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Basic and Translational Research on HPV-Related Malignancies

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Pathophysiology".

Deadline for manuscript submissions: closed (31 August 2021) | Viewed by 23047

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Special Issue Editors

Dr. Rui M. Gil da Costa

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Guest Editor

1. Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP) / RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto) / Porto Comprehensive Cancer Center (Porto.CCC), 4200-072 Porto, Portugal
2. Postgraduate Programme in Adult Health (PPGSAD), Department of Morphology, Federal University of Maranhão (UFMA), and UFMA University Hospital (HUUFMA), 65080-805 São Luís, Brazil
Interests: cancer cachexia; animal models of cancer
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Prof. Dr. Paula Oliveira

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Guest Editor

1. Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), Institute for Innovation, Capacity Building and Sustainability of Agri-Food Production (Inov4Agro), University of Trás-os-Montes and Alto Douro (UTAD), 5000-801 Vila Real, Portugal
2. Department of Veterinary Sciences, University of Trás-os-Montes and Alto Douro (UTAD), 5000-801 Vila Real, Portugal
Interests: animal models; in vivo studies; natural compounds
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear colleagues,

The development of HPV vaccines has changed the paradigm of cervical cancer prevention and, in combination with screening programmes, is expected to have a major impact on cancer incidence. However, many developing countries still experience significant difficulties in implementing HPV vaccination and screening. Additionally, the incidence of other HPV-related cancers, especially HPV⁺ head-and-neck squamous cell carcinoma, is rising alarmingly. The prognosis for advanced and metastatic HPV-related cancers remains poor, and there is a need for less-toxic and more effective therapies.

This Special Issue will address basic and translational studies on all HPV-related malignancies, including cervical cancer, HPV⁺ head-and-neck cancer, and other anogenital cancers like anal and penile cancers. The scope of this Issue is broad, ranging from basic mechanistic studies to pre-clinical trials of potential new therapies. In vivo studies involving animal models of disease and works based on alternative models (e.g., 3D cell culture, organ on a chip) are particularly welcomed, as well as works dealing with less-studied lesions such as penile cancer.

Dr. Rui M. Gil da Costa
Dr. Paula A. Oliveira
Guest Editors

Manuscript Submission Information

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Keywords

HPV
translational research
basic research
pre-clinical

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Published Papers (6 papers)

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Research

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17 pages, 2527 KiB

Open AccessArticle

Direct Comparison of HPV16 Viral Genomic Integration, Copy Loss, and Structural Variants in Oropharyngeal and Uterine Cervical Cancers Reveal Distinct Relationships to E2 Disruption and Somatic Alteration

by Travis P. Schrank, Sulgi Kim, Hina Rehmani, Aditi Kothari, Di Wu, Wendell G. Yarbrough and Natalia Issaeva

Cancers 2022, 14(18), 4488; https://doi.org/10.3390/cancers14184488 - 16 Sep 2022

Cited by 9 | Viewed by 2074

Abstract

Squamous cell carcinoma of the oropharynx caused by HPV type 16 (HPV16+ OPSCC) is the most common HPV-associated malignancy in the USA and has many molecular differences from uterine cervical squamous cell carcinoma (UCSCC). Our understanding of HPV oncogenesis relied on studies of UCSCC revealing a consensus model reliant on HPV integration with a loss of E2. Here, we compare patterns of HPV integration in UCSCC and OPSCC by analysis of affinity capture sequencing of the HPV16 genome in 104 OPSCC and 44 UCSCC tumors. These cohorts were contemporaneously sequenced using an identical strategy. Integration was identified using discordant read pair clustering and assembly-based approaches. Viral integration sites, structural variants, and copy losses were examined. While large-scale deep losses of HPV16 genes were common in UCSCC and were associated with E2 loss, deep copy losses of the HPV16 genome were infrequent in HPV16+ OPSCC. Similarly, structural variants within HPV16 favored E2 loss in UCSCC but not OPSCC. HPV16 integration sites were non-random, with recurrent integration hot-spots identified. OPSCC tumors had many more integration sites per tumor when compared to UCSCC and had more integration sites in genomic regions with high gene density. These data show that viral integration and E2 disruption are distinct in UCSCC and OPSCC. Our findings also add to growing literature suggesting that HPV tumorigenesis in OPSCC does not follow the model developed based on UCSCC. Full article

(This article belongs to the Special Issue Basic and Translational Research on HPV-Related Malignancies)

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19 pages, 1968 KiB

Open AccessArticle

PIK3CA Gene Mutations in HNSCC: Systematic Review and Correlations with HPV Status and Patient Survival

by Daniela Cochicho, Susana Esteves, Miguel Rito, Fernanda Silva, Luís Martins, Pedro Montalvão, Mário Cunha, Miguel Magalhães, Rui M. Gil da Costa and Ana Felix

Cancers 2022, 14(5), 1286; https://doi.org/10.3390/cancers14051286 - 2 Mar 2022

Cited by 18 | Viewed by 3485

Abstract

PIK3CA mutations are believed to contribute to the pathogenesis of human papillomavirus (HPV)-associated head and neck squamous cell carcinomas (HNSCC). This study aims to establish the frequency of PIK3CA mutations in a Portuguese HNSCC cohort and to determine their association with the HPV status and patient survival. A meta-analysis of scientific literature also revealed widely different mutation rates in cohorts from different world regions and a trend towards improved prognosis among patients with PIK3CA mutations. DNA samples were available from 95 patients diagnosed with HNSCC at the Portuguese Institute of Oncology in Lisbon between 2010 and 2019. HPV status was established based on viral DNA detected using real-time PCR. The evaluation of PIK3CA gene mutations was performed by real-time PCR for four mutations (H1047L; E542K, E545K, and E545D). Thirty-seven cases were found to harbour PIK3CA mutations (39%), with the E545D mutation (73%) more frequently detected. There were no significant associations between the mutational status and HPV status (74% WT and 68% MUT were HPV (+); p = 0.489) or overall survival (OS) (3-year OS: WT 54% and MUT 65%; p = 0.090). HPV status was the only factor significantly associated with both OS and disease-free survival (DFS), with HPV (+) patients having consistently better outcomes (3-year OS: HPV (+) 65% and HPV (−) 36%; p = 0.007; DFS HPV (+) 83% and HPV (−) 43%; p = 0.001). There was a statistically significant interaction effect between HPV status and PIK3CA mutation regarding DFS (Interaction test: p = 0.026). In HPV (+) patients, PIK3CA wild-type is associated with a significant 4.64 times increase in the hazard of recurrence or death (HR = 4.64; 95% CI 1.02–20.99; p = 0.047). Overall, PIK3CA gene mutations are present in a large number of patients and may help define patient subsets who can benefit from therapies targeting the PI3K pathway. The systematic assessment of PIK3CA gene mutations in HNSCC patients will require further methodological standardisation. Full article

(This article belongs to the Special Issue Basic and Translational Research on HPV-Related Malignancies)

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18 pages, 11043 KiB

Open AccessArticle

Genome-Wide Profiling Reveals HPV Integration Pattern and Activated Carcinogenic Pathways in Penile Squamous Cell Carcinoma

by Kang-Bo Huang, Sheng-Jie Guo, Yong-Hong Li, Xin-Ke Zhang, Dong Chen, Philippe E. Spiess, Zai-Shang Li, Chuang-Zhong Deng, Jie-Ping Chen, Qiang-Hua Zhou, Zheng Hu, Xin Ma, Jie-Tian Jin, Yun Cao, Jun-Hang Luo, Xiao-Bin Wang, Fang-Jian Zhou, Ran-Yi Liu and Hui Han

Cancers 2021, 13(23), 6104; https://doi.org/10.3390/cancers13236104 - 3 Dec 2021

Cited by 14 | Viewed by 3004

Abstract

Human papillomavirus (HPV) is a significant etiologic driver of penile squamous cell carcinoma (PSCC). The integration pattern of HPV and its carcinogenic mechanism in PSCC remain largely unclear. We retrospectively reviewed 108 PSCC cases who received surgery between 2008 and 2017. Using high-throughput viral integration detection, we identified 35 HPV-integrated PSCCs. Unlike cervical cancer, the HPV E2 oncogene was not prone to involvement in integration. Eleven of the 35 (31.4%) HPV-integrated PSCCs harbored intact HPV E2; these tumors had lower HPV E6 and E7 expression and higher expression of p53 and pRb proteins than those with disrupted E2 did (p < 0.001 and p = 0.024). Integration breakpoints are preferentially distributed in or near host genes, including previously reported hotspots (KLF5, etc.) and newly identified hotspots (CADM2, etc.), which are mainly involved in oncogenic signaling pathways (MAPK, JAK/STAT, etc.). Regarding the phosphorylation levels of JNK, p38 was higher in HPV-positive tumors with MAPK-associated integration than those in HPV-positive tumors with other integration and those in HPV-negative tumors. In vitro, KLF5 knockdown inhibited proliferation and invasion of PSCC cells, while silencing CADM2 promoted migration and invasion. In conclusion, this study enhances our understanding of HPV-induced carcinogenesis in PSCC, which may not only rely on the E6/E7 oncogenes, but mat also affect the expression of critical genes and thus activate oncogenic pathways. Full article

(This article belongs to the Special Issue Basic and Translational Research on HPV-Related Malignancies)

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12 pages, 2216 KiB

Open AccessArticle

Low Frequency of Human Papillomavirus in Strictly Site-Coded Oral Squamous Cell Carcinomas, Using the Latest NHI/SEER-ICD Systems: A Pilot Observational Study and Critical Review

by Vera Panzarella, Giuseppina Campisi, Ylenia Giardina, Laura Maniscalco, Giuseppina Capra, Vito Rodolico, Olga Di Fede and Rodolfo Mauceri

Cancers 2021, 13(18), 4595; https://doi.org/10.3390/cancers13184595 - 13 Sep 2021

Cited by 7 | Viewed by 5236

Abstract

The aim of this study was to evaluate HPV status in oral squamous cell carcinoma (OSCC), as coded by the latest classifications and applying a combination of detection methods used in clinical practice. Forty-two patients with suspect OSCC were consecutively recruited. Patients underwent an incisional biopsy for histological OSCC diagnosis and HPV identification by PCR DNA and p16 IHC. All lesions were coded by the latest ICD-0-3.2 site/histology classifications, as proposed for OSCC by the National Cancer Institute Surveillance, Epidemiology and End Results Programs. Moreover, a comparative analysis review, critically evaluated by the same site-coded systems and HPV detection methods, was performed. In 40 confirmed cases of OSCC, the frequency of HPV infection was 10% (4/40). Among positive patients, two cases were PCR DNA/p16 IHC positive (high-risk HPV 51, high-risk HPV 67), two cases were PCR DNA positive/p16 IHC negative (high-risk HPV 31 + 68, high-risk HPV 66). Applying the latest site coding systems for OSCC, the frequency of HPV infection in this study and in similar, reviewed investigations was low (from 3.3% to 12.5%). These results suggested no significant HPV role in oral carcinogenesis, particularly where an updated site-coded classification of OSCCs (categorically excluding the base of the tongue) had been performed. Full article

(This article belongs to the Special Issue Basic and Translational Research on HPV-Related Malignancies)

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10 pages, 1264 KiB

Open AccessArticle

Prevalence and Type Distribution of High-Risk Human Papillomavirus (HPV) in Breast Cancer: A Qatar Based Study

by Gulab Sher, Nadia Aziz Salman, Michal Kulinski, Rayyan Abdulaziz Fadel, Vinod Kumar Gupta, Ambika Anand, Salahddin Gehani, Sheraz Abayazeed, Omer Al-Yahri, Fakhar Shahid, Salman Alshaibani, Sara Hassan, M. Zafar Chawdhery, Giles Davies, Said Dermime, Shahab Uddin, G. Hossein Ashrafi and Kulsoom Junejo

Cancers 2020, 12(6), 1528; https://doi.org/10.3390/cancers12061528 - 10 Jun 2020

Cited by 25 | Viewed by 4390

Abstract

Human papillomavirus (HPV) has been implicated in the etiology of a variety of human cancers. Studies investigating the presence of high-risk (HR) HPV in breast tissue have generated considerable controversy over its role as a potential risk factor for breast cancer (BC). This is the first investigation reporting the prevalence and type distribution of high-risk HPV infection in breast tissue in the population of Qatar. A prospective comparison blind research study herein reconnoitered the presence of twelve HR-HPV types’ DNA using multiplex PCR by screening a total of 150 fresh breast tissue specimens. Data obtained shows that HR-HPV types were found in 10% of subjects with breast cancer; of which the presence of HPV was confirmed in 4/33 (12.12%) of invasive carcinomas. These findings, the first reported from the population of Qatar, suggest that the selective presence of HPV in breast tissue is likely to be a related factor in the progression of certain cases of breast cancer. Full article

(This article belongs to the Special Issue Basic and Translational Research on HPV-Related Malignancies)

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Review

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15 pages, 930 KiB

Open AccessReview

Experimental Models for Studying HPV-Positive and HPV-Negative Penile Cancer: New Tools for An Old Disease

by Beatriz Medeiros-Fonseca, Antonio Cubilla, Haissa Brito, Tânia Martins, Rui Medeiros, Paula Oliveira and Rui M. Gil da Costa

Cancers 2021, 13(3), 460; https://doi.org/10.3390/cancers13030460 - 26 Jan 2021

Cited by 7 | Viewed by 3609

Abstract

Penile cancer is an uncommon malignancy that occurs most frequently in developing countries. Two pathways for penile carcinogenesis are currently recognized: one driven by human papillomavirus (HPV) infection and another HPV-independent route, associated with chronic inflammation. Progress on the clinical management of this disease has been slow, partly due to the lack of preclinical models for translational research. However, exciting recent developments are changing this landscape, with new in vitro and in vivo models becoming available. These include mouse models for HPV⁺ and HPV⁻ penile cancer and multiple cell lines representing HPV⁻ lesions. The present review addresses these new advances, summarizing available models, comparing their characteristics and potential uses and discussing areas that require further improvement. Recent breakthroughs achieved using these models are also discussed, particularly those developments pertaining to HPV-driven cancer. Two key aspects that still require improvement are the establishment of cell lines that can represent HPV⁺ penile carcinomas and the development of mouse models to study metastatic disease. Overall, the growing array of in vitro and in vivo models for penile cancer provides new and useful tools for researchers in the field and is expected to accelerate pre-clinical research on this disease. Full article

(This article belongs to the Special Issue Basic and Translational Research on HPV-Related Malignancies)

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