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Integrative genomic analyses of APOBEC-mutational signature, expression and germline deletion of APOBEC3 genes, and immunogenicity in multiple cancer types

Published on Dec 1, 2019in BMC Medical Genomics2.568
· DOI :10.1186/s12920-019-0579-3
Zhishan Chen (VUMC: Vanderbilt University Medical Center), Wanqing Wen52
Estimated H-index: 52
(VUMC: Vanderbilt University Medical Center)
+ 6 AuthorsXingyi Guo24
Estimated H-index: 24
(VUMC: Vanderbilt University Medical Center)
Abstract
Although APOBEC-mutational signature is found in tumor tissues of multiple cancers, how a common germline APOBEC3A/B deletion affects the mutational signature remains unclear. Using data from 10 cancer types generated as part of TCGA, we performed integrative genomic and association analyses to assess inter-relationship of expressions for isoforms APOBEC3A and APOBEC3B, APOBEC-mutational signature, germline APOBEC3A/B deletions, neoantigen loads, and tumor infiltration lymphocytes (TILs). We found that expression level of the isoform uc011aoc transcribed from the APOBEC3A/B chimera was associated with a greater burden of APOBEC-mutational signature only in breast cancer, while germline APOBEC3A/B deletion led to an increased expression level of uc011aoc in multiple cancer types. Furthermore, we found that the deletion was associated with elevated APOBEC-mutational signature, neoantigen loads and relative composition of T cells (CD8+) in TILs only in breast cancer. Additionally, we also found that APOBEC-mutational signature significantly contributed to neoantigen loads and certain immune cell abundances in TILs across cancer types. These findings reveal new insights into understanding the genetic, biological and immunological mechanisms through which APOBEC genes may be involved in carcinogenesis, and provide potential genetic biomarker for the development of disease prevention and cancer immunotherapy.
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References48
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PURPOSE: APOBEC3A and APOBEC3B cytidine deaminases have been implicated in the pathogenesis of multiple cancers, including breast cancer (BC). A germline deletion linking APOBEC3A and APOBEC3B loci (A3A/B) has been associated with higher APOBEC-mediated mutational burden, but its association with BC risk have been controversial. Therefore, this study investigated the association between A3A/B and BC susceptibility and clinical presentation in a Brazilian cohort. METHODS: A3A/B deletion was evalu...
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#1Nicole E. Mealey (U of C: University of Calgary)
#2Dylan E. O'Sullivan (Queen's University)H-Index: 5
Last. Darren R. Brenner (AHS: Alberta Health Services)H-Index: 9
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BACKGROUND: The incidence of breast cancer among young women (aged 40 years) using data from The Cancer Genome Atlas. We examined mutated genes, mutational load, and types of mutations. We used complementary R packages "deconstructSigs" and "SomaticSignatures" to extract mutational signatures. A recursively partitioned mixture model was used to identify whether combinations of mutational signatures were related to age of onset. RESULTS: Older patients had a higher proportion of mutations in PIK3...
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