HLA class II alleles have been associated with an increased risk of developing cervical cancer through infection with oncogenic forms of human papilloma virus (HPV). We have examined the association of variation at the DRB1 and DQB1 loci with HPV16 infection and risk of development of cervical cancer by analysis of 440 cases diagnosed with cervical cancer in situ and 476 age-matched controls in a retrospective casecontrol study. The infection history of a woman was studied by analysis of cervical smears taken at multiple times during a period of up to 27 years (1969 -95 Key words: HLA; HPV; cervical cancerInfection with oncogenic forms of human papillomavirus (HPV) is the major etiologic factor for the development of cervical cancer. Using sensitive detection methods, oncogenic HPVs have been found in almost every cervical tumor. 1,2 However, infection with oncogenic HPVs is common among women having normal cytology, 3 mild lesions regress without intervention and most infections are cleared spontaneously. This implies that factors determining the course of an HPV infection contribute to the risk of developing cervical cancer. Such factors may include the inherent ability to respond to HPV infection.It has been suggested that differences in the immune response to HPV affect whether an HPV infection is cleared or becomes persistent. 4 Given the pivotal role of HLA molecules in the recognition of foreign peptides, several studies have been performed to examine the association of specific HLA alleles with HPV infection status and development of cervical cancer. In 1991, the HLA-DQw3 antigen was reported to be associated with cervical cancer in a German cohort, 4 and later studies in Spanish, 5 British 6 and African-American cohorts 7 showed similar results. Other HLA alleles have also been proposed to increase the risk of cervical cancer: DRB1*1501, 5,8 DRB1*04 and DRB1*11. 9 A number of alleles that are less common in patients relative to controls have also been reported, e.g., DRB1*1301, 8 DQB1*0501 9 and DQB1*0603. 5 An increased risk for HPV16-associated cervical cancer has been reported for the DRB1*1501-DQB1*0602 haplotype, 10 the DQA1*0102-DQB1*0602 haplotype 11 and for the DRB1*0701 allele. 12,13 Finally, an HPV16-specific protective effect for DR13 alleles has been reported. 10 While a direct comparison between these studies is somewhat difficult due to differences in cancer stage studied, laboratory methods and study population, they indicate an effect of HLA alleles on risk of cervical cancer. In our study, we have used a large case-control material to investigate the association of HLA class II alleles with infection by HPV16 and to the risk of developing cervical cancer in situ. Our results show that HLA class II alleles are associated primarily with infection of HPV and only secondarily with cervical cancer. MATERIAL AND METHODS SubjectsThe participants in our study were selected from a cohort of women residing in Uppsala County, Sweden, between 1969 -95. 14 The participants had to fulfill the follow...

Background: Progress in cancer biomarker discovery is dependent on access to high-quality biological materials and high-resolution clinical data from the same cases. To overcome current limitations, a systematic prospective longitudinal sampling of multidisciplinary clinical data, blood and tissue from cancer patients was therefore initiated in 2010 by Uppsala and Umeå Universities and involving their corresponding University Hospitals, which are referral centers for one third of the Swedish population. Material and Methods: Patients with cancer of selected types who are treated at one of the participating hospitals are eligible for inclusion. The healthcare-integrated sampling scheme encompasses clinical data, questionnaires, blood, fresh frozen and formalin-fixed paraffin-embedded tissue specimens, diagnostic slides and radiology bioimaging data. Results: In this ongoing effort, 12,265 patients with brain tumors, breast cancers, colorectal cancers, gynecological cancers, hematological malignancies, lung cancers, neuroendocrine tumors or prostate cancers have been included until the end of 2016. From the 6914 patients included during the first five years, 98% were sampled for blood at diagnosis, 83% had paraffin-embedded and 58% had fresh frozen tissues collected. For Uppsala County, 55% of all cancer patients were included in the cohort. Conclusions: Close collaboration between participating hospitals and universities enabled prospective, longitudinal biobanking of blood and tissues and collection of multidisciplinary clinical data from cancer patients in the U-CAN cohort. Here, we summarize the first five years of operations, present U-CAN as a highly valuable cohort that will contribute to enhanced cancer research and describe the procedures to access samples and data.ARTICLE HISTORY

Cervical cancer is strongly associated with infection by oncogenic forms of human papillomavirus (HPV). Although most women are able to clear an HPV infection, some develop persistent infections that may lead to cancer. The determinants of persistent infection are largely unknown. We have previously shown that women developing carcinoma in situ of the cervix uteri have higher titers of HPV 16 long before development of cervical neoplasia, indicating that the immune response to HPV is important in determining the outcome of an infection. The HLA class II alleles DRB1*1501 and DQB1*0602 have previously been associated with an increased risk of HPV infection, and carriers of these alleles also tend to have more long-term infections. Together these results indicate that certain HLA alleles may affect the ability to control the HPV copy number. To evaluate this possibility, we studied the HLA class II DRB1*1501-DQB1*0602 haplotype, as well as the alleles individually, and the HPV 16 titer in 928 women from a retrospective casecontrol study (441 cases and 487 controls). Carriers of the haplotype DRB1*1501-DQB1*0602 allele have a significantly higher HPV 16 titer compared to noncarriers (t-test with unequal variance, p ‫؍‬ 0.017). An association was found between the HLA haplotype carrier frequency and HPV 16 titer (Mantel-Haenszel statistics p ‫؍‬ 0.005). To study whether titer is related to the persistency of infection, women were divided into groups with long-term and short-term infection. A strong correlation is seen between long-term infection and high viral load and between short-term infection and low viral load. These results show that host genetic factors, e.g., variation at the HLA class II loci studied, may affect the immune reaction to the virus and thereby indirectly increase the susceptibility to carcinoma in situ of the cervix uteri. © 2002 Wiley-Liss, Inc. Key words: HLA; HPV titer; cervical cancerHPV is the major etiologic factor in cervical cancer and is found in the majority of cervical tumors. Although infection with oncogenic forms of HPV are common among young women, less than 1% of those infected develop cervical cancer. [1][2][3] Both the length of the infection and a high viral load several years before diagnosis have been shown to increase the risk of developing cervical cancer. 4 -6 HPV has a number of means by which it is able to reduce the immune response of the host or evade the immune system. For instance, since HPV does not infect antigen presenting cells (APCs) of the epithelium or lyse keratinocytes, it reduces the opportunity for the APC to present virally derived antigens to the immune system. During the infection, HPV never reaches the blood vessels, further limiting the exposure to the APCs. At the very late stages of invasive cancer, when tumor cells have penetrated the basal cell membrane and could present a suitable immune target, the main fraction of the viral genomes are integrated in the host genome and only a small fraction remains in episomal form. Viral gene expression a...

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Cervical cancer is caused by a combination of environmental and genetic risk factors. Infection by oncogenic types of human papillomavirus is recognized as the major environmental risk factor and epidemiological studies indicate that host genetic factors predispose to disease development. A number of genetic susceptibility factors have been proposed, but with exception of the human leukocyte antigen CHLA, class II, have not shown consistent results among studies. We have performed the first genomewide linkage scan using 278 affected sib-pairs to identify loci involved in susceptibility to cervical cancer. A two-step qualitative non-parametric linkage analysis using 387 microsatellites with an average spacing of 10.5 cM revealed excess allelic sharing at nine regions on eight chromosomes. These regions were further analysed with 125 markers to increase the map density to 1.28 cM. Nominal significant linkage was found for three of the nine loci [9q32 (maximum lod-score, MLS) =1.95, P<0.002), 12q24 (MLS=1.25, P<0.015) and 16q24 (MLS=1.35, P<0.012)]. These three regions have previously been connected to human cancers that share characteristics with cervical carcinoma, such as esophageal cancer and Hodgkin's lymphoma. A number of candidate genes involved in defence against viral infections, immune response and tumour suppression are found in these regions. One such gene is the thymic stromal co-transporter (TSCOT). Analyses of TSCOT single nucleotide polymorphisms further strengthen the linkage to this region (MLS=2.40, P<0.001). We propose that the 9q32 region contains susceptibility locus for cervical cancer and that TSCOT is a candidate gene potentially involved in the genetic predisposition to this disease.