APOBEC3A/B deletion polymorphism and cancer risk

Gansmo, Liv Beathe; Romundstad, P.; Hveem, Kristian; Vatten, Lars J.; Nik-Zainal, Serena; Lønning, Per Eystein; Knappskog, Stian

doi:10.1093/carcin/bgx131

Cited by 41 publications

(63 citation statements)

References 35 publications

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“…Somewhat surprisingly given the demonstrated mutagenic and pro-growth functions of A3B in breast cancer cell lines, this deletion allele is associated with an approximately two-fold increased breast and ovarian cancer risk in Asian populations and in certain European cohorts , Xuan et al 2013, Qi et al 2014, Middlebrooks et al 2016, Wen et al 2016. A recent Scandinavian study meanwhile found an increased lung cancer risk in A3A_B carriers aged younger than 50 years and a similar agerelated trend for prostate cancer risk but no association with breast cancer risk, a result consistent with a further study conducted in Sweden (Göhler et al 2016, Gansmo et al 2018. The reason for the increased cancer risk associated with A3A_B remains unclear, but it was shown that breast cancers from women carrying at least one copy of the deletion allele harbour an increased burden of A3-related mutations, suggesting another A3 enzyme is hyper-activated in these tumours .…”

Section: Figuresupporting

confidence: 84%

The APOBEC3 genes and their role in cancer: insights from human papillomavirus

Smith

Fenton

2019

Journal of Molecular Endocrinology

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The interaction between human papillomaviruses (HPV) and the apolipoprotein-B mRNA-editing catalytic polypeptide-like (APOBEC)3 (A3) genes has garnered increasing attention in recent years, with considerable efforts focused on understanding their apparent roles in both viral editing and in HPV-driven carcinogenesis. Here, we review these developments and highlight several outstanding questions in the field. We consider whether editing of the virus and mutagenesis of the host are linked or whether both are essentially separate events, coincidentally mediated by a common or distinct A3 enzymes. We discuss the viral mechanisms and cellular signalling pathways implicated in A3 induction in virally infected cells and examine which of the A3 enzymes might play the major role in HPV-associated carcinogenesis and in the development of therapeutic resistance. We consider the parallels between A3 induction in HPV-infected cells and what might be causing aberrant A3 activity in HPV-independent cancers such as those arising in the bladder, lung and breast. Finally, we discuss the implications of ongoing A3 activity in tumours under treatment and the therapeutic opportunities that this may present.

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Section: Figuresupporting

confidence: 84%

The APOBEC3 genes and their role in cancer: insights from human papillomavirus

Smith

Fenton

2019

Journal of Molecular Endocrinology

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“…Some of these are common deletions that delete genes such as RHD and GSTM1 (Supporting Information), while a number are in highlyrecombinant regions such as the immunoglobulin heavy chain locus on chromosome 14q32.33, and are unlikely to be functional. We also find evidence of known diseaseassociated gene deletions in our cohorts, such as a common 30kb deletion of APOBEC3B (chr22:38982347-38992804) that has been associated with increased risk of lung cancer, prostate cancer, (Gansmo et al, 2018), breast cancer, (Han et al, 2016;Long et al, 2013;Xuan et al, 2013) and HIV-1 susceptibility (Singh et al, 2016), as well as a common CNV at the FCGR3B locus (1:161623196-161631963) linked to autoimmune disease susceptibility (Fanciulli et al, 2007) and malaria severity (Faik et al, 2017). We also find evidence of known diseaseassociated gene deletions in our cohorts, such as a common 30kb deletion of APOBEC3B (chr22:38982347-38992804) that has been associated with increased risk of lung cancer, prostate cancer, (Gansmo et al, 2018), breast cancer, (Han et al, 2016;Long et al, 2013;Xuan et al, 2013) and HIV-1 susceptibility (Singh et al, 2016), as well as a common CNV at the FCGR3B locus (1:161623196-161631963) linked to autoimmune disease susceptibility (Fanciulli et al, 2007) and malaria severity (Faik et al, 2017).…”

Section: Gene Deletionssupporting

confidence: 55%

Population‐wide copy number variation calling using variant call format files from 6,898 individuals

Png

Süveges

Park

et al. 2019

Genetic Epidemiology

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Copy number variants (CNVs) play an important role in a number of human diseases, but the accurate calling of CNVs remains challenging. Most current approaches to CNV detection use raw read alignments, which are computationally intensive to process. We use a regression tree‐based approach to call germline CNVs from whole‐genome sequencing (WGS, >18x) variant call sets in 6,898 samples across four European cohorts, and describe a rich large variation landscape comprising 1,320 CNVs. Eighty‐one percent of detected events have been previously reported in the Database of Genomic Variants. Twenty‐three percent of high‐quality deletions affect entire genes, and we recapitulate known events such as the GSTM1 and RHD gene deletions. We test for association between the detected deletions and 275 protein levels in 1,457 individuals to assess the potential clinical impact of the detected CNVs. We describe complex CNV patterns underlying an association with levels of the CCL3 protein (MAF = 0.15, p = 3.6x10−12) at the CCL3L3 locus, and a novel cis‐association between a low‐frequency NOMO1 deletion and NOMO1 protein levels (MAF = 0.02, p = 2.2x10−7). This study demonstrates that existing population‐wide WGS call sets can be mined for germline CNVs with minimal computational overhead, delivering insight into a less well‐studied, yet potentially impactful class of genetic variant.

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“…Their main function is related to innate immunity and is considered important restriction factors against a broad range of viruses . However, APOBEC3 proteins are also involved in cellular processes related to mutagenic activity, including the development of several types of cancer, while APOBEC3B specifically has been associated with an increased risk of lung cancer …”

Section: Discussionmentioning

confidence: 99%