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      Defining the genetic susceptibility to cervical neoplasia—A genome-wide association study

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          Abstract

          A small percentage of women with cervical HPV infection progress to cervical neoplasia, and the risk factors determining progression are incompletely understood. We sought to define the genetic loci involved in cervical neoplasia and to assess its heritability using unbiased unrelated case/control statistical approaches. We demonstrated strong association of cervical neoplasia with risk and protective HLA haplotypes that are determined by the amino-acids carried at positions 13 and 71 in pocket 4 of HLA-DRB1 and position 156 in HLA-B. Furthermore, 36% (standard error 2.4%) of liability of HPV-associated cervical pre-cancer and cancer is determined by common genetic variants. Women in the highest 10% of genetic risk scores have approximately >7.1% risk, and those in the highest 5% have approximately >21.6% risk, of developing cervical neoplasia. Future studies should examine genetic risk prediction in assessing the risk of cervical neoplasia further, in combination with other screening methods.

          Author summary

          Around 1% of women with cervical human papillomavirus (HPV) infection progress to cervical cancer. Previous studies had indicated that a person’s genetic makeup could predispose to HPV-associated cervical cancer, and that some of the genes likely to be involved include the immune-related human leukocyte antigen (HLA) genes among the major histocompatibility complex (MHC). However, it has been difficult to determine which alleles might be associated with cervical pre-cancer or cancer due to the complex and high level of co-inheritance of MHC alleles. Here, we performed a genome-wide association study that assessed the correlation of genetic variants among those with cervical cancer and healthy controls. We show that host genetics is a major determinant of HPV-associated cervical cancer, with 36% of liability due to common genetic variants in the population, and identify both risk and protective HLA alleles. Our study was also sufficiently powerful to identify particular residue variants on a number of the immune-related proteins that provide risk or protection, providing further insight into the biological basis for cervical cancer development. Our findings could lay the foundation for screening for people at increased risk of developing cancer following HPV infection, and aid in the treatment and prognosis of cervical cancer.

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          Most cited references35

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          Worldwide burden of cervical cancer in 2008.

          The knowledge that persistent human papillomavirus infection is the main cause of cervical cancer has resulted in the development of assays that detect nucleic acids of the virus and prophylactic vaccines. Up-to-date and reliable data are needed to assess impact of existing preventive measures and to define priorities for the future. Best estimates on cervical cancer incidence and mortality are presented using recently compiled data from cancer and mortality registries for the year 2008. There were an estimated 530,000 cases of cervical cancer and 275,000 deaths from the disease in 2008. It is the third most common female cancer ranking after breast (1.38 million cases) and colorectal cancer (0.57 million cases). The incidence of cervical cancer varies widely among countries with world age-standardised rates ranging from 50 per 100,000. Cervical cancer is the leading cause of cancer-related death among women in Eastern, Western and Middle Africa; Central America; South-Central Asia and Melanesia. The highest incidence rate is observed in Guinea, with ∼6.5% of women developing cervical cancer before the age of 75 years. India is the country with the highest disease frequency with 134,000 cases and 73 000 deaths. Cervical cancer, more than the other major cancers, affects women <45 years. In spite of effective screening methods, cervical cancer continues to be a major public health problem. New methodologies of cervical cancer prevention should be made available and accessible for women of all countries through well-organised programmes.
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            Sequence variants at the TERT-CLPTM1L locus associate with many cancer types.

            The common sequence variants that have recently been associated with cancer risk are particular to a single cancer type or at most two. Following up on our genome-wide scan of basal cell carcinoma, we found that rs401681[C] on chromosome 5p15.33 satisfied our threshold for genome-wide significance (OR = 1.25, P = 3.7 x 10(-12)). We tested rs401681 for association with 16 additional cancer types in over 30,000 cancer cases and 45,000 controls and found association with lung cancer (OR = 1.15, P = 7.2 x 10(-8)) and urinary bladder, prostate and cervix cancer (ORs = 1.07-1.31, all P < 4 x 10(-4)). However, rs401681[C] seems to confer protection against cutaneous melanoma (OR = 0.88, P = 8.0 x 10(-4)). Notably, most of these cancer types have a strong environmental component to their risk. Investigation of the region led us to rs2736098[A], which showed stronger association with some cancer types. However, neither variant could fully account for the association of the other. rs2736098 corresponds to A305A in the telomerase reverse transcriptase (TERT) protein and rs401681 is in an intron of the CLPTM1L gene.
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              Environmental and heritable causes of cancer among 9.6 million individuals in the Swedish Family-Cancer Database.

              The genetic and environmental components in 15 common cancers were estimated using the nationwide Swedish Family-Cancer Database. Tetrachoric correlations were used to describe similarity in cancer liability among family members. Structural equation modeling was used to derive estimates of the importance of genetic and environmental effects. Statistically significant estimates of proportion of cancer susceptibility, accounted for by genetic effects, were obtained for all studied cancers except for leukemia. The estimate was highest in thyroid cancer (53%), followed by tumors at endocrine glands (28%), testis (25%), breast (25%), cervix (22%), melanoma (21%), colon (13%), nervous system (12%), rectum (12%), non-Hodgkin lymphoma (10%), lung (8%), kidney (8%), urinary bladder (7%), stomach (1%) and leukemia (1%). The estimates of shared environmental effects ranged from 0% (cervix) to 15% (stomach). The childhood shared environmental effects were most important in testicular cancer (17%), stomach cancer (13%) and cervix in situ (13%). Our results indicate that environment has a principal causative role in cancer at all studied sites except for thyroid. The relatively large effect of heritability in cancer at some sites, on the other hand, indicates that even though susceptibility genes have been described at many cancer sites, they are likely to explain only part of the genetic effects. Copyright 2002 Wiley-Liss, Inc.
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                Author and article information

                Contributors
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: SupervisionRole: Writing – review & editing
                Role: Data curationRole: SupervisionRole: Writing – review & editing
                Role: Formal analysisRole: Writing – review & editing
                Role: Data curationRole: SupervisionRole: Writing – review & editing
                Role: Data curationRole: SupervisionRole: Writing – review & editing
                Role: Data curationRole: SupervisionRole: Writing – review & editing
                Role: Data curationRole: SupervisionRole: Writing – review & editing
                Role: Data curationRole: SupervisionRole: Writing – review & editing
                Role: Data curationRole: MethodologyRole: Writing – review & editing
                Role: Data curationRole: SupervisionRole: Writing – review & editing
                Role: Data curationRole: SupervisionRole: Writing – review & editing
                Role: Data curationRole: SupervisionRole: Writing – review & editing
                Role: Data curationRole: SupervisionRole: Writing – review & editing
                Role: Data curationRole: MethodologyRole: Writing – review & editing
                Role: Formal analysisRole: Writing – review & editing
                Role: Formal analysisRole: Writing – review & editing
                Role: Formal analysisRole: Writing – review & editing
                Role: Data curationRole: MethodologyRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: Data curationRole: SupervisionRole: Writing – review & editing
                Role: Data curationRole: SupervisionRole: Writing – review & editing
                Role: Data curationRole: SupervisionRole: Writing – review & editing
                Role: Data curationRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: MethodologyRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: MethodologyRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: MethodologyRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS Genet
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, CA USA )
                1553-7390
                1553-7404
                14 August 2017
                August 2017
                : 13
                : 8
                : e1006866
                Affiliations
                [1 ] Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Australia
                [2 ] Program in Epidemiology, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America
                [3 ] Department of Population Sciences, Beckman Research Institute, City of Hope, Duarte, CA, United States of America
                [4 ] Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden
                [5 ] Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
                [6 ] Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
                [7 ] Center for Primary Health Care Research, Lund University, Lund, Sweden
                [8 ] Nutritional Research, Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
                [9 ] MHC Laboratory for Cytopathology, Dr.Steinberg GmbH, Soest, Germany
                [10 ] Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
                [11 ] Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
                [12 ] Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States of America
                [13 ] Division of Cancer Epidemiology, McGill University, Montreal, QC, Canada
                [14 ] Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, QC, Canada
                [15 ] Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy University of Gothenburg, Gothenburg, Sweden
                [16 ] Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
                [17 ] Regional World Health Organisation Human Papillomavirus Laboratory Network, Department of Microbiology and Infectious Diseases, The Royal Women’s Hospital, Parkville, Victoria, 3052, Australia
                [18 ] Department of Obstetrics and Gynaecology, University of Melbourne, Murdoch Childrens Research Institute, The Royal Children’s Hospital, Parkville, Victoria, 3052, Australia
                [19 ] Cancer Council NSW, Sydney, NSW, Australia
                [20 ] Sydney School of Public Health, University of Sydney, Camperdown, NSW, Australia
                [21 ] School of Public Health and Community Medicine, University of New South Wales, Kensington, NSW, Australia
                [22 ] School of Epidemiology, Public Health and Preventive Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Canada
                [23 ] Division of Medical Education, University of Aberdeen, Aberdeen, Scotland
                [24 ] Faculty of Medicine and Biomedical Sciences, University of Queensland, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, QLD, 4102, Australia
                University College London, UNITED KINGDOM
                Author notes

                The authors have declared that no competing interests exist.

                ‡ These authors also contributed equally to this work

                Author information
                http://orcid.org/0000-0001-8325-4134
                http://orcid.org/0000-0001-7499-8502
                http://orcid.org/0000-0002-0557-9803
                http://orcid.org/0000-0001-7031-3385
                http://orcid.org/0000-0002-4409-8084
                http://orcid.org/0000-0002-3490-007X
                Article
                PGENETICS-D-16-02290
                10.1371/journal.pgen.1006866
                5570502
                28806749
                a5fe968d-2577-4dd9-b336-e29c04e2e698
                © 2017 Leo et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 23 November 2016
                : 12 June 2017
                Page count
                Figures: 4, Tables: 5, Pages: 20
                Funding
                Funded by: National Health and Medical Research Council (AU)
                Award ID: Senior Principal Research Fellowship
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100000947, Australian Cancer Research Foundation;
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100001804, Canada Research Chairs;
                Award ID: Human Genome Epidemiology
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000054, National Cancer Institute;
                Award ID: P01CA042792
                Funded by: funder-id http://dx.doi.org/10.13039/100000054, National Cancer Institute;
                Award ID: R01CA112512
                Funded by: funder-id http://dx.doi.org/10.13039/501100000925, National Health and Medical Research Council;
                Award ID: 387701
                Funded by: funder-id http://dx.doi.org/10.13039/501100001102, Cancer Council NSW;
                Award ID: Core Grant
                Funded by: funder-id http://dx.doi.org/10.13039/501100000024, Canadian Institutes of Health Research;
                Award ID: MOP-42532
                Funded by: Réseau FRQS SIDA-MI
                Funded by: County Council of Västerbotten
                Award ID: Spjutspetsanslag VLL:159:33-2007
                Award Recipient :
                Funded by: Kempe-Foundation
                Award ID: JCK-1021
                Funded by: funder-id http://dx.doi.org/10.13039/501100000780, European Commission;
                Award ID: HEALTH-F2-2008-201865-GEFOS
                Funded by: funder-id http://dx.doi.org/10.13039/501100004359, Vetenskapsrådet;
                Funded by: Swedish Foundation for Strategic Research
                Funded by: Torsten and Ragnar Söderberg's Foundation
                Funded by: Novo Nordisk Foundation
                Funded by: Lundberg Foundation
                Funded by: ALF/LUA
                MAB was funded by a National Health and Medical Research Council (Australia) Senior Principal Research Fellowship. Support was also received from the Australian Cancer Research Foundation. JL holds a Tier 1 Canada Research Chair in Human Genome Epidemiology. The Seattle study was supported by the following grants: NIH, National Cancer Institute grants P01CA042792 and R01CA112512. Cervical Health Study (from which the NSW component was obtained) was funded by NHMRC Grant 387701, and CCNSW core grant. The Montreal study was funded by the Canadian Institutes of Health Research (grant MOP-42532) and sample processing was funded by the Réseau FRQS SIDA-MI. The Swedish Research Council, the Swedish Foundation for Strategic Research, the ALF/LUA research grant in Gothenburg and Umeå, the Lundberg Foundation, the Torsten and Ragnar Söderberg's Foundation, the Novo Nordisk Foundation, and the European Commission grant HEALTH-F2-2008-201865-GEFOS, BBMRI.se, the Swedish Society of Medicine, the Kempe-Foundation (JCK-1021), the Medical Faculty of Umeå University, the County Council of Västerbotten (Spjutspetsanslag VLL:159:33-2007). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Oncology
                Cancers and Neoplasms
                Gynecological Tumors
                Cervical Cancer
                Biology and Life Sciences
                Computational Biology
                Genome Analysis
                Genome-Wide Association Studies
                Biology and Life Sciences
                Genetics
                Genomics
                Genome Analysis
                Genome-Wide Association Studies
                Biology and Life Sciences
                Genetics
                Human Genetics
                Genome-Wide Association Studies
                Medicine and Health Sciences
                Clinical Medicine
                Clinical Immunology
                Major Histocompatibility Complex
                Biology and Life Sciences
                Immunology
                Clinical Immunology
                Major Histocompatibility Complex
                Medicine and Health Sciences
                Immunology
                Clinical Immunology
                Major Histocompatibility Complex
                Biology and Life Sciences
                Immunology
                Major Histocompatibility Complex
                Medicine and Health Sciences
                Immunology
                Major Histocompatibility Complex
                Biology and Life Sciences
                Genetics
                Heredity
                Genetic Mapping
                Haplotypes
                Biology and Life Sciences
                Genetics
                Human Genetics
                Medicine and Health Sciences
                Urology
                Genitourinary Infections
                Human Papillomavirus Infection
                Medicine and Health Sciences
                Infectious Diseases
                Sexually Transmitted Diseases
                Human Papillomavirus Infection
                Medicine and Health Sciences
                Infectious Diseases
                Viral Diseases
                Human Papillomavirus Infection
                Biology and Life Sciences
                Genetics
                Heredity
                Linkage Disequilibrium
                Biology and life sciences
                Organisms
                Viruses
                DNA viruses
                Papillomaviruses
                HPV-16
                Biology and Life Sciences
                Microbiology
                Medical Microbiology
                Microbial Pathogens
                Viral Pathogens
                Papillomaviruses
                HPV-16
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Pathogens
                Microbial Pathogens
                Viral Pathogens
                Papillomaviruses
                HPV-16
                Biology and Life Sciences
                Organisms
                Viruses
                Viral Pathogens
                Papillomaviruses
                HPV-16
                Custom metadata
                vor-update-to-uncorrected-proof
                2017-08-24
                Summary data from this study is available for download from Harvard Dataverse ( http://dx.doi.org/10.7910/DVN/2VBLLP). This includes genotyped SNP, and SNP2HLA imputed data, from the overall case and control cohorts, as well as for HPV16 vs HPV18 and histopathological subtype comparisons.

                Genetics
                Genetics

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