Valle L et al. (2008) Germline allele-specific expression of TGFBR1 confers an increased risk of colorectal cancer. Science 321: 1361–1365

Genetic variation influences predisposition to colorectal cancer and, although alleles associated with an increased risk have been identified, much of the genetic basis of this predisposition remains unexplained. Evidence exists that a common variant of the transforming growth factor-β type I receptor (TGFBR1) gene could be associated with increased colorectal cancer risk. Valle and colleagues investigated the hypothesis that mutations in TGFBR1 confer a predisposition to colorectal cancer either directly, or indirectly by modification of other genes.

The authors used three single-nucleotide polymorphisms to test for allele-specific expression of TGFBR1. Allele-specific expression of TGFBR1 is dominantly inherited, occurs in sporadic colorectal cancer and results in reduced expression of the gene. The study included 242 patients with microsatellite-instability-negative colorectal cancer; of the 96 of patients who were heterozygous for the three single-nucleotide polymorphisms, 12 showed allele-specific expression variation ratios >1.5. A further 49 patients were heterozygous for one further single-nucleotide polymorphism and 17 of these individuals had allele-specific expression values >1.5. Of the 138 patients in whom this parameter was evaluated, 29 showed allele-specific expression of TGFBR1. The authors estimated that the population attributable risk of colorectal cancer contributed by allele-specific expression of TGFBR1, in the predominantly Caucasian population studied, was 10–21%.

In conclusion, allele-specific expression of TGFBR1 is a major factor in genetic predisposition to colorectal cancer.