title: 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.
authors.affiliation: Department of Pathology, University of Melbourne, Parkville, Victoria, 3010, Australia. robyn.lindley@unimelb.edu.au.|GMDx Pty Ltd, Melbourne, Victoria, 3000, Australia. robyn.lindley@unimelb.edu.au.
authors.forename: Robyn A
authors.initials: RA
authors.lastname: Lindley
authors.affiliation: Department of Pathology, University of Melbourne, Parkville, Victoria, 3010, Australia.|Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, 3010, Australia.|Cell Cycle and Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, 3002, Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, 3010, Australia.
authors.forename: Patrick
authors.initials: P
authors.lastname: Humbert
authors.affiliation: Swinburne University of Technology, Hawthorn, Victoria, 3132, Australia.
authors.forename: Cliff
authors.initials: C
authors.lastname: Larner
authors.affiliation: HealthIQ Pty Ltd, Melbourne, Victoria, 3000, Australia.
authors.forename: Eric H
authors.initials: EH
authors.lastname: Akmeemana
authors.affiliation: AusBioCloud Pty Ltd, Melbourne, Victoria, 3000, Australia.
authors.forename: Christopher R R
authors.identifier: 0000-0002-5789-4397
authors.initials: CR
authors.lastname: Pendlebury
mesh_terms: D014408:Biomarkers, Tumor; D018284:Cystadenocarcinoma, Serous / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D053208:Kaplan-Meier Estimate; D009154:Mutation; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D011379:Prognosis
chemical_list: D014408:Biomarkers, Tumor
keywords: Cancer genetics; codon context; deaminase; ovarian cancer; targeted somatic mutation