Polymorphic Variation and Risk of Colorectal Cancer

Abstract

Colorectal cancer (CRC) is the third commonest cancer worldwide after lung and breast cancer, and two-thirds of CRCs occur in developed countries [1, 2]. Despite recent advances in treatment the prognosis for CRC patients with advanced stage disease remains poor, and there is an urgent need for strategies to identify individuals with an increased CRC risk so that colonoscopic screening and chemoprevention can be directed to those who will obtain most benefit [1]. First-degree relatives of CRC patients have an approximately twofold increased risk of developing the disease themselves, and the risk increases with increasing number of affected family members and if CRC is diagnosed at a young age [3]. This familial aggregation may be due to shared environment, inherited factors, or a combination of both, but twin studies have provided convincing evidence that approximately a third of CRC can be ascribed to inherited factors [4]. Highly penetrant mutations have been characterised in the known CRC susceptibility genes APC, mismatch repair (MMR) genes, STKI HLKB1, SMAD4, and MUTYH, which respectively result in the syndromes of familial adenomatous polyposis (FAP), hereditary non-polyposis colorectal cancer (HNPCC) or Lynch syndrome, Peutz Jeghers syndrome, juvenile polyposis syndrome, and MUTYH-associated polyposis (MAP). However, these syndromes together account for only about 5% of CRCs [5]. The nature of the remaining familial risk is unknown, but it is likely that a substantial proportion is conferred by a number of low-penetrance genetic variants with relatively high population frequency. Individually, these polymorphisms will be associated with only modest increases in risk, but when considered collectively they may confer substantial susceptibility [6]. Polymorphisms may influence CRC risk directly, may interact with each other or with relevant environmental exposures, and may influence the effectiveness of chemopreventive and chemotherapeutic agents. Identification of such low-penetrance colorectal susceptibility polymorphisms will not only permit more accurate determination of an individual's CRC risk and thus allow more effective application of screening and preventive strategies, but may also provide further insights into the molecular pathways involved in colorectal carcinogenesis, and aid the discovery of novel drugs for CRC prevention and treatment.