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

Abstract

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.

Allele-specific expression of GATA2 due to epigenetic dysregulation in CEBPA double-mutant AML

“…11 In addition to acting as a surrogate marker, ASE can directly play a pathogenic role (eg, by haploinsufficiency or preferential expression of a mutated protein). 12 Moreover, ASE of specific genes may be associated with increased risk of cancer development 13 or progression, 14 as has been shown for colon, 15 breast, and ovarian cancers. 16 Extensive data focusing on the occurrence and relevance of ASE in AML are lacking.…”

Combining cell-free RNA with cell-free DNA in liquid biopsy for hematologic and solid tumors

“…1 ). The higher number of mutations in the cfRNA most likely due to the well-documented allele-specific methylation and lower expression of the wild-type RNA enriching the relative level of mutant RNA as compared with mutant DNA [ [24] , [25] , [26] , [27] , [28] ]. However, this phenomenon is not necessarily true for all types of mutations.…”

Ανάπτυξη Και Αξιολόγηση Εφαρμογών Βιοπληροφορικής Με Κλινική Χρησιμότητα Στη Γενετική Του Καρκίνου

“…Τα ογκοκατασταλτικά γονίδια κωδικοποιούν πρωτεΐνες που ρυθμίζουν την κυτταρική διαίρεση και αντιγραφή και χωρίζονται στα γονίδια-φρουρούς (gatekeepers) και τα γονίδια-φροντιστές (caretakers) (Bunz, 2016;Epstein, 2015;van Heemst et al, 2007) (Clayton et al, 2020).…”