Showing papers by "Susanne K. Kjaer published in 2018"
TL;DR: The detection of endometrial and ovarian cancers based on genetic analyses of DNA recovered from the fluids obtained during a routine Papanicolaou (Pap) test is reported, demonstrating the potential of mutation-based diagnostics to detect gynecologic cancers at a stage when they are more likely to be curable.
Abstract: We report the detection of endometrial and ovarian cancers based on genetic analyses of DNA recovered from the fluids obtained during a routine Papanicolaou (Pap) test. The new test, called PapSEEK, incorporates assays for mutations in 18 genes as well as an assay for aneuploidy. In Pap brush samples from 382 endometrial cancer patients, 81% [95% confidence interval (CI), 77 to 85%] were positive, including 78% of patients with early-stage disease. The sensitivity in 245 ovarian cancer patients was 33% (95% CI, 27 to 39%), including 34% of patients with early-stage disease. In contrast, only 1.4% of 714 women without cancer had positive Pap brush samples (specificity, ~99%). Next, we showed that intrauterine sampling with a Tao brush increased the detection of malignancy over endocervical sampling with a Pap brush: 93% of 123 (95% CI, 87 to 97%) patients with endometrial cancer and 45% of 51 (95% CI, 31 to 60%) patients with ovarian cancer were positive, whereas none of the samples from 125 women without cancer were positive (specificity, 100%). Finally, in 83 ovarian cancer patients in whom plasma was available, circulating tumor DNA was found in 43% of patients (95% CI, 33 to 55%). When plasma and Pap brush samples were both tested, the sensitivity for ovarian cancer increased to 63% (95% CI, 51 to 73%). These results demonstrate the potential of mutation-based diagnostics to detect gynecologic cancers at a stage when they are more likely to be curable.
150 citations
TL;DR: The qHPV vaccine shows continued protection in women through at least 10 years, with a trend for continued protection through 12 years of follow-up, and a trend toward continuing effectiveness of the vaccine during that period of 10-12 years.
Abstract: Background The long-term effectiveness of the quadrivalent human papillomavirus (qHPV) vaccine was assessed by monitoring the combined incidence of cervical intraepithelial neoplasia (CIN2, CIN3), adenocarcinoma in situ (AIS), and cervical cancer related to HPV16 or HPV18 Methods Women from Nordic countries of Denmark, Iceland, Norway, and Sweden who received a 3-dose regimen of the qHPV vaccine in the beginning of FUTURE II (Females United to Unilaterally Reduce Endo/Ectocervical Disease; V501-015, base study NCT00092534) are followed through different national registries Effectiveness analyses were conducted approximately 2 years following completion of the base study and occur approximately every 2 years thereafter for 10 years (ie, 14 years from day 1 of the base study) Vaccine effectiveness against HPV16/18-related CIN2 or worse (CIN2+) was estimated by comparing the observed incidence with the expected incidence of CIN2+ in an unvaccinated cohort using historical registry data Results In the per-protocol population (2084 women) analysis of effectiveness after the first 12 years, there were no breakthrough cases of HPV16/18 CIN2+ after 9437 person- years of follow-up Statistical power was sufficient to conclude that qHPV vaccine effectiveness remains above 90% for at least 10 years The number of person-years during the follow-up interval of 10-12 years is continuing to accrue and shows a trend toward continuing effectiveness of the vaccine during that period Conclusion The qHPV vaccine shows continued protection in women through at least 10 years, with a trend for continued protection through 12 years of follow-up Clinical trials registration NCT00092534 Study identification V501-015
94 citations
Catholic University of Health and Allied Sciences1, University of Calgary2, Mayo Clinic3, University of New South Wales4, Medical University of South Carolina5, Cedars-Sinai Medical Center6, Heidelberg University7, University of Cambridge8, University of Tübingen9, University College London10, University of São Paulo11, Huntsman Cancer Institute12, University of Southern California13, University of Sydney14, University of Western Sydney15, Westmead Hospital16, Alexandra Hospital17, University of Virginia18, University of Hawaii at Manoa19, University of Copenhagen20, Stanford University21, Durham University22, Duke University23, The Breast Cancer Research Foundation24, Brunel University London25, Institute of Cancer Research26, University of British Columbia27, Pomeranian Medical University28, Fred Hutchinson Cancer Research Center29, Karolinska Institutet30, University of Washington31, University of Pittsburgh32, University of Texas MD Anderson Cancer Center33, Icahn School of Medicine at Mount Sinai34, Imperial College London35, University Hospital Heidelberg36, University of Erlangen-Nuremberg37, University of California, Los Angeles38, German Cancer Research Center39, University of Hamburg40, Roswell Park Cancer Institute41, University of Melbourne42, University of Hawaii43, Nottingham University Hospitals NHS Trust44, University of Alcalá45, Alberta Health Services46, University of New Mexico47, BC Cancer Agency48, Garvan Institute of Medical Research49
TL;DR: Block expression of p16 in clear cell and endometrioid carcinoma should be further validated as a prognostic marker, and absence in low‐grade serous carcinoma justifies CDK4 inhibition.
Abstract: We aimed to validate the prognostic association of p16 expression in ovarian high-grade serous carcinomas (HGSC) and to explore it in other ovarian carcinoma histotypes. p16 protein expression was assessed by clinical-grade immunohistochemistry in 6525 ovarian carcinomas including 4334 HGSC using tissue microarrays from 24 studies participating in the Ovarian Tumor Tissue Analysis consortium. p16 expression patterns were interpreted as abnormal (either overexpression referred to as block expression or absence) or normal (heterogeneous). CDKN2A (which encodes p16) mRNA expression was also analyzed in a subset (n = 2280) mostly representing HGSC (n = 2010). Association of p16 expression with overall survival (OS) was determined within histotypes as was CDKN2A expression for HGSC only. p16 block expression was most frequent in HGSC (56%) but neither protein nor mRNA expression was associated with OS. However, relative to heterogeneous expression, block expression was associated with shorter OS in endometriosis-associated carcinomas, clear cell [hazard ratio (HR): 2.02, 95% confidence (CI) 1.47-2.77, p < 0.001] and endometrioid (HR: 1.88, 95% CI 1.30-2.75, p = 0.004), while absence was associated with shorter OS in low-grade serous carcinomas (HR: 2.95, 95% CI 1.61-5.38, p = 0.001). Absence was most frequent in mucinous carcinoma (50%), and was not associated with OS in this histotype. The prognostic value of p16 expression is histotype-specific and pattern dependent. We provide definitive evidence against an association of p16 expression with survival in ovarian HGSC as previously suggested. Block expression of p16 in clear cell and endometrioid carcinoma should be further validated as a prognostic marker, and absence in low-grade serous carcinoma justifies CDK4 inhibition.
58 citations
TL;DR: Findings point to the possible clinical value of HPV and p16 testing when planning the most optimal management and follow-up strategy in men diagnosed with penile cancer.
Abstract: It has been shown that human papillomavirus (HPV) and p16 status has prognostic value in some HPV-associated cancers. However, studies examining survival in men with penile cancer according to HPV or p16 status are often inconclusive, mainly because of small study populations. The aim of this systematic review and meta-analysis was to examine the association between HPV DNA and p16 status and survival in men diagnosed with penile cancer. Multiple electronic databases were searched. Twenty studies were ultimately included and study-specific and pooled HRs of overall survival and disease-specific survival (DSS) were calculated using a fixed effects model. In the analysis of DSS, we included 649 men with penile cancer tested for HPV (27% were HPV-positive) and 404 men tested for p16 expression (47% were p16-positive). The pooled HRHPV of DSS was 0.61 [95% confidence interval (CI), 0.38-0.98], and the pooled HRp16 of DSS was 0.45 (95% CI, 0.30-0.69). In conclusion, men with HPV or p16-positive penile cancer have a significantly more favorable DSS compared with men with HPV or p16-negative penile cancer. These findings point to the possible clinical value of HPV and p16 testing when planning the most optimal management and follow-up strategy. Cancer Epidemiol Biomarkers Prev; 27(10); 1123-32. ©2018 AACR.
54 citations
TL;DR: The authors performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci, and identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.47 × 10-3), a potential novel locus for EOC risk.
Abstract: Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 × 10-6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10-7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 × 10-3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis.Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res; 78(18); 5419-30. ©2018 AACR.
51 citations
TL;DR: Wang, Yuxuan; Li, Lu; Douville, Christopher; Cohen, Joshua D.
Abstract: We report the detection of endometrial and ovarian cancers based on genetic analyses of DNA recovered from the fluids obtained during a routine Papanicolaou (Pap) test. The new test, called PapSEEK, incorporates assays for mutations in 18 genes as well as an assay for aneuploidy. In Pap brush samples from 382 endometrial cancer patients, 81% [95% confidence interval (CI), 77 to 85%] were positive, including 78% of patients with early-stage disease. The sensitivity in 245 ovarian cancer patients was 33% (95% CI, 27 to 39%), including 34% of patients with early-stage disease. In contrast, only 1.4% of 714 women without cancer had positive Pap brush samples (specificity, ~99%). Next, we showed that intrauterine sampling with a Tao brush increased the detection of malignancy over endocervical sampling with a Pap brush: 93% of 123 (95% CI, 87 to 97%) patients with endometrial cancer and 45% of 51 (95% CI, 31 to 60%) patients with ovarian cancer were positive, whereas none of the samples from 125 women without cancer were positive (specificity, 100%). Finally, in 83 ovarian cancer patients in whom plasma was available, circulating tumor DNA was found in 43% of patients (95% CI, 33 to 55%). When plasma and Pap brush samples were both tested, the sensitivity for ovarian cancer increased to 63% (95% CI, 51 to 73%). These results demonstrate the potential of mutation-based diagnostics to detect gynecologic cancers at a stage when they are more likely to be curable.
50 citations
TL;DR: In conclusion, women with HPV‐positive vulvar cancers have a superior survival compared to women withHPV‐negative, which could be of great clinical interest and provides insight into the differences in the natural history of HPV‐ positive and negative vulvar cancer.
Abstract: High-risk human papillomavirus (HPV) infection is essential in the carcinogenesis of a substantial part of anogenital and oropharyngeal cancers and has additionally been shown to be a possible predictive marker for survival, especially in oropharyngeal cancer. Studies examining the influence of HPV status on survival after vulvar cancer have been conflicting and limited by small study populations. Therefore, the aim of this review and meta-analysis was to examine whether HPV status influences survival after vulvar cancer, which, to our knowledge, has not been done before. We conducted a systematic search of PubMed, Cochrane Library and Embase to identify studies examining survival after histologically verified and HPV tested vulvar cancer. A total of 18 studies were eligible for inclusion. Study-specific and pooled HRs of the 5-year OS and DFS were calculated using a fixed effects model. The I2 statistic was used to describe heterogeneity. The studies included a total of 1638 women with HPV tested vulvar cancers of which 541 and 1097 were HPV positive and HPV negative, respectively. Fifteen studies included only squamous cell carcinomas. We found a pooled HR of 0.61 (95%CI: 0.48–0.77) and 0.75 (95%CI: 0.57–1.00) for 5-year OS and DFS, respectively. Across study heterogeneity was moderate to high (OS: I2 = 51%; DFS: I2 = 73%). In conclusion, women with HPV positive vulvar cancers have a superior survival compared to women with HPV negative, which could be of great clinical interest and provides insight into the differences in the natural history of HPV positive and negative vulvar cancers. This article is protected by copyright. All rights reserved.
46 citations
TL;DR: Compared with screening participants, the odds of passive non-participation was increased in women who originated from less developed countries; were unmarried; had basic education or low income; had four or more children; smoked during pregnancy; had multiple induced abortions; or had a history of obesity, intoxicant abuse or schizophrenia or other psychoses.
38 citations
Vanderbilt University Medical Center1, Vanderbilt University2, Duke University3, University of California, Irvine4, The Royal Marsden NHS Foundation Trust5, University of Bergen6, Haukeland University Hospital7, University of Cambridge8, University of Helsinki9, Peter MacCallum Cancer Centre10, University of Melbourne11, German Cancer Research Center12, University of Hamburg13, Tianjin Medical University Cancer Institute and Hospital14, Alberta Health Services15, University of New Mexico16, Brigham and Women's Hospital17, Harvard University18, Westmead Hospital19, University of Sydney20, Huntsman Cancer Institute21, Hannover Medical School22, University of Southampton23, University of Erlangen-Nuremberg24, University of California, Los Angeles25, Cedars-Sinai Medical Center26, Cancer Council Victoria27, Monash University28, Beatson West of Scotland Cancer Centre29, Mayo Clinic30, Pomeranian Medical University31, University of Washington32, Fred Hutchinson Cancer Research Center33, University of Texas MD Anderson Cancer Center34, University of Copenhagen35, Medical University of South Carolina36, Radboud University Nijmegen37, Université de Montréal38, Katholieke Universiteit Leuven39, BC Cancer Agency40, Memorial Sloan Kettering Cancer Center41, New York University42, Nagoya University43, University Health Network44, University of Glasgow45, Imperial College London46, University College London47, University of Pittsburgh48, Roswell Park Cancer Institute49, University of Texas Health Science Center at Houston50, Lund University51, Oklahoma State University Center for Health Sciences52, New Generation University College53, Seoul National University54, University of Southern California55, University of Michigan56, Oregon Health & Science University57, University of New South Wales58, Garvan Institute of Medical Research59, International Agency for Research on Cancer60, National Institutes of Health61, University of Virginia62, Hebei Medical University63, Glasgow Royal Infirmary64, Icahn School of Medicine at Mount Sinai65, University of South Florida66, Institute of Cancer Research67, Curie Institute68, University Malaya Medical Centre69, QIMR Berghofer Medical Research Institute70, Uppsala University71, Karolinska Institutet72
TL;DR: High-density genetic and DNA methylation data in white blood cells from the Framingham Heart Study were used to build genetic models to predict methylation levels and it is proposed that methylation at multiple CpG may affect EOC risk through regulation of gene expression.
Abstract: DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high-density genetic and DNA methylation data in white blood cells from the Framingham Heart Study (N = 1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of P < 7.94 × 10-7. Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely MAPT, HOXB3, ABHD8, ARHGAP27, and SKAP1. We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression. SIGNIFICANCE: Identification of novel DNA methylation markers associated with EOC risk suggests that methylation at multiple CpG may affect EOC risk through regulation of gene expression.
34 citations
TL;DR: A marked decline in HPV infection in the younger population in the 2 countries where qHPV vaccination programs started in 2008-2009 is demonstrated, suggesting that organized HPV vaccination programs resulted in a decrease of HPV types circulating in the general population.
31 citations
TL;DR: It is suggested that statin use may be associated with improved survival in endometrial cancer patients.
Abstract: Statin use has been linked to improved prognosis of some cancer types, however, for endometrial cancer, the results are equivocal. We therefore examined the effect of statin use on endometrial cancer mortality. From the Danish Cancer Registry, we identified all women in Denmark aged 30-84 years with primary endometrial cancer during 2000-2012. Data on drug use, mortality outcomes and potential confounders were retrieved from nationwide registries. We used Cox proportional hazards regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for endometrial cancer-specific and other-cause mortality associated with statin use. Among 6,694 endometrial cancer patients, 753 died from endometrial cancer and 765 from other causes during a median follow-up of 4.5 year (interquartile range: 1.9-8.1). We observed an inverse association between time-varying postdiagnosis statin use (≥2 prescriptions) and endometrial cancer mortality (HR: 0.61, 95% CI: 0.48-0.77) compared to non-use (<2 prescriptions). The associations did not differ substantially by intensity or cumulative amount of statin use. In secondary analyses including prediagnosis statin use, we observed reduced mortality among both continuing (pre- and postdiagnosis) users (HR 0.70, 95% CI 0.53-0.92) and new (postdiagnosis only) users (HR 0.43, 95% CI 0.29-0.65) compared to "never users." In sensitivity analyses with fixed exposure periods after the endometrial cancer diagnosis, the inverse association was more pronounced more than 5 years after the diagnosis. Our findings suggest that statin use may be associated with improved survival in endometrial cancer patients.
TL;DR: Investigation of the effectiveness of quadrivalent HPV vaccination against CIN2 or worse (CIN2+), by age at vaccination, number of doses, and whether optimal timing of 2 doses of qHPV vaccine can confer the same level of protection as the originally recommended three dose-schedule found no difference in risk.
Mayo Clinic1, Catholic University of Health and Allied Sciences2, University of Tübingen3, University of Melbourne4, Pomeranian Medical University5, University of São Paulo6, University Hospital Heidelberg7, Icahn School of Medicine at Mount Sinai8, University of Western Sydney9, Cedars-Sinai Medical Center10, University of Texas at Austin11, University of Calgary12, University of Pittsburgh13, Stanford University14, University of Cambridge15, Kunming Medical University16, University of Sydney17, German Cancer Research Center18, QIMR Berghofer Medical Research Institute19, University of New South Wales20, Heidelberg University21, University of Hawaii22, Peter MacCallum Cancer Centre23, Alexandra Hospital24, Roswell Park Cancer Institute25, University College London26, Alberta Health Services27, University of Copenhagen28, Medical University of South Carolina29, University of British Columbia30, Carlos III Health Institute31, University of California, Los Angeles32, Nottingham University Hospitals NHS Trust33, University of Hamburg34
TL;DR: Analysis of myeloid differentiation primary response gene 88 and Toll‐like receptor 4 expression in relation to clinical features of epithelial ovarian cancer, histologic subtypes, and overall survival shows correlation between strong MyD88 and TLR4 staining and improved survival in HGSOC and LGSOC, highlighting the biological differences between the 2 serous histotypes.
Abstract: OBJECTIVE: To evaluate myeloid differentiation primary response gene 88 (MyD88) and Toll-like receptor 4 (TLR4) expression in relation to clinical features of epithelial ovarian cancer, histologic subtypes, and overall survival. PATIENTS AND METHODS: We conducted centralized immunohistochemical staining, semi-quantitative scoring, and survival analysis in 5263 patients participating in the Ovarian Tumor Tissue Analysis consortium. Patients were diagnosed between January 1, 1978, and December 31, 2014, including 2865 high-grade serous ovarian carcinomas (HGSOCs), with more than 12,000 person-years of follow-up time. Tissue microarrays were stained for MyD88 and TLR4, and staining intensity was classified using a 2-tiered system for each marker (weak vs strong). RESULTS: Expression of MyD88 and TLR4 was similar in all histotypes except clear cell ovarian cancer, which showed reduced expression compared with other histotypes (P<.001 for both). In HGSOC, strong MyD88 expression was modestly associated with shortened overall survival (hazard ratio [HR], 1.13; 95% CI, 1.01-1.26; P=.04) but was also associated with advanced stage (P<.001). The expression of TLR4 was not associated with survival. In low-grade serous ovarian cancer (LGSOC), strong expression of both MyD88 and TLR4 was associated with favorable survival (HR [95% CI], 0.49 [0.29-0.84] and 0.44 [0.21-0.89], respectively; P=.009 and P=.02, respectively). CONCLUSION: Results are consistent with an association between strong MyD88 staining and advanced stage and poorer survival in HGSOC and demonstrate correlation between strong MyD88 and TLR4 staining and improved survival in LGSOC, highlighting the biological differences between the 2 serous histotypes.
TL;DR: This comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.
Abstract: Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg=0.57, p=4.6x10-8), breast and ovarian cancer (rg=0.24, p=7x10-5), breast and lung cancer (rg=0.18, p=1.5x10-6) and breast and colorectal cancer (rg=0.15, p=1.1x10-4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.
TL;DR: The findings suggest the maternal hormonal use affects non-lymphoid leukaemia development in children, which is an important direction for future research into its causes and prevention.
Abstract: Summary Background Maternal hormonal contraception has been suspected of being linked to an increased risk of childhood cancer The aim of this study was to assess the association between maternal use of hormonal contraception and diagnosis of leukaemia in their children Methods In this cohort study, we followed a nationwide cohort of 1 185 157 liveborn children between 1996 and 2014 listed in the Danish Medical Birth Registry and identified those diagnosed with leukaemia in the Danish Cancer Registry Redeemed prescriptions from the Danish National Prescription Registry provided information about maternal hormonal contraceptive use, categorised as: no use (never used contraception before birth; reference category), previous use (>3 months before start of pregnancy), and recent use (≤3 months before and during pregnancy) We also calculated risk estimates separately for maternal hormonal contraceptive use during pregnancy The primary outcome of interest was a diagnosis of any leukaemia in the children Secondary outcomes were diagnoses of lymphoid leukaemia and non-lymphoid leukaemia We used Cox proportional hazards models to estimate hazard ratios (HRs) with 95% CIs for risk of leukaemia in children The Data Protection Agency registration number for this study is 2017-41-5221 Findings Between Jan 1, 1996, and Dec 31, 2014, the 1 185 157 liveborn children accumulated 11 114 290 person-years of follow-up (median 9·3 years, IQR 4·6–14·2), during which 606 children were diagnosed with leukaemia (465 with lymphoid leukaemia and 141 with non-lymphoid leukaemia) Children born to women with recent use of any type of hormonal contraception were at higher risk for any leukaemia than children of women who never used contraception (HR 1·46, 95% CI 1·09–1·96; p=0·011); and for exposure during pregancy the risk was 1·78 (0·95–3·31; p=0·070) No association was found between timing of use and risk for lymphoid leukaemia (HR 1·23, 95% CI 0·97–1·57, p=0·089, for previous use and 1·27, 0·90–1·80, p=0·167, for recent use); however, the HRs for non-lymphoid leukaemia were 2·17 (1·22–3·87; p=0·008) for recent use and 3·87 (1·48–10·15; p=0·006) for use during pregnancy Hormonal contraception use close to or during pregnancy might have resulted in one additional case of leukaemia per about 50 000 exposed children, or 25 cases during the 9-year study period Interpretation Our findings suggest the maternal hormonal use affects non-lymphoid leukaemia development in children Since almost no risk factors have been established for childhood leukaemia, these findings suggest an important direction for future research into its causes and prevention Funding The Danish Cancer Research Foundation, the Arvid Nilssons Foundation, the Gangsted Foundation, the Harboe Foundation, and the Johannes Clemmesens Foundation
Journal Article•
TL;DR: It is found that increasing viral load and integrated viral genomes were significantly associated with prevalent HSIL, thus indicating that viral Load and physical state may potentially be useful triage markers for HPV16-positive women during cervical screening.
Abstract: High genome copy number (viral load) of human papillomavirus (HPV) is being discussed as a risk factor for high-grade cervical lesions. However, conflicting data about the integration status or viral load of the virus as risk factors for prevalent high-grade squamous intraepithelial lesions (HSIL) are found in the literature. To investigate whether viral load and/or integration status are indicative for prevalent ASCUS/LSIL or HSIL, we determined the HPV16 viral load and the physical state of the genome in 644 women with single HPV16 infections stratified by their cytology results from a large Danish population-based cohort consisting of 40,399 women. Cervical smear samples were tested using a multiplex quantitative real-time PCR (qPCR) with primers specific for HPV16 E2, E6 and beta actin, allowing simultaneous determination of the genome's physical state and the viral copy number per cell. The associations of viral load and physical state with cervical abnormalities were assessed using multinomial logistic regression. We found that a 10-fold increase in viral load was significantly associated with the presence of ASCUS/LSIL (OR=3.91; 95% CI, 2.49-6.13) and HSIL (OR=4.1; 95% CI, 2.45-6.68). A significant association with HSIL was observed for primarily integrated genomes (OR=6.68; 95% CI, 1.45-30.8). Among women with integrated viral genomes, we observed a trend towards increased risk of ASCUS/LSIL (OR=1.32; 95% CI -2.90-3.44) and HSIL (OR=5.10; 95% CI -0.67-38.9) per 10-fold increase in viral load, although not statistically significant. In conclusion, increasing viral load and integrated viral genomes were significantly associated with prevalent HSIL, thus indicating that viral load and physical state may potentially be useful triage markers for HPV16-positive women during cervical screening.
TL;DR: Self-sampling offered to non-attenders showed higher detection rates for ⩾CIN2 than routine cytology-based screening, and similar detection rates as HPV and cytology co-testing, which reinforces the importance of self-Sampling for screening non-Attenders in organised cervical cancer screening.
Abstract: High-grade cervical intraepithelial neoplasia in human papillomavirus self-sampling of screening non-attenders
TL;DR: Certain population groups, including women with low socioeconomic position or of nonwestern origin, were less likely to participate in self-sampling, and targeted approaches may be needed to increase screening participation in these groups.
Abstract: Background: Offering human papillomavirus–based self-sampling to nonparticipants in routine cervical cancer screening can increase screening participation. However, little is known about characteristics of women who accept self-sampling. In this population-based study, we investigated determinants for participation in self-sampling among Danish nonattenders to routine cervical cancer screening. Methods: During 2014 to 2015, a random sample of screening nonparticipants ages 27 to 65 years living in the Capital Region of Denmark were invited for self-sampling. Of 21,314 eligible women, 4,743 participated in self-sampling. Information on sociodemographic characteristics and mental and physical health of all the women was obtained from nationwide registries, and 3,707 women completed a questionnaire on lifestyle, sexual behavior, and reasons for nonparticipation in routine screening. We used logistic regression to estimate ORs for participation in self-sampling, crude, and adjusted for sociodemographic characteristics. Results: Basic education [ORadjusted = 0.79; 95% confidence interval (CI), 0.72−0.88], low income (ORadjusted = 0.66; 95% CI, 0.59–0.73), origin from a nonwestern country (ORadjusted = 0.43; 95% CI, 0.38−0.48), and being unmarried (ORadjusted = 0.66; 95% CI, 0.61−0.72) were associated with lower self-sampling participation. Long-term unscreened women (ORadjusted = 0.49; 95% CI, 0.45−0.53), women with prior schizophrenia or other psychoses (ORadjusted = 0.62; 95% CI, 0.48−0.80), women with poor self-perceived health (ORadjusted = 0.42; 95% CI, 0.25−0.69), and women who perceived screening as unnecessary (ORadjusted = 0.54; 95% CI, 0.37−0.80) or irrelevant (ORadjusted = 0.81; 95% CI, 0.78−0.96) were less likely to self-sample. Conclusions: Certain population groups, including women with low socioeconomic position or of nonwestern origin, were less likely to participate in self-sampling. Impact: Targeted approaches may be needed to increase screening participation in these groups. Cancer Epidemiol Biomarkers Prev; 27(11); 1342–51. ©2018 AACR.
TL;DR: Any postdiagnosis use of non-aspirin NSAIDs did not influence ovarian cancer mortality overall, however, more intensive use was associated with improved survival of serous ovarian cancer.
TL;DR: It is concluded that women diagnosed with CIN3 on the cone have a long‐lasting increased risk of cervical cancer even when the margins on the cones are negative.
Abstract: Using nationwide Danish registries we examined the long-term risk of cervical cancer in women diagnosed with cervical intraepithelial neoplasia grade 3 (CIN3) (including adenocarcinoma in situ (AIS)) on the cone compared to women with a normal cytology test. Initially, we identified women born 1918-1990, who were recorded as living in Denmark between January 1, 1978 and December 31, 2012. From the Pathology Data Bank information on CIN3 on the cone, margins status, histological type of CIN3 and cervical cytology results was extracted. Cox proportional hazard model was used to estimate the relative risk of subsequent cervical cancer. We included 59,464 women with CIN3 on the cone and 1,918,508 women with a normal cytology test. Overall, women diagnosed with CIN3 had a higher risk of subsequent cervical cancer compared to women with normal cytology (HR = 2.06; 95%CI: 1.81-2.35). Analyses according to time since conization showed elevated risks in all time periods, and 25 years or more after conization the relative risk was significantly increased (HR = 2.56; 95%CI: 1.37-4.77). Twenty years or more after conization, also women with negative margins had an increased relative risk (HR = 2.49; 95%CI: 1.12-5.57). In addition, the long-term relative risk of cervical cancer varied with the different histological types of CIN3 and was highest for AIS (HR = 7.50; 95%CI: 1.87-30.01, 10-14 years after conization). In conclusion, women diagnosed with CIN3 on the cone have a long-lasting increased risk of cervical cancer even when the margins on the cone are negative.
University of Queensland1, QIMR Berghofer Medical Research Institute2, Baylor College of Medicine3, University of Cambridge4, University of Michigan5, University of Southern California6, Vanderbilt University7, University of California, Los Angeles8, University of Erlangen-Nuremberg9, Flanders Institute for Biotechnology10, Katholieke Universiteit Leuven11, Fred Hutchinson Cancer Research Center12, University of Washington13, Dartmouth College14, University of Hamburg15, German Cancer Research Center16, Roswell Park Cancer Institute17, Cedars-Sinai Medical Center18, Hannover Medical School19, University of Helsinki20, University of Pittsburgh21, University of Texas Health Science Center at Houston22, University of Duisburg-Essen23, Praxis24, University of Copenhagen25, Mayo Clinic26, University of South Florida27, Cancer Council Victoria28, University of Melbourne29, Monash University30, University of Texas MD Anderson Cancer Center31, Texas Southern University32, New York University33, Memorial Sloan Kettering Cancer Center34, University of Virginia35, Duke University36, Harvard University37, Rutgers University38, University of Bergen39, Radboud University Nijmegen40, Oregon Health & Science University41, University of New Mexico42, University of British Columbia43, Simon Fraser University44, Medical University of South Carolina45, Pomeranian Medical University46, National Institutes of Health47, Curie Institute48, Peter MacCallum Cancer Centre49, Princess Anne Hospital50, University of Glasgow51, Glasgow Royal Infirmary52, Stanford University53, Icahn School of Medicine at Mount Sinai54, University of Toronto55, Yale University56, University of California, Irvine57, University College London58, University of New South Wales59, Garvan Institute of Medical Research60
TL;DR: Greater genetically predicted height was associated with increased ovarian cancer risk overall and separately for invasive and borderline tumours, suggesting genes influencing height are involved in pathways promoting ovarian carcinogenesis.
Abstract: BACKGROUND: Observational studies suggest greater height is associated with increased ovarian cancer risk, but cannot exclude bias and/or confounding as explanations for this. Mendelian randomisation (MR) can provide evidence which may be less prone to bias. METHODS: We pooled data from 39 Ovarian Cancer Association Consortium studies (16,395 cases; 23,003 controls). We applied two-stage predictor-substitution MR, using a weighted genetic risk score combining 609 single-nucleotide polymorphisms. Study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted height and risk were pooled using random-effects meta-analysis. RESULTS: Greater genetically predicted height was associated with increased ovarian cancer risk overall (pooled-OR (pOR) = 1.06; 95% CI: 1.01-1.11 per 5 cm increase in height), and separately for invasive (pOR = 1.06; 95% CI: 1.01-1.11) and borderline (pOR = 1.15; 95% CI: 1.02-1.29) tumours. CONCLUSIONS: Women with a genetic propensity to being taller have increased risk of ovarian cancer. This suggests genes influencing height are involved in pathways promoting ovarian carcinogenesis.
TL;DR: Low-dose aspirin use did not reduce mortality among ovarian cancer patients, and Hazard ratios remained neutral according to patterns of low- dose aspirin use, including prediagnosis use or established mortality predictors.
Abstract: Increasing data suggest that aspirin use may improve cancer survival; however, the evidence is sparse for ovarian cancer. We examined the association between postdiagnosis use of low-dose aspirin and mortality in a nationwide cohort of women with epithelial ovarian cancer between 2000 and 2012. Information on filled prescriptions of low-dose aspirin, dates and causes of death, and potential confounding factors was obtained from nationwide Danish registries. We used Cox regression models to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for ovarian cancer-specific or other-cause mortality associated with low-dose aspirin use. Among 4117 patients, postdiagnosis use of low-dose aspirin was associated with HRs of 1.02 (95% CI: 0.87–1.20) for ovarian cancer mortality and 1.06 (95% CI: 0.77–1.47) for other-cause mortality. Hazard ratios remained neutral according to patterns of low-dose aspirin use, including prediagnosis use or established mortality predictors. Low-dose aspirin use did not reduce mortality among ovarian cancer patients.
TL;DR: The aim of this study was to investigate whether consumption of coffee, tea and caffeine affects the risk of primary infertility in women.
Abstract: Introduction The aim of this study was to investigate whether consumption of coffee, tea and caffeine affects the risk of primary infertility in women. Material and methods We selected nulliparous Danish women aged 20-29 years from a prospective cohort and retrieved information on coffee and tea consumption from a questionnaire and an interview at enrollment. We assessed the women's fertility by linkage to the Danish Infertility Cohort and retrieved information on children and vital status from the Civil Registration System. All 7574 women included for analysis were followed for primary infertility from the date of enrollment (1991-1993) until 31 December 2010. Analyses were performed with Cox proportional hazard models. Results During follow up, primary infertility was diagnosed in 822 women. Compared with never consumers, the risk of primary infertility among women who drank coffee or tea was not affected. The risk of primary infertility was neither associated with an increasing number of daily servings of coffee (hazard ratio 1.00; 95% confidence interval (CI), 0.97-1.03) or tea (hazard ratio 1.01; 95% CI, 0.99-1.03) in consumers only. Concerning total caffeine consumption (from coffee and tea), the risk of infertility was similar among consumers compared with never consumers. Finally, none of the additional daily 100 mg of caffeine affected the risk among consumers only (hazard ratio 1.00; 95% CI 0.98-1.02). Conclusions In this population-based cohort study, not restricted to women seeking pregnancy, we found no association between coffee, tea or total caffeine consumption and the risk of primary infertility in women.
TL;DR: Estimating the lifetime risk for developing cervical cancer after vaccinating a HPV naïve girl with the 9vHPV vaccine in the hypothetical absence of cervical cancer screening demonstrates how evidence can be generated to support decision-making by individual healthcare seekers regarding cervical cancer prevention.
Abstract: Background: The nonavalent HPV (9vHPV) vaccine is indicated for active immunisation of individuals from the age of 9 years against cervical, vulvar, vaginal and anal premalignant lesions and cancer...
TL;DR: Women with benign ovarian tumors have a long-term increased risk for borderline ovarian tumors, and the associations did not change markedly when analyzed for the different histotypes of benign (solid and cystic tumors) and borderline (serous and mucinous tumors) ovarian tumors.
TL;DR: Investigating variants in 88 small GTPase genes in germline DNA of 18,736 EOC patients and 26,138 controls of European ancestry found two ARHGEF10L variants were located in super-enhancer regions and that AKAP6 rs927062 was associated with expression of G TPase gene ARHGAP5 (Rho GTPases activating protein 5).
Abstract: Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality in American women Normal ovarian physiology is intricately connected to small GTP binding proteins of the Ras superfamily (Ras, Rho, Rab, Arf, and Ran) which govern processes such as signal transduction, cell proliferation, cell motility, and vesicle transport We hypothesized that common germline variation in genes encoding small GTPases is associated with EOC risk We investigated 322 variants in 88 small GTPase genes in germline DNA of 18,736 EOC patients and 26,138 controls of European ancestry using a custom genotype array and logistic regression fitting log-additive models Functional annotation was used to identify biofeatures and expression quantitative trait loci that intersect with risk variants One variant, ARHGEF10L (Rho guanine nucleotide exchange factor 10 like) rs2256787, was associated with increased endometrioid EOC risk (OR = 133, p = 446 x 10-6) Other variants of interest included another in ARHGEF10L, rs10788679, which was associated with invasive serous EOC risk (OR = 107, p = 000026) and two variants in AKAP6 (A-kinase anchoring protein 6) which were associated with risk of invasive EOC (rs1955513, OR = 090, p = 000033; rs927062, OR = 094, p = 000059) Functional annotation revealed that the two ARHGEF10L variants were located in super-enhancer regions and that AKAP6 rs927062 was associated with expression of GTPase gene ARHGAP5 (Rho GTPase activating protein 5) Inherited variants in ARHGEF10L and AKAP6, with potential transcriptional regulatory function and association with EOC risk, warrant investigation in independent EOC study populations
University of Michigan1, University of Southern California2, Rutgers University3, University of Washington4, Fred Hutchinson Cancer Research Center5, Roswell Park Cancer Institute6, University of Hamburg7, German Cancer Research Center8, Dartmouth College9, University College London10, Radboud University Nijmegen11, University of Pittsburgh12, Mayo Clinic13, University of Kansas14, Brigham and Women's Hospital15, Harvard University16, Garvan Institute of Medical Research17, University of New South Wales18, University of California, Irvine19, University of Cambridge20, University of Virginia21, University of Copenhagen22, QIMR Berghofer Medical Research Institute23, University of Texas Health Science Center at Houston24, Duke University25, Yale University26
TL;DR: This paper extends the empirical Bayes (EB) approach previously developed for multiplicative interaction to the additive scale, and suggests that the EB approach uses the gene-environment independence assumption in a data-adaptive way and provides a gain in power compared with the standard logistic regression analysis and better control of type I error whenCompared with the analysis assuming gene- Environment independence.
Abstract: There have been recent proposals advocating the use of additive gene-environment interaction instead of the widely used multiplicative scale, as a more relevant public health measure. Using gene-environment independence enhances statistical power for testing multiplicative interaction in case-control studies. However, under departure from this assumption, substantial bias in the estimates and inflated type I error in the corresponding tests can occur. In this paper, we extend the empirical Bayes (EB) approach previously developed for multiplicative interaction, which trades off between bias and efficiency in a data-adaptive way, to the additive scale. An EB estimator of the relative excess risk due to interaction is derived, and the corresponding Wald test is proposed with a general regression setting under a retrospective likelihood framework. We study the impact of gene-environment association on the resultant test with case-control data. Our simulation studies suggest that the EB approach uses the gene-environment independence assumption in a data-adaptive way and provides a gain in power compared with the standard logistic regression analysis and better control of type I error when compared with the analysis assuming gene-environment independence. We illustrate the methods with data from the Ovarian Cancer Association Consortium.
TL;DR: Subjective perception of risk for STI was associated with women’s current risk-taking behaviours, indicating women generally are able to assess their risks for STIs.
Abstract: Objective This study examined the associations between current behaviours/characteristics and self-perceived risk for STIs, among randomly selected women aged 18–45 years from Denmark, Norway and Sweden. Method A population-based, cross-sectional, questionnaire study (paper based, web based and telephone based) was conducted during 2011–2012. We compared medium–high STI risk perception with no/low risk perception. The associations were explored for women who had ever had sexual intercourse and for women with a new partner in the last 6 months using multivariable logistic regression. Result The overall prevalence of medium–high STI risk perception was 7.4%. It was highest among women aged 18–24 years (16.2%) and among the Danish women (8.8%). Number of new sexual partners in the last 6 months (≥3vs 0 partners, OR 14.94, 95% CI 13.20 to 16.94) was strongly associated with medium–high STI risk perception. Among women with a new partner in the last 6 months, lack of condom use increased medium–high STI risk perception (OR 1.73, 95% CI 1.52 to 1.96). Genital warts in the last year, binge drinking and being single were associated with increased risk perception and remained statistically significant after additional adjustments were made for number of new partners and condom use with new partners in the last 6 months. Conclusion Subjective perception of risk for STI was associated with women’s current risk-taking behaviours, indicating women generally are able to assess their risks for STIs. However, a considerable proportion of women with multiple new partners in the last 6 months and no condom use still considered themselves at no/low risk for STI.
TL;DR: This nationwide case-control study may suggest that recent paracetamol use could have a chemopreventive effect on MBTs, whereas neither low-dose aspirin nor non-aspirin NSAIDs use seem to protect against SBTs or MBTs.
TL;DR: Overweight and obese women were more likely to have had no lifetime sexual partner or no sexual partner in the last year compared to normal weight women and had a lower likelihood of genital warts and high-risk human papillomavirus infection.
Abstract: The aim of this study was to examine sexual inactivity and occurrence of selected sexually transmitted infections in relation to body mass index. We used data from two large Danish population-based cross-sectional studies conducted in 1991-1995 (HPV study: 6869 women, aged 22-32 years) and in 2004-2005 (Liva study: 19,484 women, aged 18-45 years). Data were collected using a structured interview and measured weight, height, high-risk human papillomavirus DNA, Chlamydia DNA for the HPV study and a structured questionnaire for the Liva study. Overweight and obese women were more likely to have had no lifetime sexual partner or no sexual partner in the last year, e.g., obese women had a threefold (95 percent CI: 1.95-5.04) odds ratio of having had no sexual partner in the last year compared to normal weight women. Additionally, overweight and obese women had a lower likelihood of genital warts and high-risk human papillomavirus infection. A similar tendency was found for self-reported Chlamydia, but not with presence of Chlamydia DNA. If higher likelihood of no lifetime or recent sexual partners among overweight and obese women reflects unmet sexual needs, it could give rise to concern because quality of sexual life is associated with general quality of life.