form of this pathway is the autosomal dominantly inherited predisposition to familial adenomatous polyposis (FAP) that is initiated by germline mutations in the APC gene, and characterised by the presence of adenomatous polyps which develop into colorectal cancer if left untreated. The next pathway involves the accumulation of mutations due to a mismatch repair (MMR) deficiency, resulting in microsatellite instability (MSI) in the coding regions of genes implicated in tumour progression. This may lead to differential levels of MSI, differentiated by the number of tested loci displaying instability. Tumours with high levels of instability (MSI-H) may develop on a hereditary basis, involving the MMR genes hMSH2, hMLH1, hMSH6, hPMS2 and hPMS1, and thus predispose to hereditary non-polyposis colorectal cancer (HNPCC). The so-called ‘serrated’ pathway involves the silencing of MMR genes through promoter hypermethylation. This pathway is initiated in ‘serrated’ neoplasia through the inhibition of apoptosis, followed by the disruption of DNA repair mechanisms through epigenetic silencing. A disproportionately large number of young (<50 years) black patients present with colorectal cancer (CRC) in South Africa. Although a phenomenon previously described elsewhere in Africa, its specific molecular basis, whether sporadic or hereditary, has not been established. Molecular analysis of these tumours could link them to the features known to be associated with specific types of hereditary colorectal cancer, specifically through examination of levels of microsatellite instability, promoter methylation and the presence or absence of KRAS and BRAF mutations. The molecular features of cancer tissue samples from 44 CRC cases of black and white patients in South Africa were accordingly retrospectively analysed without knowledge of family history. Compared with samples from older blacks (>50 years), those from young black patients presented more often with a low methylation phenotype (CIMP-L) and high levels of microsatellite instability (MSI-H). Furthermore, as determined by real-time PCR using probe technology, the tissues from 35% of young blacks showed mutations within exon 1 of the KRAS gene. The BRAF-V600E mutation was only evident in the case of a single young black patient. Based on these results it seems likely that a proportion of CRC cases in young black patients from South Africa develop through the accumulation of mutations resulting in a mismatch repair deficiency linked to MSI-H and, possibly, germline mutations in the mismatch repair genes. The features in these patients are consistent with a diagnosis of the Hereditary Non-Polyposis Colorectal Cancer (HNPCC) syndrome. This finding has important implications for patient management and suggests that family members may be at high risk for CRC. : colorectal neoplasms, hereditary cancer syndromes