Tumor suppressor genes and allele-specific expression: mechanisms and significance

Recent findings indicate that allele-specific expression (ASE) at specific cancer driver gene loci may be of importance in onset/progression of the disease. Of particular interest are loss-of-function (LOF) of tumor suppressor gene (TSGs) alleles. While LOF tumor suppressor mutations are typically considered to be recessive, if these mutant alleles can be significantly differentially expressed relative to wild-type alleles in heterozygotes, the clinical consequences could be significant. LOF TSG alleles are shown to be segregating at high frequencies in world-wide populations of normal/healthy individuals. Matched sets of normal and tumor tissues isolated from 233 cancer patients representing four diverse tumor types demonstrate functionally important changes in patterns of ASE in individuals heterozygous for LOF TSG alleles associated with cancer onset/progression. While a variety of molecular mechanisms were identified as potentially contributing to changes in ASE patterns in cancer, changes in DNA copy number and allele-specific alternative splicing possibly mediated by antisense RNA emerged as predominant factors. In conclusion, LOF TSGs are segregating in human populations at significant frequencies indicating that many otherwise healthy individuals are at elevated risk of developing cancer. Changes in ASE between normal and cancer tissues indicates that LOF TSG alleles may contribute to cancer onset/progression even when heterozygous with wild-type functional alleles.