Dataset Information

Impact of the APOBEC3A/B deletion polymorphism on risk of ovarian cancer.

ABSTRACT: A germline 29.5-kb deletion variant removes the 3' end of the APOBEC3A gene and a large part of APOBEC3B, creating a hybrid gene that has been linked to increased APOBEC3 activity and DNA damage in human cancers. We genotyped the APOBEC3A/B deletion in hospital-based samples of 1398 Norwegian epithelial ovarian cancer patients without detected BRCA1/2 germline mutations and compared to 1,918 healthy female controls, to assess the potential cancer risk associated with the deletion. We observed an association between APOBEC3A/B status and reduced risk for ovarian cancer (OR = 0.75; CI = 0.61-0.91; p = 0.003) applying the dominant model. Similar results were found in other models. The association was observed both in non-serous and serous cases (dominant model: OR = 0.69; CI = 0.50-0.95; p = 0.018 and OR = 0.77; CI = 0.62-0.96; p = 0.019, respectively) as well as within high-grade serous cases (dominant model: OR = 0.79; CI = 0.59-1.05). For validation purposes, we mined an available large multinational GWAS-based data set of > 18,000 cases and > 26,000 controls for SNP rs12628403, known to be in linkage disequilibrium with the APOBEC3A/B deletion. We found a non-significant trend for SNP rs12628403 being linked to reduced risk of ovarian cancer in general and similar trends for all subtypes. For clear cell cancers, the risk reduction reached significance (OR = 0.85; CI = 0.69-1.00).

SUBMITTER: Gansmo LB

PROVIDER: S-EPMC8648731 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Impact of the APOBEC3A/B deletion polymorphism on risk of ovarian cancer.

Gansmo Liv B LB Sofiyeva Nigar N Bjørnslett Merete M Romundstad Pål P Hveem Kristian K Vatten Lars L Dørum Anne A Lønning Per E PE Knappskog Stian S

Scientific reports 20211206 1

A germline 29.5-kb deletion variant removes the 3' end of the APOBEC3A gene and a large part of APOBEC3B, creating a hybrid gene that has been linked to increased APOBEC3 activity and DNA damage in human cancers. We genotyped the APOBEC3A/B deletion in hospital-based samples of 1398 Norwegian epithelial ovarian cancer patients without detected BRCA1/2 germline mutations and compared to 1,918 healthy female controls, to assess the potential cancer risk associated with the deletion. We observed an ...[more]

PMID: 34873230

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Project description:<a href="https://www.nature.com/articles/s41467-017-00493-9" target="_blank">Chen T-W, Lee C-C, Liu H, Wu C-S, Pickering CR, Huang P-J, et al., Nature Communications 8, Article number: 465 (2017) doi:10.1038/s41467-017-00493-9</a>Oral squamous cell carcinoma is a prominent cancer worldwide, particularly in Taiwan. By integrating omics analyses in 50 matched samples, we uncover in Taiwanese patients a predominant mutation signature associated with cytidine deaminase APOBEC, which correlates with the upregulation of APOBEC3A expression in the APOBEC3 gene cluster at 22q13. APOBEC3A expression is significantly higher in tumors carrying APOBEC3B-deletion allele(s). High-level APOBEC3A expression is associated with better overall survival, especially among patients carrying APOBEC3B-deletion alleles, as examined in a second cohort (n=188; p=0.004). The frequency of APOBEC3B-deletion alleles is ~50% in 143 genotyped oral squamous cell carcinoma -Taiwan samples (27A3B-/-:89A3B+/-:27A3B+/+), compared to the 5.8% found in 314 OSCC-TCGA samples. We thus report a frequent APOBEC mutational profile, which relates to a APOBEC3B-deletion germline polymorphism in Taiwanese oral squamous cell carcinoma that impacts expression of APOBEC3A, and is shown to be of clinical prognostic relevance. Our finding might be recapitulated by genomic studies in other cancer types. Mass Spectrometry Data Sets, Provided BelowThe APOBEC-associated mutational signature enriched in the OSCC-Taiwan cohort was investigated to determine if this mutational signature might correlate with tumor-related alterations in APOBEC expression.RNA-Seq results from normal / tumor paired tissue samples were analyzed and data may be obtain from NCBI (<a href="https://www.ncbi.nlm.nih.gov/bioproject/PRJNA327548" target="_blank">BioProject:PRJNA327548</a> and <a href="https://trace.ncbi.nlm.nih.gov/Traces/sra/sra.cgi?study=SRP078156" target="_blank">SRA Study:SRP078156</a>). Corresponding enrichment of A3A-specific peptides in tumor proteomes was assessed by iTRAQ (isobaric Tags for Relative and Absolute Quantification) mass spectrometry protein quantification methods in 38 normal / tumor paired tissue samples. Peptides were digested, labeled by iTRAQ, and fractionated by on-line 2D-HPLC to 44 fractions. Each dataset (labeled as OSCC-Pxx, example OSCC-P01) contains 44 raw mass spectrometry data files (LTQ-Orbitrap ELITE). The iTRAQ 114 reagent was used to label the digestion products of 30-pairs of OSCC tissues, and iTRAQ 115 and 116 reagents were used to label peptides of non-tumor tissue and tumor tissue, respectively. The APOBEC3A (A3A) coding region is part of a APOBEC3 gene cluster at 22q13.<ul><li>Dataset imported into MassIVE from <a href="https://cptac-data-portal.georgetown.edu/cptac/s/S034">https://cptac-data-portal.georgetown.edu/cptac/s/S034</a> on 08/28/19</li></ul>

Dataset Information

Impact of the APOBEC3A/B deletion polymorphism on risk of ovarian cancer.

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Impact of the APOBEC3A/B deletion polymorphism on risk of ovarian cancer.

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