Biological and clinical aspects of HPV-related cancers

Abstract

Cancer-related diseases represent the second overall cause of death worldwide. Human papilloma virus (HPV) is an infectious agent which is mainly sexually transmitted and may lead to HPV-associated cancers in both men and women. Almost all cervical cancers are HPV-associated, however, an increasing number of head and neck cancers (HNCs), especially oropharyngeal cancer, can be linked to HPV infection. Moreover, anogenital cancers, including vaginal, vulvar, penial, and anal cancers, represent a subset of HPV-related cancers. Whereas testing and prevention of cervical cancer have significantly improved over past decades, anogenital cancers remain more difficult to confirm. Current clinical trials including patients with HPV-related cancers focus on finding proper testing for all HPV-associated cancers as well as improve the currently applied treatments. The HPV viral oncoproteins, E6 and E7, lead to degradation of, respectively, p53 and pRb resulting in entering the S phase without G1 arrest. These high-risk HPV viral oncogenes alter numerous cellular processes, including DNA repair, angiogenesis, and/or apoptosis, which eventually result in carcinogenesis. Additionally, a comprehensive analysis of gene expression and alteration among a panel of DNA double strand breaks (DSB) repair genes in HPV-negative and HPV-positive HNC cancers reveals differences pointing to HPV-dependent modifications of DNA repair processes in these cancers. In this review, we discuss the current knowledge regarding HPV-related cancers, current screening, and treatment options as well as DNA damage response-related biological aspects of the HPV infection and clinical trials.

Keywords: DNA repair; HNC; Human papillomavirus (HPV); cancer statistics; cervical cancer; clinical trials.

Figure 1

Cancer incidence and mortality numbers according to the WHO and the Centers for Disease Control (CDC). (A) Incidence (blue) and mortality (red) numbers for 10 most prominent cancer types worldwide. (B) Incidence (blue) and mortality (red) numbers for 10 most prominent cancer types in the US. (C) Number of cancer cases in the US in men (left) and women (right) according to the CDC. (D) Rates for cancer associated with the most common five risk factors in women and men. Tobacco use-associated cancers include: oral cavity and pharynx, esophagus; stomach; colon and rectum; liver; pancreas; larynx; lung, bronchus, and trachea; cervix; kidney and renal pelvis; urinary bladder; and acute myeloid leukemia. Obesity-associated cancers include adenocarcinoma of the esophagus; cancers of the breast (in postmenopausal women), colon and rectum, endometrium (corpus uterus), gallbladder, gastric cardia, kidney (renal cell), liver, ovary, pancreas, and thyroid; meningioma, and multiple myeloma. Alcohol-associated cancers include: oral cavity and pharynx, esophagus, colon and rectum, liver, larynx, and female breast cancer. Physical inactivity-associated cancers include breast cancer in postmenopausal women, endometrium (corpus uterus) cancer, and colon cancer. HPV-associated cancers include microscopically confirmed carcinoma of the cervix and squamous cell carcinomas of the vagina, vulva, penis, anus, rectum, and oropharynx.

Figure 2

HPV-associated cancer types in men and women according to the WHO and the CDC. (A) Distribution of infection-caused cancers according to infectious agents worldwide in men and women. (B) Numbers of cancers caused by distinct HPV subtypes in women. (C) Numbers of cancers caused by distinct HPV subtypes in men. (D) Percentage of different HPV-associated cancers in women. (E) Percentage of different HPV-associated cancers in men.

Figure 3

Effect of HPV E6 and E7 viral oncoproteins on cellular processes. E6 and E7 viral oncoproteins can affect angiogenesis, DNA repair, growth arrest and apoptosis by impairing G1 arrest. E6 binds to E6AP, and subsequently binds to p53 and promotes its degradation by ubiquitination. Thus, the function of p53 as a tumor suppressor is diminished and cell cycle is not properly controlled by p21, a cyclin-dependent kinase inhibitor that ensures G1/S checkpoint. E7 leads to degradation of pRb, the retinoblastoma protein that functions as a tumor suppressor. Because of RB inhibition by E7, cells can enter S phase without a G1 arrest.

Figure 4

Different frequencies in gene mutations in HPV-positive and negatives cancers. (A) Frequency of mutations in HPV-positive and HPV-negative HNC cancer patients based on TCGA bioportal in silico analysis. (B) Frequency of mutations in cervical cancer patients based on TCGA bioportal in silico analysis. (C, D) Co-expression of DNA DSB repair genes in HPV-negative (C) and HPV-positive (D) HNC patients based on TCGA bioportal in silico analysis.