ABSTRACT
Biallelic germline mutations affecting NTHL1 predispose carriers to adenomatous polyposis and colorectal cancer, but the complete phenotype is unknown. We describe 29 individuals carrying biallelic germline NTHL1 mutations from 17 families, of which 26 developed one (n = 10) or multiple (n = 16) malignancies in 14 different tissues. An unexpected high breast cancer incidence was observed in female carriers (60%). Mutational signature analysis of 14 tumors from 7 organs revealed that NTHL1 deficiency underlies the main mutational process in all but one of the tumors (93%). These results reveal NTHL1 as a multi-tumor predisposition gene with a high lifetime risk for extracolonic cancers and a typical mutational signature observed across tumor types, which can assist in the recognition of this syndrome.
Subject(s)
Biomarkers, Tumor/genetics , DNA Mutational Analysis , Deoxyribonuclease (Pyrimidine Dimer)/genetics , Gene Expression Profiling , Germ-Line Mutation , Neoplastic Syndromes, Hereditary/genetics , Transcriptome , Adult , Aged , Biomarkers, Tumor/deficiency , DNA Repair/genetics , Deoxyribonuclease (Pyrimidine Dimer)/deficiency , Europe , Female , Gene Expression Regulation, Neoplastic , Genetic Predisposition to Disease , Heredity , Humans , Male , Middle Aged , Neoplastic Syndromes, Hereditary/enzymology , Neoplastic Syndromes, Hereditary/pathology , Pedigree , Phenotype , Risk Assessment , Risk Factors , Young AdultABSTRACT
Recent advances in high-throughput sequencing technology have identified the transcription of a much larger portion of the genome than previously anticipated. Especially in the context of cancer it has become clear that aberrant transcription of both protein-coding and long non-coding RNAs (lncRNAs) are frequent events. The current dogma of RNA function describes mRNA to be responsible for the synthesis of proteins, whereas non-coding RNA can have regulatory or epigenetic functions. However, this distinction between protein coding and regulatory ability of transcripts may not be that strict. Here, we review the increasing body of evidence for the existence of multifunctional RNAs that have both protein-coding and trans-regulatory roles. Moreover, we demonstrate that coding transcripts bind to components of the Polycomb Repressor Complex 2 (PRC2) with similar affinities as non-coding transcripts, revealing potential epigenetic regulation by mRNAs. We hypothesize that studies on the regulatory ability of disease-associated mRNAs will form an important new field of research.