| 1. |
- Castro, Felipe A, et al.
(author)
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Contribution of TMC6 and TMC8 (EVER1 and EVER2) variants to cervical cancer susceptibility
- 2012
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In: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 130:2, s. 349-355
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Journal article (peer-reviewed)abstract
- Cervical cancer (CxCa) is caused by persistent human papillomavirus (HPV) infection; genetic predisposition is also suspected to play a role. Our study is a targeted candidate gene follow-up based on: (i) strong clinical evidence demonstrating that mutations in the TMC6 and TMC8 (EVER1 and EVER2) genes associate with the HPV-associated disease epidermodysplasia verruciformis (EV) and (ii) recent epidemiological data suggesting a genetic susceptibility conferred by polymorphisms in such genes for skin and CxCa. Clarifying the association of the TMC6/8 genes with risk of CxCa will help in understanding why some HPV-infected women develop persistent infection, cervical lesions and eventually cancer while others do not. Twenty-two single nucleotide polymorphisms (SNPs) harboring the TMC6/8 genes were genotyped in 2,989 cases with cervical intraepithelial neoplasia grade III or invasive CxCa and 2,281 controls from the Swedish population. Association was evaluated in logistic regression models. Two SNPs displayed association with cervical disease: rs2290907 [odds ratio (OR)(GGvsAA) = 0.6, 95% confidence interval (95% CI): 0.3-0.9, p = 0.02)] and rs16970849 (OR(AGvsGG) = 0.8, 95% CI: 0.66-0.98, p = 0.03). The present data support the involvement of the TMC6/8 region in CxCa susceptibility but further analyses are needed to replicate our findings, fully characterize the region and understand the function of the genetic variants involved.
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| 2. |
- Chen, Dan, et al.
(author)
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Genome-wide Association Study of Susceptibility Loci for Cervical Cancer
- 2013
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In: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 105:9, s. 624-633
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Journal article (peer-reviewed)abstract
- Background Cervical carcinoma has a heritable genetic component, but the genetic basis of cervical cancer is still not well understood. Methods We performed a genome-wide association study of 731 422 single nucleotide polymorphisms (SNPs) in 1075 cervical cancer case subjects and 4014 control subjects and replicated it in 1140 case subjects and 1058 control subjects. The association between top SNPs and cervical cancer was estimated by odds ratios (ORs) and 95% confidence intervals (CIs) with unconditional logistic regression. All statistical tests were two-sided. Results Three independent loci in the major histocompatibility complex (MHC) region at 6p21.3 were associated with cervical cancer: the first is adjacent to the MHC class I polypeptide-related sequence A gene (MICA) (rs2516448; OR = 1.42, 95% CI = 1.31 to 1.54; P = 1.6 x 10(-18)); the second is between HLA-DRB1 and HLA-DQA1 (rs9272143; OR = 0.67, 95% CI = 0.62 to 0.72; P = 9.3 x 10(-24)); and the third is at HLA-DPB2 (rs3117027; OR=1.25, 95% CI = 1.15 to 1.35; P = 4.9 x 10(-8)). We also confirmed previously reported associations of B*0702 and DRB1*1501-DQB1*0602 with susceptibility to and DRB1*1301-DQA1*0103-DQB1*0603 with protection against cervical cancer. The three new loci are statistically independent of these specific human leukocyte antigen alleles/haplotypes. MICA encodes a membrane-bound protein that acts as a ligand for NKG2D to activate antitumor effects. The risk allele of rs2516448 is in perfect linkage disequilibrium with a frameshift mutation (A5.1) of MICA, which results in a truncated protein. Functional analysis shows that women carrying this mutation have lower levels of membrane-bound MICA. Conclusions Three novel loci in the MHC may affect susceptibility to cervical cancer in situ, including the MICA-A5.1 allele that may cause impaired immune activation and increased risk of tumor development.
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| 3. |
- Chen, Dan, et al.
(author)
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Pathway analysis of cervical cancer genome-wide association study highlights the MHC region and pathways involved in response to infection
- 2014
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In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:22, s. 6047-6060
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Journal article (peer-reviewed)abstract
- Cervical cancer is caused by infection with human papillomavirus (HPV). A genome-wide association study (GWAS) has identified several susceptibility loci for cervical cancer, but they explain only a small fraction of cervical cancer heritability. Other variants with weaker effect may be missed due to the stringent significance threshold. To identify important pathways in cervical carcinogenesis, we performed a two-stage pathway analysis in two independent GWASs in the Swedish population, using the single-nucleotide polymorphism (SNP) ratio test. The 565 predefined pathways from Kyoto Encyclopedia of Genes and Genomes and BioCarta databases were systematically evaluated in the discovery stage (1034 cases and 3948 controls with 632 668 SNPs) and the suggestive pathways were further validated in the replication stage (616 cases and 506 controls with 341 358 SNPs). We found 12 pathways that were significant in both stages, and these were further validated using set-based analysis. For 10 of these pathways, the effect was mainly due to genetic variation within the major histocompatibility complex (MHC) region. In addition, we identified a set of novel candidate genes outside the MHC region in the pathways denoted ‘Staphylococcus aureus infection’ and ‘herpes simplex infection’ that influenced susceptibility to cervical cancer (empirical P = 4.99 × 10−5 and 4.99 × 10−5 in the discovery study; empirical P = 8.98 × 10−5 and 0.009 in the replication study, respectively). Staphylococcus aureus infection may evoke an inflammatory response that inadvertently enhances malignant progression caused by HPV infection, and Herpes simplex virus-2 infection may act in conjunction with HPV infection to increase the risk of cervical carcinoma development. These findings provide new insights into the etiology of cervical cancer.
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| 4. |
- Conway, Richard, 1978-, et al.
(author)
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Realizing Dharavi
- 2017. - 1
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In: Reinventing Dharavi. - Mumbai, India : Urban Design Research Institute. - 9789381444160 ; , s. 34-61
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Book chapter (peer-reviewed)
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| 5. |
- Engelmark, Malin, et al.
(author)
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Polymorphisms in 9q32 and TSCOT are linked to cervical cancer in affected sib-pairs with high mean age at diagnosis
- 2008
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In: Human Genetics. - : Springer Science and Business Media LLC. - 0340-6717 .- 1432-1203. ; 123:5, s. 437-443
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Journal article (peer-reviewed)abstract
- Cervical cancer is a multifactorial disease influenced by both environmental and genetic factors. We have previously found linkage to 9q32 in a genomewide scan of affected sib-pairs (ASPs) with cervical cancer and to the thymic stromal co-transporter (TSCOT), a candidate gene in this region. Here we examined the contribution of 9q32 and TSCOT to cervical cancer susceptibility using at larger material of 641 ASPs, 278 of which were included in the earlier genome-scan. Since heritable forms of cancer frequently show stronger genetic effects in families with early onset of disease, we stratified the ASPs into two groups based on mean age at diagnosis (MAAD) within sib-pairs. Surprisingly, ASPs with high MAAD (30.5-47.5 years) showed increased sharing at all microsatellite markers at 9q31.1-33.1 and linkage signals of up to MLS = 2.74 for TSCOT SNPs, while ASPs with low MAAD (19-30 years) showed no deviation from random genetic sharing (MLS = 0.00). The difference in allelic sharing between the two MAAD strata was significant (P < 0.005) and is not likely to be explained by the HLA haplotype, a previously known genetic susceptibility factor for cervical cancer. Our results indicate locus heterogeneity in the susceptibility to cervical cancer between the two strata, with polymorphisms in the 9q32 region mainly showing an effect in women with high MAAD.
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| 6. |
- Engelmark, Malin T., et al.
(author)
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Identification of susceptibility loci for cervical carcinoma by genome scan of affected sib-pairs
- 2006
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In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 15:22, s. 3351-3360
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Journal article (peer-reviewed)abstract
- 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.
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| 7. |
- Enroth, Stefan, 1976-, et al.
(author)
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Data-driven analysis of a validated risk score for ovarian cancer identifies clinically distinct patterns during follow-up and treatment
- 2022
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In: Communications Medicine. - : Springer Nature. - 2730-664X. ; 2:1
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Journal article (peer-reviewed)abstract
- BackgroundOvarian cancer is the eighth most common cancer among women and due to late detection prognosis is poor with an overall 5-year survival of 30–50%. Novel biomarkers are needed to reduce diagnostic surgery and enable detection of early-stage cancer by population screening. We have previously developed a risk score based on an 11-biomarker plasma protein assay to distinguish benign tumors (cysts) from malignant ovarian cancer in women with adnexal ovarian mass.MethodsProtein concentrations of 11 proteins were characterized in plasma from 1120 clinical samples with a custom version of the proximity extension assay. The performance of the assay was evaluated in terms of prediction accuracy based on receiver operating characteristics (ROC) and multiple hypothesis adjusted Fisher’s Exact tests on achieved sensitivity and specificity.ResultsThe assay’s performance is validated in two independent clinical cohorts with a sensitivity of 0.83/0.91 and specificity of 0.88/0.92. We also show that the risk score follows the clinical development and is reduced upon treatment, and increased with relapse and cancer progression. Data-driven modeling of the risk score patterns during a 2-year follow-up after diagnosis identifies four separate risk score trajectories linked to clinical development and survival. A Cox proportional hazard regression analysis of 5-year survival shows that at time of diagnosis the risk score is the second-strongest predictive variable for survival after tumor stage, whereas MUCIN-16 (CA-125) alone is not significantly predictive.ConclusionThe robust performance of the biomarker assay across clinical cohorts and the correlation with clinical development indicates its usefulness both in the diagnostic work-up of women with adnexal ovarian mass and for predicting their clinical course.
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| 8. |
- Gyllensten, Ulf B., et al.
(author)
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Next Generation Plasma Proteomics Identifies High-Precision Biomarker Candidates for Ovarian Cancer
- 2022
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In: Cancers. - : MDPI AG. - 2072-6694. ; 14:7
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Journal article (peer-reviewed)abstract
- Simple Summary Ovarian cancer is the eighth most common cancer among women and has a 5-year survival of only 30-50%. The survival is close to 90% for patients in stage I but only 20% for patients in stage IV. The presently available biomarkers have insufficient sensitivity and specificity for early detection and there is an urgent need to identify novel biomarkers. The aim of our study was to broadly measure protein biomarkers to find tests for the early detection of ovarian cancer. We found that combinations of 4-7 protein biomarkers can provide highly accurate detection of early- and late-stage ovarian cancer compared to benign conditions. The performance of the tests was then validated in a second independent cohort. Background: Ovarian cancer is the eighth most common cancer among women and has a 5-year survival of only 30-50%. The survival is close to 90% for patients in stage I but only 20% for patients in stage IV. The presently available biomarkers have insufficient sensitivity and specificity for early detection and there is an urgent need to identify novel biomarkers. Methods: We employed the Explore PEA technology for high-precision analysis of 1463 plasma proteins and conducted a discovery and replication study using two clinical cohorts of previously untreated patients with benign or malignant ovarian tumours (N = 111 and N = 37). Results: The discovery analysis identified 32 proteins that had significantly higher levels in malignant cases as compared to benign diagnoses, and for 28 of these, the association was replicated in the second cohort. Multivariate modelling identified three highly accurate models based on 4 to 7 proteins each for separating benign tumours from early-stage and/or late-stage ovarian cancers, all with AUCs above 0.96 in the replication cohort. We also developed a model for separating the early-stage from the late-stage achieving an AUC of 0.81 in the replication cohort. These models were based on eleven proteins in total (ALPP, CXCL8, DPY30, IL6, IL12, KRT19, PAEP, TSPAN1, SIGLEC5, VTCN1, and WFDC2), notably without MUCIN-16. The majority of the associated proteins have been connected to ovarian cancer but not identified as potential biomarkers. Conclusions: The results show the ability of using high-precision proteomics for the identification of novel plasma protein biomarker candidates for the early detection of ovarian cancer.
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| 9. |
- Hedlund Lindberg, Julia, et al.
(author)
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Toward ovarian cancer screening with protein biomarkers using dried, self-sampled cervico-vaginal fluid
- 2024
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In: iScience. - : Cell Press. - 2589-0042. ; 27:2
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Journal article (peer-reviewed)abstract
- Early detection is key for increased survival in ovarian cancer, but no general screening program exists today due to lack of biomarkers and overall cost versus benefit over traditional clinical methods. Here, we used dried cervico-vaginal fluid (CVF) as sampling matrix coupled with mass spectrometry for detection of protein biomarkers. We find that self-collected CVF on paper cards yields robust results and is suitable for high-throughput proteomics. Artificial intelligence–based methods were used to identify an 11-protein panel that separates cases from controls. In validation data, the panel achieved a sensitivity of 0.97 (95% CI 0.91–1.00) at a specificity of 0.67 (0.40–0.87). Analyses of samples collected prior to development of symptoms indicate that the panel is informative also of future risk of disease. Dried CVF is used in cervical cancer screening, and our results opens the possibility for a screening program also for ovarian cancer, based on self-collected CVF samples.
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| 10. |
- Ivansson, Emma, 1975-
(author)
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Contribution of Immunogenetic Factors in Susceptibility to Cervical Cancer
- 2009
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Doctoral thesis (other academic/artistic)abstract
- Cervical cancer is the second most common cancer in women worldwide. Persistent infection by an oncogenic type of human papillomavirus (HPV) is a necessary but not sufficient cause and there is also a genetic component. This thesis aims to identify host genetic risk factors for cervical cancer based on the hypothesis that susceptibility is affected by genetic variation in the immune response towards HPV infection. Paper I analyzed allergy in sons and cervical cancer in their mothers, and revealed an inverse association between cervical cancer and allergy across generations. Mothers of allergic sons have a lower incidence of cervical cancer, supporting the importance of immunogenetic factors. Paper II investigated the HPV type in 1079 women diagnosed 1965-1993. All women were from families with at least two affected. It appeared that HPV 16 was becoming less common with time. There was no evidence that related women were prone to infection by the same type, indicating that the immunogenetic factors act in a general, rather than an HPV type specific, manner. Paper III and IV analysed the association of candidate genes with susceptibility to cervical cancer in 1306 women with cervical cancer in situ and 288 unrelated controls. Paper III showed the association of variation in the two immune response genes chemokine receptor 2 (CCR-2) and interleukin 4 receptor (IL-4R) with cervical cancer. In paper IV variation at several loci in the MHC region was studied and the importance of the HLA class II locus DQB1 emphasized. This thesis work supports the contribution of genes of the immune system to cervical cancer susceptibility. The genetic risk factors so far identified account for only a part of the genetic susceptibility, which implies that other yet undiscovered variants of importance remain to be identified.
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