Etiology of Carcinoma of the Cervix
A Prospective Study on Type, Persistence, and Viral Load of Human Papillomavirus in the Etiology of Carcinoma of the Cervix
Our long-term objective is to bring about improved prevention of cervix cancer through enhanced biologic understanding and more cost-effective screening strategies.
Although human papilloma virus (HPV) infection is an established cause of cervical cancer, it is incompletely known what quantitative risk is associated with different HPV types, and with persistent infection, and whether viral load of HPV influences tumor progression from cancer in situ (CIS) to invasive cancer and/or interacts with genetic factors. The relative differences between cervical cancer of squamous and glandular origin are also incompletely described. Since clinical intervention precludes direct observation of this progression, unconventional approaches are needed.
Our main specific aims are to:
1) quantify the absolute and relative risks for CIS and invasive cancer (SCC) as a function of time since detected HPV infection, and of viral load of HPV 16,
2) compare the relative risk functions between CIS and invasive cancer, and
3) assess whether Chlamydia trachomatis infection, and/or HLA haplotype, modulates the final outcome of HPV infection in terms of cervical cancer risk and whether such modulation is mediated via an effect on HPV viral load.
Building on experience from an earlier study of CIS (funded by NCI), we have taken advantage of unique prerequisites in Sweden created by extensive population-based Papanicolaou smear screening documented in computerized registers, ascertainment of all incident cases of CIS and SCC, and access to archival smears and tissue specimens. Using a nested design in this large cohort with up to 25 years of complete follow-up, we have collected repeated samples from women with SCC, women with CIS and individually matched control women to each case woman. We have collected around 700 CIS case-control pairs and 500 SCC case-control pairs. Using validated and sensitive PCR assays, the presence of HPV DNA - and for HPV 16 and HPV18, also the viral load, - have been analyzed in all archival smears from these women taken during the follow-up period.
Main results as of 2013
- Infections with HPV 16 and 18 are detectable up to at least 14 years before diagnosis of cervical adenocarcinoma. Our data provide prospective evidence that the association of HPV 16/18 with cervical adenocarcinoma is strong and causal. (Dahlström et al, 2010)
- We confirm that HPV16/18 detected already in the first cervical smear is associated with greatly increased risks for future CIS and SCC. Furthermore, we provide prospective evidence that non-16/18 HRHPV types also increase the risk for future cervical cancer. (Sundström et al, 2010)
- Low viral load (VL) of HPV16 is common among both CIS and SCC case women, until 1 to 2 years before diagnosis when a surge in VL occurs.. For women with medium to high VL, the risk for CIS was greatly increased from 5 years before diagnosis. In SCC, a high VL conferred an increased risk, but only from 3 years before diagnosis. We thus conclude that HPV16 viral load is important, yet appears highly complex which may limit its use in cervical screening programs. (Sundström et al, 2013).
Currently, we are undertaking Chlamydia analyses in this material, and we are exploring the significance of interaction effects between different categories of HPV types, and possible association to risk for CIS and SCC. In addition, analyses are ongoing on HPV18 viral load.
Project leaders: Hans-Olov Adami, Joakim Dillner, Pär Sparén
Main financing: National Cancer Institute, National Institutes of Health, (PI: Hans-Olov Adami) and the Swedish Cancer Society (PI: Pär Sparén)
Other participants: Sonia Andersson, Lisen Arnheim Dahlström, Ninoa Malki, Juni Palmgren, Alexander Ploner, Samuli Ripatti, Carani Sanjeevi, Nathalie Ylitalo
Prospective study of HPV16 viral load and risk of in situ and invasive squamous cervical cancer.
Cancer Epidemiol. Biomarkers Prev. 2013 Jan;22(1):150-8
Prospective study of human papillomavirus (HPV) types, HPV persistence, and risk of squamous cell carcinoma of the cervix.
Cancer Epidemiol. Biomarkers Prev. 2010 Oct;19(10):2469-78
Prospective study of human papillomavirus and risk of cervical adenocarcinoma.
Int. J. Cancer 2010 Oct;127(8):1923-30
Viral load of human papilloma virus 16 as a determinant for development of cervical carcinoma in situ: a nested case-control study.
Lancet 2000 Jun;355(9222):2189-93
Consistent high viral load of human papillomavirus 16 and risk of cervical carcinoma in situ: a nested case-control study.
Lancet 2000 Jun;355(9222):2194-8