Genomics of Cervical Cancer and the Role of Human Papillomavirus Pathobiology

Abstract

Cervical cancer represents one of the most common malignancies in women worldwide and predominantly affects women of poor socioeconomic status. Persistent infection with high-risk human papillomavirus (HPV) 3 is an essential factor for development of cervical cancer. HPV infection is also associated with cancers of the vulva, vagina, anus, and oropharynx. Globally, an estimated 610 000 (4.8%) of the 12.7 million new cancer cases that occurred in 2008 could be attributed to HPV infection, and Ͼ500 000 of those cases represent cancers of the cervix alone (1 ). Within the last 2 decades, research has culminated in major advances in techniques for cervical cancer screening using HPV DNA and has led to a vaccine to prevent HPV infection. Yet, our strategies for the care and treatment of today's patients already infected with HPV need urgent attention. Women diagnosed with invasive and metastatic cervical cancer are in critical need of more-sophisticated prognostic markers, targeted therapeutic options, and more-accurate surveillance strategies. Viral Integration and Oncoprotein TargetsThere are about 120 HPV types, and types 16 and 18 are associated with 70% of the cases of cervical cancer worldwide. Many studies have shown that HPV-18 -associated cervical cancer is a strong independent prognostic factor for poorer disease-free survival for women undergoing surgery or radiation for early-stage invasive cervical cancer (2 ). The biology behind the poorer outcomes is unknown, but studies have suggested that sequence variation in HPV genes produces differences in their oncogenic potential. For example, HPV-18 E64 (E6 transforming protein) oncogene variants differentially regulate members of the Akt/P13K pathway and show increased expression of genes involved in cancer cell extravasation and metastasis (3, 4 ).HPV integration into the host genome is a critical step in cervical carcinogenesis and is found in almost all invasive cervical cancers. Integration frequently disrupts HPV E2 (E2 regulatory protein) gene expression, leading to increases in E6 and E7 viral oncoproteins, which in turn promote cellular immortalization and transformation. E6 and E7 (E7 transforming protein) gene overexpression contribute to marked genomic instability, accumulation of secondary mutations, and malignant transformation (5 ). In addition, the virus integrates into host genes and regulatory elements, which may cause structural alteration of the host genome and transcriptional deregulation of gene expression (6 ). The sites of integration occur frequently at common fragile sites in the genome, but these sites may be less random than originally appreciated. Further evaluation of HPV integration sites by the various HPV types could shed light on additional cancer-causing genes.The 8-kb HPV genomes have CpGs scattered throughout their genes. With advancing disease, these CpGs are increasingly methylated by the host cell's DNA methyltransferases. This methylation may alter the expression patterns of viral genes that are relevant to transforma...

Apigenin Inhibits Histamine-Induced Cervical Cancer Tumor Growth by Regulating Estrogen Receptor Expression

“…Cervical cancer, as a gynecological tumor, remains one of the most common causes of cancer-related deaths worldwide, which consists of 528,000 new cases and 266,000 deaths worldwide each year [1,2]. Most of the cervical cancer cases result from infection with human papillomavirus, and the primary treatment options for these patients include surgery followed by radiotherapy [3]. Nevertheless, poor prognosis is attributed to their toxic side effects and the increased incidence of other risk factors, such as vascular space invasion and lymph node metastases [4].…”

Spermidine‑induced growth inhibition and apoptosis via autophagic activation in cervical cancer

“…Cervical cancer accounts for 528,000 new cases and 266,000 deaths worldwide each year, more than any other gynecologic tumor (2). Effective preventive vaccines are available for the most important carcinogenic HPV strains, but their use remains poor (3). At present, the combination of radiotherapy and platinum-based chemotherapy is the gold-standard therapy for advanced cervical cancer (4).…”

Integrated genomic and molecular characterization of cervical cancer

“…Effective prophylactic vaccines against the most important carcinogenic HPV types are available, but uptake remains poor. Although early cervical cancer can be treated with surgery or radiation, metastatic cervical cancer is incurable and new therapeutic approaches are needed 3 .…”

“…The NCI Project Coordinator was Ina Felau 1 and the overall Analysis Coordinator and Data Coordinator was Christopher P. Vellano 2 . Special thanks also go out to TCGA network members who made substantial contributions to this work: Christopher P. Vellano 2 (Analysis Coordinator; Data Coordinator; Co-manuscript Coordinator; RPPA analysis), Nicolas Wentzensen 1 (Co-manuscript Coordinator; HPV analysis subgroup co-leader), Akinyemi I. Ojesina 3,4,56 (Co-manuscript Coordinator; HPV analysis subgroup co-leader; somatic alteration analysis), A. Gordon Robertson 5 (miRNA analysis; HPV analysis), Michael D. McLellan 6 (mutation calling); Ludmila Danilova 7 (methylation analysis); Bradley A. Murray 4 (copy number and ABSOLUTE analysis); Zhenlin Ju 2 (RPPA analysis); J. Todd Auman 8 (mRNA sequencing analysis; fusion analysis); Prabhakar Chalise 9 (iCluster analysis); Christina Yau 10 (PARADIGM pathway analysis); Giovanni Ciriello 53 (MEMo pathway analysis); Dmitry A. Gordenin 12 (APOBEC analysis); Rosemary Zuna 13 (Pathologist); Hailei Zhang 4 (mutation analysis; Firehose); Angeliki Pantazi 14 (structural variant analysis subgroup leader; low-pass sequencing); Matthew H. Bailey 6 (mutation analysis); Lixia Diao 2 (EMT analysis); Devin Koestler 9 (methylation data processing; FEM analysis); Karen Mungall 5 (HPV analysis); Lynette Lim 5 (HPV analysis); Reanne Bowlby 5 (miRNA analysis); Sara Sadeghi 5 (HPV analysis); Denise Brooks 5 (miRNA analysis); Chandra Sekhar Pedamallu 4 (HPV analysis); Ken Chen 2 (fusion analysis); Hao Zhao 2 (fusion analysis); Zechen Chong 2 (fusion analysis); Emmanuel Martinez-Ledesma 2 (fusion analysis); Roeland G. Verhaak 2 (fusion analysis); Kristen M. Leraas 15 (BCR); Tara M. Lichtenberg 15 (BCR); Daniel G. Tiezzi 16 (immune response gene analysis); Michael C. Ryan 2 (splicing analysis); Sheila M. Reynolds 21 (Regulome Explorer analysis); Gordon B. Mills 2 (Project Co-chair); and Janet S. Rader 17 (Project Co-chair).…”