{"doi":"10.1002/cam4.825","title":"Association between targeted somatic mutation (TSM) signatures and HGS‐OvCa progression","abstract":"<jats:title>Abstract</jats:title><jats:p>Evidence already exists that the activation‐induced cytidine deaminase (<jats:styled-content style=\"fixed-case\">AID</jats:styled-content>/<jats:styled-content style=\"fixed-case\">APOBEC</jats:styled-content>) and the adenosine deaminase (<jats:styled-content style=\"fixed-case\">ADAR</jats:styled-content>) families of enzymes are implicated as powerful mutagens in oncogenic processes in many somatic tissues. Each deaminase is identified by the <jats:styled-content style=\"fixed-case\">DNA</jats:styled-content> or <jats:styled-content style=\"fixed-case\">RNA</jats:styled-content> nucleotide sequence (“motif”) surrounding the nucleotide targeted for deamination. The primary objective of this study is to develop an <jats:italic>in silico</jats:italic> 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 (<jats:styled-content style=\"fixed-case\">HGS</jats:styled-content>‐OvCa) exomes, the results confirm the ability of the novel <jats:italic>in silico</jats:italic> approach used to identify changes in the preferred target motifs for <jats:styled-content style=\"fixed-case\">AID</jats:styled-content>,<jats:styled-content style=\"fixed-case\"> APOBEC</jats:styled-content>3G, <jats:styled-content style=\"fixed-case\">APOBEC</jats:styled-content>3B, and <jats:styled-content style=\"fixed-case\">ADAR</jats:styled-content>1 during oncogenesis. Using this approach, a set of new cancer‐progression associated signatures (C‐<jats:styled-content style=\"fixed-case\">PAS</jats:styled-content>s) were identified. Furthermore, it was found that the C‐<jats:styled-content style=\"fixed-case\">PAS</jats:styled-content> 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 <jats:italic>in silico</jats:italic> methodology used to identify changes in deaminase motifs during oncogenesis also suggests new links between immune system function and tumorigenesis.</jats:p>","journal":"Cancer Medicine","year":2016,"id":622056,"datarank":0.47670807455219194,"base_score":3.1780538303479458,"endowment":3.1780538303479458,"self_citation_contribution":0.47670807455219194,"citation_network_contribution":0.0,"self_endowment_contribution":0.47670807455219194,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":23,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1606617,"name":"Patrick Humbert","orcid":null,"position":1,"is_corresponding":false},{"id":1606618,"name":"Cliff Larner","orcid":null,"position":2,"is_corresponding":false},{"id":1606619,"name":"Eric H. Akmeemana","orcid":null,"position":3,"is_corresponding":false},{"id":1606620,"name":"Christopher R. R. Pendlebury","orcid":"0000-0002-5789-4397","position":4,"is_corresponding":false},{"id":1606616,"name":"Robyn A. Lindley","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Association between targeted somatic mutation (TSM) signatures and HGS‐OvCa progression","abstract":"<jats:title>Abstract</jats:title><jats:p>Evidence already exists that the activation‐induced cytidine deaminase (<jats:styled-content style=\"fixed-case\">AID</jats:styled-content>/<jats:styled-content style=\"fixed-case\">APOBEC</jats:styled-content>) and the adenosine deaminase (<jats:styled-content style=\"fixed-case\">ADAR</jats:styled-content>) families of enzymes are implicated as powerful mutagens in oncogenic processes in many somatic tissues. Each deaminase is identified by the <jats:styled-content style=\"fixed-case\">DNA</jats:styled-content> or <jats:styled-content style=\"fixed-case\">RNA</jats:styled-content> nucleotide sequence (“motif”) surrounding the nucleotide targeted for deamination. The primary objective of this study is to develop an <jats:italic>in silico</jats:italic> 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 (<jats:styled-content style=\"fixed-case\">HGS</jats:styled-content>‐OvCa) exomes, the results confirm the ability of the novel <jats:italic>in silico</jats:italic> approach used to identify changes in the preferred target motifs for <jats:styled-content style=\"fixed-case\">AID</jats:styled-content>,<jats:styled-content style=\"fixed-case\"> APOBEC</jats:styled-content>3G, <jats:styled-content style=\"fixed-case\">APOBEC</jats:styled-content>3B, and <jats:styled-content style=\"fixed-case\">ADAR</jats:styled-content>1 during oncogenesis. Using this approach, a set of new cancer‐progression associated signatures (C‐<jats:styled-content style=\"fixed-case\">PAS</jats:styled-content>s) were identified. Furthermore, it was found that the C‐<jats:styled-content style=\"fixed-case\">PAS</jats:styled-content> 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 <jats:italic>in silico</jats:italic> methodology used to identify changes in deaminase motifs during oncogenesis also suggests new links between immune system function and tumorigenesis.</jats:p>","is_dataset_classified":null,"base_score":3.1780538303479458,"endowment":3.1780538303479458,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"27485054","pmcid":"PMC5055158","openalex_id":"https://openalex.org/W2477436231","authors":[],"funders":[],"total_grants":0,"fwci":1.9242,"citation_percentile":0.86013163,"influential_citations":0,"citation_trend":[{"year":2016,"count":2},{"year":2017,"count":2},{"year":2018,"count":2},{"year":2019,"count":6},{"year":2020,"count":5},{"year":2021,"count":2},{"year":2023,"count":1},{"year":2024,"count":1},{"year":2025,"count":2}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/cam4.825","host_type":"journal"},{"url":"https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/cam4.825","host_type":"publisher"},{"url":"https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1002%2Fcam4.825","host_type":"publisher"},{"url":"https://onlinelibrary.wiley.com/doi/pdf/10.1002/cam4.825","host_type":"publisher"},{"url":"https://doi.org/10.1002/cam4.825","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/27485054","host_type":"repository"},{"url":"http://hdl.handle.net/11343/260739","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/5055158","host_type":"repository"},{"url":"http://hdl.handle.net/1959.3/431587","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC5055158","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC5055158?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["CRISPR and Genetic Engineering","RNA and protein synthesis mechanisms","RNA modifications and cancer","Biomarkers, Tumor","Cystadenocarcinoma, Serous","Disease Progression","Female","Genetic Association Studies","Genetic Predisposition to Disease","Humans","Kaplan-Meier Estimate","Mutation","Neoplasm Grading","Neoplasm Staging","Ovarian Neoplasms","Prognosis"],"mesh_terms":["Female","Humans","Mutation","Neoplasm Staging","Ovarian Neoplasms","Prognosis","Biomarkers, Tumor","Cystadenocarcinoma, Serous","Disease Progression","Genetic Predisposition to Disease","Kaplan-Meier Estimate","Genetic Association Studies","Neoplasm Grading"],"keywords":["APOBEC","Cytidine deaminase","Biology","In silico","Carcinogenesis","Genetics","Exome sequencing","Germline mutation","Sanger sequencing","Mutation","Computational biology","Cancer research","Bioinformatics","Cancer","Genome","Gene","Ovarian cancer","Cancer Genetics","Deaminase","Codon Context","Targeted Somatic Mutation"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-03T18:02:42.941521Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}