Henrik Grönberg

Karolinska Institutet, Solna, Stockholm, Sweden

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Publications (236)1791.15 Total impact

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    ABSTRACT: Background: Inflammation has been hypothesized to increase the risk of cancer development as an initiator or promoter, yet no large-scale study of inherited variation across cancer sites has been conducted. Methods: We conducted a cross-cancer genomic analysis for the inflammation pathway based on 48 genome-wide association studies within the National Cancer Institute GAME-ON Network across five common cancer sites, with a total of 64 591 cancer patients and 74 467 control patients. Subset-based meta-analysis was used to account for possible disease heterogeneity, and hierarchical modeling was employed to estimate the effect of the subcomponents within the inflammation pathway. The network was visualized by enrichment map. All statistical tests were two-sided. Results: We identified three pleiotropic loci within the inflammation pathway, including one novel locus in Ch12q24 encoding SH2B3 (rs3184504), which reached GWAS significance with a P value of 1.78 x 10(-8), and it showed an association with lung cancer (P = 2.01 x 10(-6)), colorectal cancer (GECCO P = 6.72x10(-6); CORECT P = 3.32x10(-5)), and breast cancer (P = .009). We also identified five key subpathway components with genetic variants that are relevant for the risk of these five cancer sites: inflammatory response for colorectal cancer (P = .006), inflammation related cell cycle gene for lung cancer (P = 1.35x10(-6)), and activation of immune response for ovarian cancer (P = .009). In addition, sequence variations in immune system development played a role in breast cancer etiology (P = .001) and innate immune response was involved in the risk of both colorectal (P = .022) and ovarian cancer (P = .003). Conclusions: Genetic variations in inflammation and its related subpathway components are keys to the development of lung, colorectal, ovary, and breast cancer, including SH2B3, which is associated with lung, colorectal, and breast cancer.
    JNCI Journal of the National Cancer Institute 11/2015; 107(11):djv246. DOI:10.1093/jnci/djv246 · 12.58 Impact Factor
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    ABSTRACT: Objective: This study aimed to evaluate the association between perceived stress, social support, disease progression and mortality in a nationwide population-based cohort of men with prostate cancer. Materials and methods: The study surveyed 4105 Swedish men treated for clinically localized prostate cancer regarding stress, grief, sleep habits and social support. Associations between these factors and mortality were assessed using multivariate Cox regression analysis. Results: Men with the highest levels of perceived stress had a statistically significantly increased rate of prostate cancer-specific mortality compared with men with low stress levels (hazard ratio 1.66, 95% confidence interval 1.05-2.63). Men with high stress levels also had a high frequency of grieving and sleep loss. They also had fewer people with whom to share their emotional problems and felt an inability to share most of their problems with partners, friends and family. Conclusions: This study contributes to the growing field of psychosocial quality of life research in men with prostate cancer. The findings show a significant association between prostate cancer-specific mortality and perceived stress in patients initially diagnosed with localized, non-metastatic prostate cancer. Significant associations between perceived stress and various psychosocial factors were also seen. The findings of this study could prove useful to target interventions to improve quality of life in men with prostate cancer.
    Scandinavian Journal of Urology 09/2015; DOI:10.3109/21681805.2015.1079796 · 1.25 Impact Factor
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    ABSTRACT: BackgroundUnderstanding the heterogeneous genotypes and phenotypes of prostate cancer is fundamental to improving the way we treat this disease. As yet, there are no validated descriptions of prostate cancer subgroups derived from integrated genomics linked with clinical outcome.
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    ABSTRACT: Epidemiological studies have reported inconsistent associations between telomere length (TL) and risk for various cancers. These inconsistencies are likely attributable, in part, to biases that arise due to post-diagnostic and post-treatment TL measurement. To avoid such biases, we used a Mendelian randomization approach and estimated associations between nine TL-associated SNPs and risk for five common cancer types (breast, lung, colorectal, ovarian and prostate cancer, including subtypes) using data on 51,725 cases and 62,035 controls. We then used an inverse-variance weighted average of the SNP-specific associations to estimate the association between a genetic score representing long TL and cancer risk. The long TL genetic score was significantly associated with increased risk of lung adenocarcinoma (P=6.3x10(-15)), even after exclusion of a SNP residing in a known lung cancer susceptibility region (TERT-CLPTM1L) P=6.6x10(-6)). Under Mendelian randomization assumptions, the association estimate (odds ratio (OR)=2.78) is interpreted as the OR for lung adenocarcinoma corresponding to a 1000 base pair increase in TL. The weighted TL SNP score was not associated with other cancer types or subtypes. Our finding that genetic determinants of long TL increase lung adenocarcinoma risk avoids issues with reverse causality and residual confounding that arise in observational studies of TL and disease risk. Under Mendelian randomization assumptions, our finding suggests that longer TL increases lung adenocarcinoma risk. However, caution regarding this causal interpretation is warranted in light of the potential issue of pleiotropy, and a more general interpretation is that SNPs influencing telomere biology are also implicated in lung adenocarcinoma risk. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    Human Molecular Genetics 07/2015; 24(18). DOI:10.1093/hmg/ddv252 · 6.39 Impact Factor
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    ABSTRACT: Background. For risk-stratified screening to be implemented as a screening program for breast and prostate cancer it has to be accepted among the general population. Investigating public interest in stratified screening and its acceptability to the public is therefore essential since as yet little is known. Method. Cross-sectional web survey sent to a sample of 10 000 individuals (20–74 years of age) representative of the Swedish population as registered in 2009. Results. Among the responders (28%), a vast majority (94%) expressed an interest in knowing their breast or prostate cancer risk and stated wanting to know to ‘avoid worrying’. Men and women were equally interested in knowing their prostate and breast cancer risk, respectively. However, men showed more certainty. Trusting the healthcare workers with personal information (63%) as well as genetic information (70%), in order to calculate the risk, did not seem to be a major issue. Furthermore, 87% would agree to get screened more often if identified with a high risk, whereas, if identified with a low risk, only 27% would agree to get screened less often. Finally, although a consultation with a physician seemed to be the preferred way to communicate the risk, a majority would agree to receive it via a letter or a phone call. Conclusion. Risk-stratified screening has the possibility to be accepted by the general public. Knowledge about interest and acceptability of the prospect of risk-stratified screening for breast and prostate cancer will help when implementing new screening strategies.
    Acta oncologica (Stockholm, Sweden) 05/2015; DOI:10.3109/0284186X.2015.1043024 · 3.00 Impact Factor
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    ABSTRACT: Most men diagnosed with prostate cancer will experience indolent disease; hence, discovering genetic variants that distinguish aggressive from nonaggressive prostate cancer is of critical clinical importance for disease prevention and treatment. In a multistage, case-only genome-wide association study of 12,518 prostate cancer cases, we identify two loci associated with Gleason score, a pathological measure of disease aggressiveness: rs35148638 at 5q14.3 (RASA1, P=6.49 × 10(-9)) and rs78943174 at 3q26.31 (NAALADL2, P=4.18 × 10(-8)). In a stratified case-control analysis, the SNP at 5q14.3 appears specific for aggressive prostate cancer (P=8.85 × 10(-5)) with no association for nonaggressive prostate cancer compared with controls (P=0.57). The proximity of these loci to genes involved in vascular disease suggests potential biological mechanisms worthy of further investigation.
    Nature Communications 05/2015; 6:6889. DOI:10.1038/ncomms7889 · 11.47 Impact Factor
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    ABSTRACT: Body Mass index (BMI) has been shown to affect risk and mortality of several cancers. Prostate cancer and obesity are major public health concerns for middle-aged and older men. Previous studies of pre-diagnostic BMI have found an increased risk of prostate cancer mortality in obese patients. To study the associations between BMI at time of prostate cancer diagnosis and prostate cancer specific and overall mortality. BMI was analyzed both as a continuous variable and categorized into four groups based on the observed distribution in the cohort (BMI < 22.5, 22.5 < 25, 25 < 27.5 and ≥27.5 kg/m2). The association between BMI and mortality was assessed using stratified Cox proportional hazards models and by fitting regression splines for dose response analysis in 3,161 men diagnosed with prostate cancer. After 11 years of follow up via linkage to the population-based cause of death registry, we identified 1,161 (37%) deaths off which 690 (59%) were due to prostate cancer. High BMI (BMI ≥ 27.5 kg/m2) was associated with a statistically significant increased risk of prostate cancer specific mortality (HR:1.44, 95%CI: 1.09–1.90) and overall mortality (HR:1.33, 95%CI: 1.09–1.63) compared to the reference group (BMI 22.5 < 25 kg/m2). Additionally, men with a low BMI (<22.5 kg/m2), had a statistically significant increased risk of prostate cancer specific mortality (HR:1.33, 95%CI: 1.02–1.74) and overall mortality (HR:1.36, 95%CI: 1.11–1.67) compared to the reference. However, this effect disappeared when men who died within the first two years of follow-up were excluded from the analyses while the increased risk of prostate cancer specific mortality and overall mortality remained statistically significant for men with a BMI ≥ 27.5 kg/m2 (HR:1.44, 95%CI: 1.09–1.90 and HR: 1.33, 95%CI: 1.09–1.63, respectively). This study showed that a high BMI at time of prostate cancer diagnosis was associated with increased overall mortality. Prostate 75: 1129–1136, 2015.
    The Prostate 04/2015; 75(11). DOI:10.1002/pros.23001 · 3.57 Impact Factor
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    ABSTRACT: Background: Bloodstream infection following a transrectal prostate biopsy is a well-known and feared complication. Previous studies have shown an increase in multi-resistant bacterial infections as a consequence of higher usage of antibiotics in investigated populations. Our aim was to analyze bacterial resistance patterns in positive blood cultures, after prostate biopsies in Stockholm, Sweden, where the use of antibiotics has been low and decreasing during the last 10 years. Methods: From the three pathology laboratories in Stockholm, reports of prostate examinations were retrieved (n = 56,076) from 2003 to 2012. By linking men to the National Patient Register all but prostate core biopsies were excluded (n = 12,024). Prostate biopsies in men younger than 30 years of age were excluded (n = 5) leaving 44,047 biopsies for analysis. From laboratory information systems data regarding blood cultures were retrieved. Proportions of blood cultures within 30 days by year were calculated. Crude and adjusted logistic regression models were used to estimate ORs. Results: In total, 44,047 prostate biopsies were performed in 32,916 men over 10 years. On 620 occasions a blood culture was drawn within 30 days of the biopsy; 266 of these were positive. The proportions with positive blood cultures in 2003 and 2012 were 0.38 and 1.14%, respectively. The proportion of multidrug-resistant bacteria increased significantly during the study. In the crude and the adjusted analysis, the year of biopsy and Charlson Comorbidity Index were associated with the risk of having a positive blood culture. Conclusion: Multidrug-resistant enteric bacilli are becoming a problem in Sweden, despite low antimicrobial use. Men need to be informed about the increasing risks of infectious complications of transrectal prostate biopsy. One out of 50 men undergoing a prostate biopsy will develop symptoms suggestive of a bloodstream infection after the biopsy and one in 100 men will have a positive blood culture.
    The Prostate 03/2015; 75(9). DOI:10.1002/pros.22979 · 3.57 Impact Factor
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    ABSTRACT: A decreased risk of prostate cancer (PCa) has been suggested in men taking aspirin, statins and metformin, although the evidence has been conflicting. We estimated the association between prescribed medications, prostate specific antigen (PSA) levels and the risk of either any PCa or high-grade PCa. This population-based cohort study included 185,667 men having a first recorded PSA test and 18,574 men having a first prostate biopsy in Stockholm County, Sweden for the period 2007-2012. Detailed clinical information including PSA levels, biopsy results, comorbidities and educational level were obtained from population-based registers. High-grade prostate cancer was defined as a Gleason score of seven or higher. Differences in PSA levels by medication status were estimated using linear regression on log PSA values. PCa risk was estimated using multivariate logistic regression. Compared with men who were not on medication, the PSA level at the first PSA test was lower among men using 75mg/dose aspirin (-3.9% change in PSA concentration; 95% confidence interval (CI): -5.8 to -2.1), statin (-4.6%; 95% CI: -6.2 to -2.9), metformin (-14%; 95% CI: -17 to -12) and insulin (-16%; 95% CI: -18 to -14). Men using any statins had an increased risk of both high-grade PCa (odds ratio (OR) 1.25; 95% CI: 1.10-1.42) and PCa of any grade (OR 1.16; 95% CI 1.04-1.29). There were no significant associations between aspirin or any antidiabetic medication and the risk of PCa. We found no protective effect of aspirin, statins or antidiabetics in terms of risk for any PCa or high-grade PCa. Use of any statins was associated with an elevated risk of being diagnosed with high-grade prostate cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.
    European journal of cancer (Oxford, England: 1990) 02/2015; 51(6). DOI:10.1016/j.ejca.2015.02.003 · 5.42 Impact Factor
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    ABSTRACT: Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis
    Nature 02/2015; 518(7538). DOI:10.1038/nature14177 · 41.46 Impact Factor
  • Henrik Falconer · Li Yin · Henrik Grönberg · Daniel Altman
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    ABSTRACT: Recent genetic and morphologic studies have challenged the traditional view on the pathogenesis of ovarian cancer; suggesting that ovarian cancer predominantly arises within the fallopian tubes or the uterus. We hypothesize that surgical removal of the fallopian tubes is associated with a reduced risk for ovarian cancer. In this population-based cohort study, we used data on women with previous surgery on benign indication (sterilization, salpingectomy, hysterectomy, and bilateral salpingo-oophorectomy [BSO], hysterectomy; n = 251465) compared with the unexposed population (n = 5449119) between 1973 and 2009 and analyzed with Cox regression models. The effects of one- and two-sided salpingectomy were considered in a subanalysis. All statistical tests were two-sided. There was a statistically significantly lower risk for ovarian cancer among women with previous salpingectomy (HR = 0.65, 95% CI = 0.52 to 0.81) when compared with the unexposed population. In addition, statistically significant risk reductions were observed among women with previous hysterectomy (HR = 0.79, 95% CI = 0.70 to 0.88), sterilization (HR = 0.72, 95% CI = 0.64 to 0.81), and hysterectomy with BSO (HR = 0.06, 95% CI = 0.03 to 0.12). Bilateral salpingectomy was associated with a 50% decrease in risk of ovarian cancer compared with the unilateral procedure (HR = 0.35, 95% CI = 0.17 to 0.73, and 0.71, 95% CI = 0.56 to 0.91, respectively). Salpingectomy on benign indication is associated with reduced risk of ovarian cancer. These data support the hypothesis that a substantial fraction of ovarian cancer arises in the fallopian tube. Our results suggest that removal of the fallopian tubes by itself, or concomitantly with other benign surgery, is an effective measure to reduce ovarian cancer risk in the general population. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
    JNCI Journal of the National Cancer Institute 02/2015; 107(2). DOI:10.1093/jnci/dju410 · 12.58 Impact Factor
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    ABSTRACT: Few studies have investigated the association between post-diagnosis physical activity and mortality among men diagnosed with prostate cancer. The aim of this study was to investigate the effect of physical activity after a prostate cancer diagnosis on both overall and prostate cancer-specific mortality in a large cohort. Data from 4,623 men diagnosed with localized prostate cancer 1997-2002 and followed-up until 2012 were analyzed. HRs with 95% confidence intervals (CI) were estimated using Cox proportional hazards models to examine the association between post-diagnosis recreational MET-h/d, time spent walking/bicycling, performing household work or exercising, and time to overall and prostate cancer-specific death. All models were adjusted for potential confounders. During the follow-up, 561 deaths of any cause and 194 deaths from prostate cancer occurred. Statistically significantly lower overall mortality rates were found among men engaged in ≥5 recreational MET-h/d (HR, 0.63; 95% CI, 0.52-0.77), walking/bicycling ≥20 min/d (HR, 0.70; 95% CI, 0.57-0.86), performing household work ≥1 h/d (HR, 0.71; 95% CI, 0.59-0.86), or exercising ≥1 h/wk (HR, 0.74; 95% CI, 0.61-0.90), compared with less active men within each activity type. For prostate cancer-specific mortality, statistically significantly lower mortality rates were seen among men walking/bicycling ≥20 min/d (HR, 0.61; 95% CI, 0.43-0.87) or exercising ≥1 h/wk (HR, 0.68; 95% CI, 0.48-0.94). Higher levels of physical activity were associated with reduced rates of overall and prostate cancer-specific mortality. Our study further strengthens previous results indicating beneficial effects of physical activity on survival among men with prostate cancer. Cancer Epidemiol Biomarkers Prev; 1-8. ©2014 AACR. ©2014 American Association for Cancer Research.
    Cancer Epidemiology Biomarkers & Prevention 12/2014; 24(1). DOI:10.1158/1055-9965.EPI-14-0707 · 4.13 Impact Factor
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    ABSTRACT: Background Cancers arise from multiple acquired mutations, which presumably occur over many years. Early stages in cancer development might be present years before cancers become clinically apparent. Methods We analyzed data from whole-exome sequencing of DNA in peripheral-blood cells from 12,380 persons, unselected for cancer or hematologic phenotypes. We identified somatic mutations on the basis of unusual allelic fractions. We used data from Swedish national patient registers to follow health outcomes for 2 to 7 years after DNA sampling. Results Clonal hematopoiesis with somatic mutations was observed in 10% of persons older than 65 years of age but in only 1% of those younger than 50 years of age. Detectable clonal expansions most frequently involved somatic mutations in three genes (DNMT3A, ASXL1, and TET2) that have previously been implicated in hematologic cancers. Clonal hematopoiesis was a strong risk factor for subsequent hematologic cancer (hazard ratio, 12.9; 95% confidence interval, 5.8 to 28.7). Approximately 42% of hematologic cancers in this cohort arose in persons who had clonality at the time of DNA sampling, more than 6 months before a first diagnosis of cancer. Analysis of bone marrow–biopsy specimens obtained from two patients at the time of diagnosis of acute myeloid leukemia revealed that their cancers arose from the earlier clones. Conclusions Clonal hematopoiesis with somatic mutations is readily detected by means of DNA sequencing, is increasingly common as people age, and is associated with increased risks of hematologic cancer and death. A subset of the genes that are mutated in patients with myeloid cancers is frequently mutated in apparently healthy persons; these mutations may represent characteristic early events in the development of hematologic cancers. (Funded by the National Human Genome Research Institute and others.)
    New England Journal of Medicine 11/2014; 371(26). DOI:10.1056/NEJMoa1409405 · 55.87 Impact Factor
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    ABSTRACT: Ductal adenocarcinoma (DAC) is considered an aggressive subtype of prostate cancer with greater risk of progression than acinar adenocarcinoma (AC). It has been debated whether DAC is a distinct subtype or not. Our aim was to examine the protein expression of DAC and compare the results with AC. A tissue microarray was constructed from 60 DAC and 46 AC matched by Gleason score and stained for 28 immunomarkers (hormonal receptors, prostate specific markers, cell cycle related markers, oncogenes and molecular biomarkers). HMWCK was positive in 8.5% of DAC, but negative in AC (p = 0.045). p16 was positive in 53.3% of DAC and 26.1% of AC (p = 0.005). p53 was positive in 42.4% of DAC and 26.7% of AC (p = 0.031). A distinct patchy positivity of CK20 was seen in 23.7% of DAC and 9.1% of AC (p = 0.047). Villin was positive in 3.4% of DAC while negative in AC. Ki-67 labeling index was higher in DAC than in AC [mean 9.2% (95% CI 6.4-12.0) and 2.6% (1.9-3.4), p < 0.001]. While there is some overlap in the immunohistochemical expression of DAC and AC, the differences between these morphotypes of prostatic carcinoma are consistent with DAC having a more aggressive phenotype than AC.
    Pathology 10/2014; 46:S109. DOI:10.1097/01.PAT.0000454473.54205.a1 · 2.19 Impact Factor
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    ABSTRACT: Metastatic prostate cancer is a monoclonal disease. We previously failed to identify a common somatic denominator between primary tumor tissue and two lymph-node metastases by exome sequencing [Lindberg J, et al. Eur Urol 2013;63:702–8]. To track the seeding clone we performed copy-number alteration analysis on 34 morphologically distinct tissue areas in one prostatectomy specimen. Using break-point regions to infer phylogenetic relationships, the clone most closely related to the metastases was found in intraductal carcinoma of the prostate. Although the majority of tumor areas harbored events also found in the metastases, three carried none. This emphasizes the importance of intraprostatic tumor heterogeneity for prediction of prognosis. These findings also support recent evidence that intraductal carcinoma is a marker of aggressive disease. Patient summary We identified the area in the prostate that gave rise to metastases by searching for metastatic-specific DNA alterations in multiple regions of the prostate. The metastasizing component grew within prostatic ducts, suggesting that intraductal cancer should be reported when found in needle biopsies. It is also important to be aware of tumor heterogeneity when assessing somatic changes linked to tumor aggressiveness.
    European Urology 09/2014; 67(5). DOI:10.1016/j.eururo.2014.09.006 · 13.94 Impact Factor

Publication Stats

11k Citations
1,791.15 Total Impact Points


  • 2002–2015
    • Karolinska Institutet
      • Department of Medical Epidemiology and Biostatistics
      Solna, Stockholm, Sweden
    • Helsingborgs Lasarett
      Hälsingborg, Skåne, Sweden
  • 1992–2014
    • Umeå University
      • • Department of Surgical and Perioperative Sciences
      • • Department of Radiation Sciences
      Umeå, Västerbotten, Sweden
  • 2008
    • Translational Genomics Research Institute
      Phoenix, Arizona, United States
  • 2007
    • Universität Ulm
      Ulm, Baden-Württemberg, Germany
  • 2004
    • Sahlgrenska University Hospital
      • Department of Cardiology
      Goeteborg, Västra Götaland, Sweden
    • Wake Forest School of Medicine
      • Center for Cancer Genomics
      Winston-Salem, NC, United States
  • 2003
    • Karolinska University Hospital
      • Nephrology Section
      Tukholma, Stockholm, Sweden
  • 1998
    • Norrlands universitetssjukhus
      Umeå, Västerbotten, Sweden