Mutations in the HPV16 genome induced by APOBEC3 are associated with viral clearance

Zhu, Bin; Xiao, Yanzi; Yeager, Meredith; Clifford, Gary M.; Wentzensen, Nicolas; Cullen, Michael; Boland, Joseph F.; Bass, Sara; Steinberg, Mia; Raine‐Bennett, Tina; Lee, Dong Hyuk; Burk, Robert D.; Pinheiro, Maísa; Song, Lei; Dean, Michael; Nelson, Chase W.; Burdett, Laurie; Yu, Kai; Roberson, David A.; Lorey, Thomas; Franceschi, Silvia; Castle, Philip E.; Walker, Joan L.; Zuna, Rosemary E.; Schiffman, Mark; Mirabello, Lisa

doi:10.1038/s41467-020-14730-1

Cited by 60 publications

(109 citation statements)

References 92 publications

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“…We find that the genomic events differ dependent of lesion severity but more importantly that these are strikingly different between HPV16 and HPV18 positive samples. To our knowledge, we are the first to show that with increasing lesion severity variation in NCR increases and report, in line with other studies [10,18], decreases in APOBEC3-related nucleotide substitutions in HPV16 positive samples. As previously reported [21,41], HPV18 samples show higher integration frequencies compared to HPV16, while we found an increase in integration frequencies in or in close proximity to cancer-related genes with increasing lesion severity.…”

Section: Discussionsupporting

confidence: 91%

HPV16 and HPV18 type-specific APOBEC3 and integration profiles in different diagnostic categories of cervical samples

Lagström

Løvestad

Umu

et al. 2020

Preprint

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Human papillomavirus 16 and 18 are the most predominant types in cervical cancer. Only a small fraction of HPV infections progress to cancer, indicating that genomic factors, such as minor nucleotide variation caused by APOBEC3 and chromosomal integration, contribute to the carcinogenesis.We analysed minor nucleotide variants (MNVs) and integration in HPV16 and HPV18 positive cervical samples with different morphology. Samples were sequenced using an HPV whole genome sequencing protocol TaME-seq. A total of 80 HPV16 and 51 HPV18 positive cervical cell samples passed the sequencing depth criteria of 300× reads, showing the following distribution: non-progressive disease (HPV16 n=21, HPV18 n=12); cervical intraepithelial neoplasia (CIN) grade 2 (HPV16 n=27, HPV18 n=9); CIN3/adenocarcinoma in situ (AIS) (HPV16 n=27, HPV18 n=30); cervical cancer (HPV16 n=5).Similar rates of MNVs in HPV16 and HPV18 samples were observed for most viral genes but for HPV16, the non-coding region (NCR) showed a trend towards increasing variation with increasing lesion severity. APOBEC3 signatures were observed in HPV16 lesions, while similar mutation patterns were not detected for HPV18. The proportion of samples with integration was 13% for HPV16 and 59% for HPV18 positive samples, with a noticeable portion located within or close to cancer-related genes.

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Section: Discussionsupporting

confidence: 91%

HPV16 and HPV18 type-specific APOBEC3 and integration profiles in different diagnostic categories of cervical samples

Lagström

Løvestad

Umu

et al. 2020

Preprint

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“…Accumulating evidence indicates that HPV genomes often undergo mutagenesis in infected individuals, and APOBEC3 is a prime candidate for host proteins that generate such withinhost viral genomic variability (Mirabello et al, 2017;Hirose et al, 2018;Mariaggi et al, 2018). APOBEC3 signature mutations in the HPV16 genome are more often detected in low-grade cervical lesions than in precancer/cancer samples, implying that APOBEC3 is involved in defending against HPV infections (Zhu et al, 2020). In the current study, we extended viral genomic analysis to asymptomatically HPV16-infected normal FIGURE 3 | Biological activities of within-host variants of E1 and E2 proteins.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, comprehensive genomics studies of HPV16 have documented that nucleotide variations in the HPV16 genome within individual clinical specimens were mostly C-to-T or G-to-A substitutions, which are believed to be mediated by cellular APOBEC3 cytosine deaminases as a host defense response to virus infection (Hirose et al, 2018;Zhu et al, 2020). We therefore examined the mutational spectrum in our clinical samples, based on six types of substitutions, i.e., C-to-A, C-to-G, C-to-T, T-to-A, T-to-C, and T-to-G (all substitutions are referred to by the pyrimidine of the mutated Watson-Crick base pair).…”

Section: Patterns Of Nucleotide Substitutions Of Within-host Variationsmentioning

confidence: 99%

“…In the HPV16 genome, these are mostly predominated by C-to-T or C-to-G substitutions, clearly implying the involvement of cellular APOBEC3 cytosine deaminases in their generation (Mirabello et al, 2017;Hirose et al, 2018). Such signature mutations are more frequently detected in normal or low-grade specimens of the cervix, suggesting that APOBEC3 mediates viral clearance by introducing deleterious mutations into the HPV16 genome (Hirose et al, 2018;Zhu et al, 2020). In contrast, in precancer/cancer specimens, some nucleotide variations in the HPV16 genome were found to be enriched to relatively high levels within a specimen (de Oliveira et al, 2015;Hirose et al, 2018;van der Weele et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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High Levels of Within-Host Variations of Human Papillomavirus 16 E1/E2 Genes in Invasive Cervical Cancer

et al. 2020

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Human papillomavirus type 16 (HPV16) is the most common HPV genotype found in invasive cervical cancer (ICC). Recent comprehensive genomics studies of HPV16 have revealed that a large number of minor nucleotide variations in the viral genome are present in each infected woman; however, it remains unclear whether such within-host variations of HPV16 are linked to cervical carcinogenesis. Here, by employing next-generation sequencing approaches, we explored the mutational profiles of the HPV16 genome within individual clinical specimens from ICC (n = 31) and normal cervix (n = 21) in greater detail. A total of 367 minor nucleotide variations (167 from ICC and 200 from the normal cervix) were detected throughout the viral genome in both groups, while nucleotide variations at high frequencies (>10% abundance in relative read counts in a single sample) were more prevalent in ICC (10 in ICC versus 1 in normal). Among the high-level variations found in ICC, six were located in the E1/E2 genes, and all of them were non-synonymous substitutions (Q142K, M207I, and L262V for E1; D153Y, R302T, and T357A for E2). In vitro functional analyses of these E1/E2 variants revealed that E1/M207I, E2/D153Y, and E2/R302T had reduced abilities to support viral replication, and that E2/D153Y and E2/R302T failed to suppress the viral early promoter. These results imply that some within-host variations of E1/E2 present at high levels in ICC may be positively selected for and contribute to cervical cancer development through dysfunction or de-stabilization of viral replication/transcription proteins.

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“…lung cancer BLCA HPV-associated cancer mutagenesis A3A and A3B [3,4,9,24,134,139], A3H Hap I [5] A3A and A3B [4,134,175,176], A3H Hap I [5] A3A and A3B [4,134,135] A3A and A3B [4,28,207,213] prognosis A3B [140,141] A3A and A3B [34,133] A3A [134] A3-induced mutations [132,134] carcinogenesis A3B [3,144] A3B [220] cancer progression A3B [147] royalsocietypublishing.org/journal/rsob Open Biol. 10: 200188…”

Section: Brcamentioning

confidence: 99%

The interesting relationship between APOBEC3 deoxycytidine deaminases and cancer: a long road ahead

2020

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Cancer is considered a group of diseases characterized by uncontrolled growth and spread of abnormal cells and is propelled by somatic mutations. Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3) family of enzymes are endogenous sources of somatic mutations found in multiple human cancers. While these enzymes normally act as an intrinsic immune defence against viruses, they can also catalyse ‘off-target’ cytidine deamination in genomic single-stranded DNA intermediates. The deamination of cytosine forms uracil, which is promutagenic in DNA. Key factors to trigger the APOBEC ‘off-target’ activity are overexpression in a non-normal cell type, nuclear localization and replication stress. The resulting uracil-induced mutations contribute to genomic variation, which may result in neutral, beneficial or harmful consequences for the cancer. This review summarizes the functional and biochemical basis of the APOBEC3 enzyme activity and highlights their relationship with the most well-studied cancers in this particular context such as breast, lung, bladder, and human papillomavirus-associated cancers. We focus on APOBEC3A, APOBEC3B and APOBEC3H haplotype I because they are the leading candidates as sources of somatic mutations in these and other cancers. Also, we discuss the prognostic value of the APOBEC3 expression in drug resistance and response to therapies.

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Mutations in the HPV16 genome induced by APOBEC3 are associated with viral clearance

Cited by 60 publications

References 92 publications

HPV16 and HPV18 type-specific APOBEC3 and integration profiles in different diagnostic categories of cervical samples

HPV16 and HPV18 type-specific APOBEC3 and integration profiles in different diagnostic categories of cervical samples

High Levels of Within-Host Variations of Human Papillomavirus 16 E1/E2 Genes in Invasive Cervical Cancer

The interesting relationship between APOBEC3 deoxycytidine deaminases and cancer: a long road ahead

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