The Role of Modifier Genes in Lynch Syndrome

Abstract

There are a number of inherited predispositions to colorectal cancer (CRC) which can be broadly categorized into two groups; those with associated polyposis, such as familial adenomatous polyposis and the hamartomatous polyposis syndromes; and those that are linked to the non-polyposis syndromes, such as hereditary non polyposis colorectal cancer (HNPCC). The genetic basis of both the polyposis and non-polyposis syndromes are reflected in the CRC population who have no apparent family history of disease. Approximately 80% of all cases of CRC are associated with chromosomal instability [1] and are likely to have mutations in the Adenomatous Polyposis Coli (APC) gene whereas the remaining 20% with microsatellite instability appears to be due primarily to epigenetic inactivation of the DNA mismatch repair (MMR) gene MLH1 [2]. The disease HNPCC accounts for somewhere between 2% and 5% of all CRCs diagnosed and is associated with a younger age of disease onset compared to the general population [3,4]. HNPCC is a disease by definition based on the Amsterdam Criteria where there need to be three cases of CRC, one of which must be diagnosed under the age of 50 years, one patient must be a first degree relative of the other two, span two generations and familial adenomatous polyposis should be excluded [5]. Modification of the Amsterdam Criteria has been ongoing since its original inception due to an increasing awareness of what constitutes this disease. HNPCC used to be known as either the Cancer Family Syndrome or Lynch Syndrome [6]. It is now accepted that families where a mutation in the DNA mismatch repair genes (MMR) MSH2, MLH1, MSH6 or PMS2 has been identified are now termed Lynch Syndrome families whereas those with no mutation are termed HNPCC [7]. The primary function of MMR genes is to eliminate base-base mismatches and insertion-deletion loops which arise as a consequence of DNA polymerase slippage during DNA replication [8]. MMR confers several genetic stabilisation functions; it corrects DNA biosynthesis errors, ensures the fidelity of genetic recombination and participates in the earliest steps of cell cycle checkpoint control and apoptotic responses [9,10]. MMR gene defects increases the risk of malignant transformation of cells, which ultimately results in the disruption of one or