Genetic and environmental modifiers of cancer risk in lynch syndrome

Abstract

Lynch syndrome, caused by pathogenic mutations in DNA mismatch repair genes, is associated with high risks of colorectal and endometrial cancer. Approximately 1 in 280 (0.35%) of the population are estimated to carry a pathogenic mutation in one of these genes. However, penetrance (age-specific cancer risk) estimates for mutation carriers have been found to vary substantially depending on person’s sex and which gene is mutated. Further, penetrance is also highly variable across carriers with mutations in the same gene. These observed differences in risk are consistent with that genetic and environmental factors are likely to modify cancer risks for people with Lynch syndrome. Identifying and characterising these risk-modifying factors are essential to enable targeted risk-based screening/treatment and risk-reduction strategies on the basis of ‘individual’ risk estimates rather than ‘average’ risk estimates. In this chapter, we review the latest evidence on genetic and environmental factors that have been investigated in association with cancer risk, primarily colorectal cancer, for people with Lynch syndrome.