Affiliation: | aMRC Research Unit for Human Genetics, Division of Human Genetics, Institute for Infectious Diseases and Molecular Medicine, Faculty of Health Sciences, University of Cape Town Medical School, Anzio Road, Observatory 7925, South Africa bCancer Research UK, Cancer Immunogenetics Laboratory, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom cBiostatistics Unit, Medical Research Council, Box 19070, Tygerberg 7505, South Africa dSurgical Gastroenterology Unit, Groote Schuur Hospital, University of Cape Town, South Africa |
Abstract: | The variability in phenotype that occurs for so-called ‘single-gene disorders’ may be because of germline alterations in numerous primary and “modifier” genes. Within HNPCC families harbouring the same primary predisposing mutation, differences exist in the site of cancer, age of onset of disease symptoms and, consequently, survival until diagnosis of disease. The current study investigated a cohort of 129 individuals, from 13 different families, who harbour the identical nonsense mutation (C1528T) in the hMLH1 gene, predisposing them primarily to Lynch I syndrome. This cohort was screened for previously described polymorphisms in the glutathione-S-transferase genes, viz. GSTT1 and GSTM1. Male null carriers for both GSTT1 and GSTM1 were approximately three times more at risk of developing cancer at an earlier age when compared to non-null males. This work, particularly because of the relatively large “homogeneous” primary mutation cohort, provides evidence that genotypic changes distinct from the primary ‘HNPCC-causing’ mutation, influence the survival period until diagnosis of disease. It provides an impetus for expanding the study to include a wider range of candidate modifier genes. Such work may potentially lead to the development of individualised interval screening regimens for individuals with varying modifier genotypes—an attractive option in a resource-poor country. |