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

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”)...

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Bibliographic Details
Published in:	Cancer medicine (Malden, MA) Vol. 5; no. 9; pp. 2629 - 2640
Main Authors:	Lindley, Robyn A., Humbert, Patrick, Larner, Cliff, Akmeemana, Eric H., Pendlebury, Christopher R. R.
Format:	Journal Article
Language:	English
Published:	United States John Wiley & Sons, Inc 01-09-2016 John Wiley and Sons Inc
Subjects:	Adenocarcinoma Adenosine Adenosine deaminase Biomarkers, Tumor Breast cancer Cancer genetics Cancer Prevention codon context Cystadenocarcinoma, Serous - genetics Cystadenocarcinoma, Serous - mortality Cystadenocarcinoma, Serous - pathology Cytidine deaminase deaminase Deamination Deoxyribonucleic acid Disease Progression DNA Enzymes Female Genetic Association Studies Genetic Predisposition to Disease HIV Human immunodeficiency virus Humans Immune system Kaplan-Meier Estimate Mutagens Mutation Neoplasm Grading Neoplasm Staging Nucleotide sequence Original Research Ovarian cancer Ovarian Neoplasms - genetics Ovarian Neoplasms - mortality Ovarian Neoplasms - pathology Prognosis Ribonucleic acid RNA Studies targeted somatic mutation Tumorigenesis deaminase Cancer genetics codon context ovarian cancer targeted somatic mutation
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Summary:	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. The aim of our study was to use a new bioinformatics approach to identify genetic signature changes that occur during oncogenesis. Using 194 TCGA GHGS‐OvCa samples, we identified a set of genetic signatures that might be adapted for use as a genetic assay to predict the progression‐free survival probability within 60 months following the initial diagnosis (sensitivity 95%, specificity 90%).
ISSN:	2045-7634 2045-7634
DOI:	10.1002/cam4.825