Uppsala Biobank-the development of a biobank organization in a local, regional, and national setting.

A biobank is generally in an international setting considered as a sample collection with linked data. In Sweden we have a lot of sample collections, but the definition of a biobank has changed, and it has become an organization that administrates many sample collections as well as an infrastructure to support research. Uppsala Biobank was started in September 2008 as a joint biobank organization between Uppsala County Council and Uppsala University. At the start there were 138 registered biobanks in Uppsala for these two principals. The decision was to have only one biobank, where all previous biobanks would be transformed to be sample collections. Uppsala Biobank has gone from the wish to centralize biobanking administration to be a research infrastructure, a national model for hospital-integrated biobanking, a support structure for biobanking activities in the health care region, and the local competence center for all biobank issues in Uppsala.

U-CAN: a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden.

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.

Identification of susceptibility loci for cervical carcinoma by genome scan of affected sib-pairs.

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.

Interaction of host and viral risk factors for development of cervical carcinoma in situ.

Infection by oncogenic human papillomavirus (HPV) is a necessary but not sufficient cause of cervical carcinoma. Several host genetic and viral factors have been reported to increase the risk of carcinoma development given an HPV infection. In our study, we have analysed the contribution of HPV 16 E6 sequence subtype and allelic variation at human leukocyte antigen (HLA) class II loci to the risk of developing cervical carcinoma in situ. Non-European-like HPV 16 E6 sequence subtypes were not found to be associated with an increased risk of cervical carcinoma, as compared to European-like variants. However, an association was found between the HPV 16 E6 L83V variant and the DR*04-DQ*03 haplotype. This association has been observed in several independent studies and shows that both the host HLA class II genotype and viral subtype will affect the risk of an infection progressing into cervical carcinoma.

HLA class II allele control of HPV load in carcinoma in situ of the cervix uteri.

Human papillomavirus (HPV) infection is the most important risk factor for development of cervical carcinoma. Carriers of certain HLA class II alleles, e.g., DRB1*1501 and DQB1*0602, are more prone to HPV 16 infection and cervical carcinoma, whereas other alleles, e.g., DRB1*1301 and DQB1*0603, render carriers less susceptible to the disease. In our study comprising 484 cases and 601 controls, we examine the effect of HLA class II alleles on viral load of the oncogenic types HPV 18/45 and HPV 31 and risk of developing cervical carcinoma in situ. We find that carriers of the commonly reported protective DRB1*1301 and DQB1*0603 alleles have lower HPV 18/45 load compared to noncarriers and a lower risk of developing HPV 18/45-positive cervical carcinoma. This provides further evidence that the HLA class II-mediated immune response to HPV is important for controlling viral load and outcome of an infection.

Affected sib-pair analysis of the contribution of HLA class I and class II loci to development of cervical cancer.

Cervical cancer is a multifactorial disease and infection by oncogenic human papilloma viruses represents the main environmental risk factor. Only a subset of infections becomes persistent and develops into cancer, implying that genetic susceptibility factors are needed for malignant progression. Here, we use a population-based cohort of affected sib-pairs (ASPs) to examine the role of the human leukocyte antigen (HLA) class I and class II loci in cervical cancer susceptibility. Analysis of 278 ASPs revealed significant excess genetic sharing for all three HLA class II loci studied, DPB1, DQB1 and DRB1, with the strongest evidence for DQB1 and DRB1. No evidence of excess sharing was observed for the HLA class I HLA-B and HLA-A loci. When the material was stratified on the basis of the DQB1*0602/DRB1*1501 susceptibility haplotype, carriers showed significant sharing for all loci, whereas non-carriers showed no evidence of excess genetic sharing at any of the loci. However, for the DPB1 locus there was no difference in allele frequency between carriers and non-carriers indicating that the effect seen in DPB1 is not simply due to linkage disequilibrium. Our results show that the HLA class II represents a major genetic susceptibility locus to cervical cancer in contrary to the class I that do not appear to have a significant impact on predisposition to the disease. The strongest class II effects are coming from the DQB1 and DRB1 loci, but the DPB1 locus also contributes to the susceptibility to cervical cancer.

Host genetic control of HPV 16 titer in carcinoma in situ of the cervix uteri.

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 case-control 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.