Human papillomavirus-independent cervical cancer

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Abstract

Cervical cancer is the fourth most frequent cancer in women worldwide, representing nearly 8% of all female cancer deaths every year. The majority of cases of cervical cancer are caused by human papillomavirus (HPV); however, up to 5% of tumors are not associated with HPV-persistent infection and, moreover, the new WHO Female Genital Tumors classification subdivided cervical squamous and adenocarcinomas into HPV-associated and HPV-independent tumors. Based on this new information, the aim of this review is to provide an overview of HPV-independent cervical cancer, evaluating diagnostic techniques, molecular profiles, and clinical outcomes. The HPV-independent tumors are characterized by a differentiated molecular profile with lower proliferative activity, a p53 immunostaining, a decreased expression of cyclin-dependent kinase inhibitor proteins, such as p16, p14, and p27, and alterations in PTEN, p53, KRAS, CTNNB1, ARID1A, and ARID5B. HPV-independent tumors are associated with both adenocarcinomas and squamous histologic subtypes, with lymph node involvement in the early stages, more distant metastasis, and generally worse oncological outcomes. Thus far, no specific therapeutic strategies have been developed based on HPV status; however, with advancing knowledge of differences in the molecular profiles and possible targetable alterations, novel approaches may offer potential options in the near future. Investigators should report on clinical outcomes, evaluating the overall response rates to specific treatments, and consider new biomarkers to establish more accurate prognostics factors.

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Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

Hyuna Sung, Jacques Ferlay, Rebecca Siegel … (2021)

This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2-fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.

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Estimates of incidence and mortality of cervical cancer in 2018: a worldwide analysis

Marc Arbyn, Elisabete Weiderpass, Laia Bruni … (2019)

Summary Background The knowledge that persistent human papillomavirus (HPV) infection is the main cause of cervical cancer has resulted in the development of prophylactic vaccines to prevent HPV infection and HPV assays that detect nucleic acids of the virus. WHO has launched a Global Initiative to scale up preventive, screening, and treatment interventions to eliminate cervical cancer as a public health problem during the 21st century. Therefore, our study aimed to assess the existing burden of cervical cancer as a baseline from which to assess the effect of this initiative. Methods For this worldwide analysis, we used data of cancer estimates from 185 countries from the Global Cancer Observatory 2018 database. We used a hierarchy of methods dependent on the availability and quality of the source information from population-based cancer registries to estimate incidence of cervical cancer. For estimation of cervical cancer mortality, we used the WHO mortality database. Countries were grouped in 21 subcontinents and were also categorised as high-resource or lower-resource countries, on the basis of their Human Development Index. We calculated the number of cervical cancer cases and deaths in a given country, directly age-standardised incidence and mortality rate of cervical cancer, indirectly standardised incidence ratio and mortality ratio, cumulative incidence and mortality rate, and average age at diagnosis. Findings Approximately 570 000 cases of cervical cancer and 311 000 deaths from the disease occurred in 2018. Cervical cancer was the fourth most common cancer in women, ranking after breast cancer (2·1 million cases), colorectal cancer (0·8 million) and lung cancer (0·7 million). The estimated age-standardised incidence of cervical cancer was 13·1 per 100 000 women globally and varied widely among countries, with rates ranging from less than 2 to 75 per 100 000 women. Cervical cancer was the leading cause of cancer-related death in women in eastern, western, middle, and southern Africa. The highest incidence was estimated in Eswatini, with approximately 6·5% of women developing cervical cancer before age 75 years. China and India together contributed more than a third of the global cervical burden, with 106 000 cases in China and 97 000 cases in India, and 48 000 deaths in China and 60 000 deaths in India. Globally, the average age at diagnosis of cervical cancer was 53 years, ranging from 44 years (Vanuatu) to 68 years (Singapore). The global average age at death from cervical cancer was 59 years, ranging from 45 years (Vanuatu) to 76 years (Martinique). Cervical cancer ranked in the top three cancers affecting women younger than 45 years in 146 (79%) of 185 countries assessed. Interpretation Cervical cancer continues to be a major public health problem affecting middle-aged women, particularly in less-resourced countries. The global scale-up of HPV vaccination and HPV-based screening—including self-sampling—has potential to make cervical cancer a rare disease in the decades to come. Our study could help shape and monitor the initiative to eliminate cervical cancer as a major public health problem. Funding Belgian Foundation Against Cancer, DG Research and Innovation of the European Commission, and The Bill & Melinda Gates Foundation.

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Integrated genomic and molecular characterization of cervical cancer

(2017)

Cervical cancer remains one of the leading causes of cancer-related deaths worldwide. Reported here is an extensive molecular characterization of 228 primary cervical cancers, the largest comprehensive genomic study of cervical cancer to date. We observed striking APOBEC mutagenesis patterns and identified SHKBP1, ERBB3, CASP8, HLA-A, and TGFBR2 as novel significantly mutated genes in cervical cancer. We also discovered novel amplifications in immune targets CD274/PD-L1 and PDCD1LG2/PD-L2, and the BCAR4 lncRNA that has been associated with response to lapatinib. HPV integration was observed in all HPV18-related cases and 76% of HPV16-related cases, and was associated with structural aberrations and increased target gene expression. We identified a unique set of endometrial-like cervical cancers, comprised predominantly of HPV-negative tumors with high frequencies of KRAS, ARID1A, and PTEN mutations. Integrative clustering of 178 samples identified Keratin-low Squamous, Keratin-high Squamous, and Adenocarcinoma-rich subgroups. These molecular analyses reveal new potential therapeutic targets for cervical cancers.