Association between targeted somatic mutation (TSM) signatures and HGS‐OvCa progression

Abstract

Evidence already exists that the activation‐induced cytidine deaminase (AID/APOBEC) and the adenosine deaminase (ADAR) families of enzymes are implicated as powerful mutagens in oncogenic processes in many somatic tissues. Each deaminase is identified by the DNA or RNA nucleotide sequence (“motif”) surrounding the nucleotide targeted for deamination. The primary objective of this study is to develop an in silico approach to identify nucleotide sequence changes of the target motifs of key deaminases during oncogenesis. If successful, a secondary objective is to investigate if such changes are associated with disease progression indicators that include disease stage and progression‐free survival time. Using a discovery cohort of 194 high‐grade serous ovarian adenocarcinoma (HGS‐OvCa) exomes, the results confirm the ability of the novel in silico approach used to identify changes in the preferred target motifs for AID, APOBEC3G, APOBEC3B, and ADAR1 during oncogenesis. Using this approach, a set of new cancer‐progression associated signatures (C‐PASs) were identified. Furthermore, it was found that the C‐PAS identified can be used to differentiate between the cohort of patients that remained progression‐free for longer than 60 months, from those in which disease progressed within 60 months (sensitivity 95%, specificity 90%). The spectrum of outcomes observed here could provide a foundation for future clinical assessment of susceptibility variants in ovarian, and several other cancers as disease progresses. The ability of the in silico methodology used to identify changes in deaminase motifs during oncogenesis also suggests new links between immune system function and tumorigenesis.

Reverse Transcriptase Mechanism of Somatic Hypermutation: 60 Years of Clonal Selection Theory

“…Recent publications should be consulted for further definitive ADAR A-to-I editing of both RNA and DNA moieties at RNA:DNA hybrids within Transcription Bubbles ( 11 , 14 , 15 ). Not only is it important to understand the correct molecular mechanism of SHM for cancer diagnosis and detection ( 16 , 17 ) but also to the current efforts to better understand ( 18 , 19 ) the origin of Ig diversity involving the mechanism of evolution of the sets germline V segments and the long IGHV and IGLV haplotypes in individual human beings ( 20 , 21 ).…”

Inosine‐specific ribonuclease activity of natural variants of human endonuclease V

“…Moreover, the trace of this strand‐biased WA‐site A‐to‐I RNA editing signature is now also embedded as A‐to‐G in DNA in codon context (via a reverse transcription step). This has been observed in many cancer genomes examined and has been used as a cancer diagnostic and prognostic of cancer exomic mutations during progression .…”

Molecular model linking Th2 polarized M2 tumour‐associated macrophages with deaminase‐mediated cancer progression mutation signatures

“…Whilst the antiviral functions of these deaminases are well studied, it has also been established that genomic mutations of the host cell occur as “collateral damage” and can accumulate from one cell generation to the next when such anti‐pathogen deaminase responses become dysregulated. Ultimately, the accumulation of deaminase mutations during transcription may lead to tumorigenesis …”