Etiology of Carcinoma of the Cervix

Project description

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 (ICC) 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 ICC, 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.
4. Describe which subtype/variant lineages of HPV16 – the dominant oncogenic HPV type – are found in the study.
5. Investigate prospectively whether conserved status and/or hypovariability of the HPV16 E7 gene typically precedes diagnosis of CIS or ICC.

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 (squamous carcinoma in situ/CIS and adenocarcinoma in situ/AIS) and ICC (squamous cell carcinoma/SCC and adenocarcinoma/AC), 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/AC, women with CIS/AIS and individually matched control women to each case woman. We have collected around 700 CIS case-control pairs, 500 SCC case-control pairs, 140 AIS case-control pairs and 120 AC 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. A total of 242 HPV16 positive specimens from our set of cases and controls have also been whole-genome sequenced, and we have obtained metrics to demonstrate the high quality and depth of our assay when used on our Illumina NextSeq platform.

Main results as of 2017

• Infections with HPV16 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).
• Co-infection with LRHPV is associated with a lower risk of future invasive disease and longer time to diagnosis than infection with HRHPV alone. We propose that co-infection with LRHPV interferes with the rate of progression to invasive cervical cancer (Sundström et al, 2015).
• We did not find any risk for cervical adenocarcinoma and/or AIS conferred by Chlamydia trachomatis infection as found in cervical smears from women around age 25 and upwards. C. trachomatis thus appears not to be immediately involved in cervical adenocarcinomas occurring in women around 30 years of age, but the significance of adolescent C. trachomatis infection and cervical adenocarcinoma risk remains unclear (Smelov et al, 2016).

Ongoing research

Currently, we are undertaking next-generation sequencing of all HPV16-positive samples in the study on CIS and SCC, and associated bioinformatical development. Preliminary data are promising and results are forthcoming.

Participants

Project leaders: Hans-Olov Adami, Joakim Dillner, Pär Sparén, Karin Sundström
Main financing: National Cancer Institute, National Institutes of Health, (PI: Hans-Olov Adami) and the Swedish Cancer Society (PI: Pär Sparén, Hans-Olov Adami)

Other participants: Sonia Andersson, Lisen Arnheim Dahlström, Ninoa Malki, Juni Palmgren, Alexander Ploner, Samuli Ripatti, Carani Sanjeevi, Nathalie Ylitalo, Sara Arroyo-Mühr, Carina Eklund, Camilla Lagheden, Emilie Hultin.