Mechanistic Signatures of Human Papillomavirus Insertions in Anal Squamous Cell Carcinomas

Morel, Adeline; Neuzillet, Cindy; Wack, Maxime; Lameiras, Sonia; Vacher, Sophie; Deloger, Marc; Servant, Nicolas; Veyer, David; Péré, Hélène; Mariani, Odette; Baulande, Sylvain; Rouzier, Roman; Kamal, Maud; Alam, Elsy El; Jeannot, Emmanuelle; Nicolas, Alain; Bièche, Ivan; Cacheux, Wulfran

doi:10.3390/cancers11121846

Cited by 23 publications

(30 citation statements)

References 33 publications

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“…As expected, HPV16 was the most abundant subtype and was detected in more than 90% of HPV positive patients, and all HPV positive patients harbored at least one subtype categorized as carcinogenic by the IARC. A similar distribution of HPV subtypes was also observed by Morel et al [29]. This recent study investigated the mechanistic signatures of HPV insertion in anal SCC.…”

Section: Discussionsupporting

confidence: 81%

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Evaluation of PD-L1 Expression and HPV Genotyping in Anal Squamous Cell Carcinoma

Wessely

Heppt

Kammerbauer

et al. 2020

Cancers

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Anal squamous cell carcinoma (SCC) is a rare cancer with increasing incidence. Infection with high-risk human papillomavirus (HPV) subtypes is the major cause for its development. We retrospectively analyzed tumor samples from 54 anal SCC patients for infection with a panel of 32 HPV subtypes in a PCR-based approach, determined the PD-L1 expression status, and correlated the findings with the clinical data and the survival of the patients. Forty-two patients (77.8%) were HPV-positive and harbored at least one carcinogenic HPV subtype. HPV16 was the most frequently detected (n = 39, 72.2%). Four patients were infected with multiple HPV subtypes. HPV infection was significantly more often detected in female than in male patients (90.3% vs. 60.9%, p = 0.018). Patients with PD-L1 positive tumors showed a significantly better median overall survival (OS) compared with patients with PD-L1 negative tumors (69.3 vs. 28.3 months, p = 0.006). The median OS was significantly different among the distinct tumor stages (p = 0.029). Sex, grade of differentiation, and HPV infection status did not influence the median OS. Furthermore, HPV infection status and PD-L1 expression were not correlated. A multivariate Cox regression analysis revealed that PD-L1 expression status was an independent prognostic marker for survival (p = 0.012).

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Section: Discussionsupporting

confidence: 81%

“…Notably, HPV integration signatures and clinico-pathological features were not significantly associated. However, the authors did not evaluate the PD-L1 expression status of the patients [29].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of PD-L1 Expression and HPV Genotyping in Anal Squamous Cell Carcinoma

Wessely

Heppt

Kammerbauer

et al. 2020

Cancers

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“…The distribution of HPV signatures in our CC cohort differed from that previously described in HPV-positive anal squamous cell carcinoma with a lower rate of episomal HPV as compared to anal cancer (45%). 17 No significant association was observed between HPV integration signatures and treatment type, histological subtype or FIGO staging. MJ viral integration signatures were predominant in HPV16-positive samples and tumours with viral integration (2J or MJ) had less frequent activating mutations in PIK3CA than those harbouring episomal HPV, confirming previously reported data.…”

Section: Discussionmentioning

confidence: 94%

Human papilloma virus (HPV) integration signature in Cervical Cancer: identification of MACROD2 gene as HPV hot spot integration site

Kamal

Lameiras²,

Deloger³

et al. 2020

Br J Cancer

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Background Cervical cancer (CC) remains a leading cause of gynaecological cancer-related mortality with infection by human papilloma virus (HPV) being the most important risk factor. We analysed the association between different viral integration signatures, clinical parameters and outcome in pre-treated CCs. Methods Different integration signatures were identified using HPV double capture followed by next-generation sequencing (NGS) in 272 CC patients from the BioRAIDs study [NCT02428842]. Correlations between HPV integration signatures and clinical, biological and molecular features were assessed. Results Episomal HPV was much less frequent in CC as compared to anal carcinoma (p < 0.0001). We identified >300 different HPV-chromosomal junctions (inter- or intra-genic). The most frequent integration site in CC was in MACROD2 gene followed by MIPOL1/TTC6 and TP63. HPV integration signatures were not associated with histological subtype, FIGO staging, treatment or PFS. HPVs were more frequently episomal in PIK3CA mutated tumours (p = 0.023). Viral integration type was dependent on HPV genotype (p < 0.0001); HPV18 and HPV45 being always integrated. High HPV copy number was associated with longer PFS (p = 0.011). Conclusions This is to our knowledge the first study assessing the prognostic value of HPV integration in a prospectively annotated CC cohort, which detects a hotspot of HPV integration at MACROD2; involved in impaired PARP1 activity and chromosome instability.

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“…Cervical cancer (CC) is one of the most common tumours, ranking fourth for both incidence and mortality in women worldwide [ 1 – 3 ]. CC is the result of continuous infection with some strains of human papillomavirus (HPV), such as HPV16 and HPV18 [ 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

Connecting METTL3 and intratumoural CD33+ MDSCs in predicting clinical outcome in cervical cancer

Zhang

Huang

et al. 2020

J Transl Med

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Background Methyltransferase-like 3 (METTL3) is a member of the m6A methyltransferase family and acts as an oncogene in cancers. Recent studies suggest that host innate immunity is regulated by the enzymes controlling m6A epitranscriptomic changes. Here, we aim to explore the associations between the levels of METTL3 and CD33+ myeloid-derived suppressor cells (MDSCs) in tumour tissues and the survival of patients with cervical cancer (CC). Methods Specimens of paraffin embedded tumour from 197 CC patients were collected. The expression levels of METTL3 and CD33 were measured by immunohistochemical (IHC) staining. The clinical associations of the IHC variants were analysed by Pearson’s or Spearman’s chi-square tests. Overall survival (OS) and disease-free survival (DFS) were estimated by the Kaplan–Meier method and log-rank test. Hazard ratios (HRs) and independent significance were obtained via Cox proportional hazards models for multivariate analyses. METTL3 in CD33+ cells or CC-derived cells was knocked down by METTL3-specific siRNA, and MDSC induction in vitro was performed in a co-culture system in the presence of METTL3-siRNA and METTL3-knockdown-CC-derived cells compared with that of the corresponding controls. Results We found that tumour tissues displayed increased levels of METTL3 and CD33+ MDSCs compared with tumour-adjacent tissues from the same CC patients. Importantly, METTL3 expression was positively related to the density of CD33+ cells in tumour tissues (P = 0.011). We further found that the direct CD33+CD11b+HLA-DR− MDSC induction and tumour-derived MDSC induction in vitro were decreased in the absence of METTL3. The level of METTL3 in tumour microenvironments was significantly related to advanced tumour stage. The levels of METTL3 and CD33+ MDSCs in tumour tissues were notably associated with reduced DFS or OS. Cox model analysis revealed that the level of METTL3 in tumour cells was an independent factor for patient survival, specifically for DFS (HR = 3.157, P = 0.022) and OS (HR = 3.271, P = 0.012), while the CD33+ MDSC number was an independent predictor for DFS (HR: 3.958, P = 0.031). Interestingly, in patients with advanced-disease stages (II–IV), METTL3 in tumour cells was an independent factor for DFS (HR = 6.725, P = 0.010) and OS (HR = 5.140, P = 0.021), while CD33+ MDSC density was an independent factor for OS (HR = 8.802, P = 0.037). Conclusion Our findings suggest that CD33+ MDSC expansion is linked to high levels of METTL3 and that METTL3 and CD33+ MDSCs are independent prognostic factors in CC.

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Mechanistic Signatures of Human Papillomavirus Insertions in Anal Squamous Cell Carcinomas

Cited by 23 publications

References 33 publications

Evaluation of PD-L1 Expression and HPV Genotyping in Anal Squamous Cell Carcinoma

Evaluation of PD-L1 Expression and HPV Genotyping in Anal Squamous Cell Carcinoma

Human papilloma virus (HPV) integration signature in Cervical Cancer: identification of MACROD2 gene as HPV hot spot integration site

Connecting METTL3 and intratumoural CD33+ MDSCs in predicting clinical outcome in cervical cancer

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