Publications by authors named "Stephen K Van Den Eeden"

183 Publications

Interpersonal violence and painful bladder symptoms in community-dwelling midlife to older women.

Am J Obstet Gynecol 2021 Sep 20. Epub 2021 Sep 20.

University of California, San Francisco, Department of Medicine, San Francisco, California; University of California, San Francisco, Department of Urology, San Francisco, California.

Background: Women are more likely to present with genitourinary complaints immediately after exposure to interpersonal violence, but little is known about long-term effects on women's urologic health such as their susceptibility to bladder pain and infections.

Objective: To determine whether lifetime interpersonal violence exposure and current post-traumatic stress disorder (PTSD) symptoms are associated with prevalence or severity of painful bladder symptoms as well as greater lifetime history of antibiotic-treated urinary tract infections in community-dwelling midlife and older women.

Study Design: We examined cross-sectional data from a multiethnic cohort of community-dwelling women aged 40-80 years enrolled in a northern California integrated healthcare system. Women completed structured self-report questionnaires about their past exposure to physical and verbal/emotional intimate partner violence as well as sexual assault. Symptoms of PTSD were assessed using the PSTD Checklist for DSM-IV, Civilian Version. Additional structured self-report measures assessed current bladder pain, other lower urinary tract symptoms, and history of antibiotic-treated urinary tract infections. Multivariable logistic regression models examined self-reported interpersonal violence exposure history and current PTSD symptoms in relation to current bladder pain and antibiotic-treated urinary tract infection history.

Results: Among 1,974 women (39% non-Latina White, 21% Black, 20% Latina, and 19% Asian), 22% reported lifetime interpersonal violence exposure, 22% bladder pain, and 60% history of ever having an antibiotic-treated urinary tract infection. Lifetime experience of sexual assault (OR[95%CI] = 1.39 [1.02, 1.88]) and current PTSD symptoms (OR[95%CI] = 1.96 [1.45, 2.65]) were associated with current bladder pain. Lifetime experience of physical intimate partner violence was associated with ever having a urinary tract infection (OR[95%CI] = 1.38 [1.00, 1.86]), as was emotional IPV (OR[95%CI] = 1.88 [1.43, 2.48]), sexual assault (OR[95%CI] = 1.44 [1.09, 1.91]), and current PTSD symptoms (OR[95%CI] = 1.54 [1.16, 2.03]).

Conclusion: In this ethnically diverse, community-based cohort, lifetime interpersonal violence exposures and current PTSD symptoms were independently associated with current bladder pain and lifetime history of antibiotic-treated urinary tract infections in midlife to older women. Findings suggest that interpersonal violence and PTSD symptoms may be under-recognized markers of risk for urologic pain and infections in women, highlighting a need for trauma-informed care of these issues.
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http://dx.doi.org/10.1016/j.ajog.2021.09.017DOI Listing
September 2021

Hepcidin-regulating iron metabolism genes and pancreatic ductal adenocarcinoma: a pathway analysis of genome-wide association studies.

Am J Clin Nutr 2021 Jul 13. Epub 2021 Jul 13.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.

Background: Epidemiological studies have suggested positive associations for iron and red meat intake with risk of pancreatic ductal adenocarcinoma (PDAC). Inherited pathogenic variants in genes involved in the hepcidin-regulating iron metabolism pathway are known to cause iron overload and hemochromatosis.

Objectives: The objective of this study was to determine whether common genetic variation in the hepcidin-regulating iron metabolism pathway is associated with PDAC.

Methods: We conducted a pathway analysis of the hepcidin-regulating genes using single nucleotide polymorphism (SNP) summary statistics generated from 4 genome-wide association studies in 2 large consortium studies using the summary data-based adaptive rank truncated product method. Our population consisted of 9253 PDAC cases and 12,525 controls of European descent. Our analysis included 11 hepcidin-regulating genes [bone morphogenetic protein 2 (BMP2), bone morphogenetic protein 6 (BMP6), ferritin heavy chain 1 (FTH1), ferritin light chain (FTL), hepcidin (HAMP), homeostatic iron regulator (HFE), hemojuvelin (HJV), nuclear factor erythroid 2-related factor 2 (NRF2), ferroportin 1 (SLC40A1), transferrin receptor 1 (TFR1), and transferrin receptor 2 (TFR2)] and their surrounding genomic regions (±20 kb) for a total of 412 SNPs.

Results: The hepcidin-regulating gene pathway was significantly associated with PDAC (P = 0.002), with the HJV, TFR2, TFR1, BMP6, and HAMP genes contributing the most to the association.

Conclusions: Our results support that genetic susceptibility related to the hepcidin-regulating gene pathway is associated with PDAC risk and suggest a potential role of iron metabolism in pancreatic carcinogenesis. Further studies are needed to evaluate effect modification by intake of iron-rich foods on this association.
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http://dx.doi.org/10.1093/ajcn/nqab217DOI Listing
July 2021

A prognostic information system for real-time personalized care: Lessons for embedded researchers.

Healthc (Amst) 2021 Jun 23;8 Suppl 1:100486. Epub 2021 Jun 23.

The Permanente Medical Group, Oakland, CA, USA; Department of Oncology, Kaiser Permanente Oakland Medical Center, CA, Oakland, USA.

Embedded researchers could play a central role in developing tools to personalize care using electronic medical records (EMRs). However, few studies have described the steps involved in developing such tools, or evaluated the key factors in success and failure. This case study describes how we used an EMR-derived data warehouse to develop a prototype informatics tool to help oncologists counsel patients with pancreatic cancer about their prognosis. The tool generated real-time prognostic information based on tumor type and stage, age, comorbidity status and lab tests. Our multidisciplinary team included embedded researchers, application developers, user experience experts, and an oncologist leader.This prototype succeeded in establishing proof of principle, but did not reach adoption into actual practice. In pilot testing, oncologists succeeded in generating prognostic information in real time. A few found it helpful in patient encounters, but all identified critical areas for further development before implementation. Generalizable lessons included the need to (1) include a wide range of potential use cases and stakeholders when selecting use cases for such tools; (2) develop talking points for clinicians to explain results from predictive tools to patients; (3) develop ways to reduce lag time between events and data availability; and (4) keep the options presented in the user interface very simple. This case demonstrates that embedded researchers can lead collaborations using EMR-derived data to create systems for real-time personalized patient counseling, and highlights challenges that such teams can anticipate.
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http://dx.doi.org/10.1016/j.hjdsi.2020.100486DOI Listing
June 2021

Characterizing the Spectrum of Bladder Health and Lower Urinary Tract Symptoms (LUTS) Among Women: Results From the CARDIA Study.

Urology 2021 Jun 2. Epub 2021 Jun 2.

School of Public Health, Birmingham, AL.

Objectives: To operationalize a new definition for bladder health, we examined the distribution of lower urinary tract symptoms (LUTS) and impact, along with associated factors, among women in the Coronary Artery Risk Development in Young Adults (CARDIA) study.

Methods: We performed cluster analyses using validated LUTS symptom burden and impact scales collected between 2005-2006 and 2010-2011. We performed multinomial logistic regression analyses to evaluate cardiovascular factors (metabolic syndrome, cardiovascular health behaviors, and inflammation) between clusters after adjusting for covariates (demographic, obstetric/gynecologic, co-morbidities).

Results: Among CARDIA women (median age 51, range 42-59) with complete LUTS data (n = 1302), we identified and compared 4 cluster groups: women who reported no or very mild symptoms and no impact on well-being (bladder health, 44%, n = 569), versus women with LUTS and negative impact on well-being ranging from mild (31%, n = 407), moderate (20%, n = 259), to severe (5%, n = 67). With each 1-point lower BMI (kg/m), odds of membership in mild (OR 0.97, CI 0.95-0.99), moderate (OR 0.95, CI 0.93-0.98), and severe (OR 0.90, CI 0.88-0.94) LUTS cluster groups versus the bladder health group were lower. Compared to women with metabolic syndrome, women without metabolic syndrome had lower odds of membership in mild (OR 0.67, CI 0.45-0.99), moderate (OR 0.51, CI 0.33-0.79), and severe (OR 0.48, CI 0.24-0.94) LUTS cluster groups versus the bladder health group.

Conclusion: Two out of 5 midlife women met our definition of bladder health. Bladder health and cardiovascular health among women may share common factors, including lower BMI and the absence of metabolic syndrome.
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http://dx.doi.org/10.1016/j.urology.2021.05.032DOI Listing
June 2021

Particulate Air Pollution and Risk of Cardiovascular Events Among Adults With a History of Stroke or Acute Myocardial Infarction.

J Am Heart Assoc 2021 05 4;10(10):e019758. Epub 2021 May 4.

Kaiser Permanente Division of Research Oakland CA.

Background Previous studies have found associations between fine particulate matter <2.5 µm in diameter (PM) and increased risk of cardiovascular disease (CVD) among populations with no CVD history. Less is understood about susceptibility of adults with a history of CVD and subsequent PM-related CVD events and whether current regulation levels for PM are protective for this population. Methods and Results This retrospective cohort study included 96 582 Kaiser Permanente Northern California adults with a history of stroke or acute myocardial infarction. Outcome, covariate, and address data obtained from electronic health records were linked to time-varying 1-year mean PM exposure estimates based on residential locations. Cox proportional hazard models estimated risks of stroke, acute myocardial infarction, and cardiovascular mortality associated with PM exposure, adjusting for multiple covariates. Secondary analyses estimated risks below federal and state regulation levels (12 µg/m for 1-year mean PM). A 10-µg/m increase in 1-year mean PM exposure was associated with an increase in risk of cardiovascular mortality (hazard ratio [HR], 1.20; 95% CI, 1.11-1.30), but no increase in risk of stroke or acute myocardial infarction. Analyses of <12 µg/m showed increased risk for CVD mortality (HR, 2.31; 95% CI, 1.96-2.71), stroke (HR, 1.41; 95% CI, 1.09-1.83]), and acute myocardial infarction (HR, 1.51; 95% CI, 1.21-1.89) per 10-µg/m increase in 1-year mean PM. Conclusions Adults with a history of CVD are susceptible to the effects of PM exposure, particularly on CVD mortality. Increased risks observed at exposure levels <12 µg/m highlight that current PM regulation levels may not be protective for this susceptible population.
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http://dx.doi.org/10.1161/JAHA.120.019758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200700PMC
May 2021

Particulate Matter and Cardiovascular Risk in Adults with Chronic Obstructive Pulmonary Disease.

Am J Respir Crit Care Med 2021 07;204(2):159-167

Kaiser Permanente Division of Research, Kaiser Permanente, Oakland, California; and.

People with chronic obstructive pulmonary disease (COPD) have an increased risk of cardiovascular disease and may be more susceptible to air pollution exposure. However, no study has examined the association between long-term fine particulate matter exposure (≤2.5 μm in aerodynamic diameter) and risk of cardiovascular events in this potentially vulnerable population. To estimate the association between long-term fine particulate matter and risk of cardiovascular events among adults with COPD. This retrospective cohort study included 169,714 adults with COPD who were members of the Kaiser Permanente Northern California health plan during 2007-2016. Electronic health record data were linked to 1 km modeled particulate matter ≤2.5 μm in aerodynamic diameter exposure estimates. We fit Cox proportional hazard models, adjusting for age, sex, race/ethnicity, calendar year, smoking, body mass index, comorbidities, medications, and socioeconomic status. In low exposure analyses, we examined effects below the current regulation limit (12 μg/m). Among adults with COPD, a 10-μg/m increase in 1-year mean fine particulate matter exposure was associated with an elevated risk of cardiovascular mortality (hazard ratio, 1.10; 95% confidence interval [CI], 1.01-1.20). Effects were stronger in low exposure analyses (hazard ratio, 1.88; 95% CI, 1.56-2.27). Fine particulate matter exposure was not associated with acute myocardial infarction or stroke in overall analyses. Long-term fine particulate matter exposure was associated with an increased risk of cardiovascular mortality among adults with COPD. Current regulations may not sufficiently protect those with COPD.
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http://dx.doi.org/10.1164/rccm.202007-2901OCDOI Listing
July 2021

Cross-cancer evaluation of polygenic risk scores for 16 cancer types in two large cohorts.

Nat Commun 2021 02 12;12(1):970. Epub 2021 Feb 12.

Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.

Even distinct cancer types share biological hallmarks. Here, we investigate polygenic risk score (PRS)-specific pleiotropy across 16 cancers in European ancestry individuals from the Genetic Epidemiology Research on Adult Health and Aging cohort (16,012 cases, 50,552 controls) and UK Biobank (48,969 cases, 359,802 controls). Within cohorts, each PRS is evaluated in multivariable logistic regression models against all other cancer types. Results are then meta-analyzed across cohorts. Ten positive and one inverse cross-cancer associations are found after multiple testing correction. Two pairs show bidirectional associations; the melanoma PRS is positively associated with oral cavity/pharyngeal cancer and vice versa, whereas the lung cancer PRS is positively associated with oral cavity/pharyngeal cancer, and the oral cavity/pharyngeal cancer PRS is inversely associated with lung cancer. Overall, we validate known, and uncover previously unreported, patterns of pleiotropy that have the potential to inform investigations of risk prediction, shared etiology, and precision cancer prevention strategies.
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http://dx.doi.org/10.1038/s41467-021-21288-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880989PMC
February 2021

Smoking Modifies Pancreatic Cancer Risk Loci on 2q21.3.

Cancer Res 2021 Jun 11;81(11):3134-3143. Epub 2021 Feb 11.

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland.

Germline variation and smoking are independently associated with pancreatic ductal adenocarcinoma (PDAC). We conducted genome-wide smoking interaction analysis of PDAC using genotype data from four previous genome-wide association studies in individuals of European ancestry (7,937 cases and 11,774 controls). Examination of expression quantitative trait loci data from the Genotype-Tissue Expression Project followed by colocalization analysis was conducted to determine whether there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and < 5 × 10 was considered statistically significant. Genome-wide significant evidence of qualitative interaction was identified on chr2q21.3 in intron 5 of the transmembrane protein 163 (TMEM163) and upstream of the cyclin T2 (CCNT2). The most significant SNP using the Empirical Bayes method, in this region that included 45 significantly associated SNPs, was rs1818613 [per allele OR in never smokers 0.87, 95% confidence interval (CI), 0.82-0.93; former smokers 1.00, 95% CI, 0.91-1.07; current smokers 1.25, 95% CI 1.12-1.40, = 3.08 × 10). Examination of the Genotype-Tissue Expression Project data demonstrated an expression quantitative trait locus in this region for TMEM163 and CCNT2 in several tissue types. Colocalization analysis supported a shared SNP, rs842357, in high linkage disequilibrium with rs1818613 ( = 0. 94) driving both the observed interaction and the expression quantitative trait loci signals. Future studies are needed to confirm and understand the differential biologic mechanisms by smoking status that contribute to our PDAC findings. SIGNIFICANCE: This large genome-wide interaction study identifies a susceptibility locus on 2q21.3 that significantly modified PDAC risk by smoking status, providing insight into smoking-associated PDAC, with implications for prevention.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178175PMC
June 2021

Multicenter Comparison of 17-Gene Genomic Prostate Score as a Predictor of Outcomes in African American and Caucasian American Men with Clinically Localized Prostate Cancer.

J Urol 2021 Apr 1;205(4):1047-1054. Epub 2020 Dec 1.

Genomic Health Inc., an Exact Sciences corporation, Redwood City, California.

Purpose: Adoption of prognostic molecular assays for prostate cancer requires evidence of robust performance in different racial groups. Retrospective analysis was conducted to assess the performance of the Oncotype DX Genomic Prostate Score test in African American and Caucasian American men with surgically treated prostate cancer.

Materials And Methods: We compared the assay results (scale 0-100) and the 4 gene group scores in biopsy specimens from 201 African American and 1,144 Caucasian American men with clinically localized prostate cancer in 6 cohorts. Adverse pathology was defined as high grade (primary Gleason pattern 4 or any pattern 5) and/or nonorgan-confined disease (≥pT3). Binary logistic regression models were used for adverse pathology. Biochemical recurrence was defined as 2 successive prostate specific antigen levels >0.2 ng/ml or initiation of salvage therapy after radical prostatectomy. Cox proportional hazards models evaluated the association of the assay result or racial group with time to biochemical recurrence.

Results: Each cohort had different clinical risk distributions and percentages of African Americans, although median and interquartile ranges of the assay results and gene group scores were similar between both racial groups. In a multivariable model with the assay and pathological/clinical features including race, the assay was significantly associated with adverse pathology (p ≤0.004) and biochemical recurrence (p <0.001). Race was not a significant predictor of either end point.

Conclusions: The assay is similarly predictive of outcomes in African American and Caucasian American patients, and improves risk stratification in men with newly diagnosed prostate cancer from both racial groups.
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http://dx.doi.org/10.1097/JU.0000000000001484DOI Listing
April 2021

Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.

Nat Genet 2021 01 4;53(1):65-75. Epub 2021 Jan 4.

Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.
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http://dx.doi.org/10.1038/s41588-020-00748-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148035PMC
January 2021

Long-Term PM Exposure and Risks of Ischemic Heart Disease and Stroke Events: Review and Meta-Analysis.

J Am Heart Assoc 2021 01 31;10(1):e016890. Epub 2020 Dec 31.

Kaiser Permanente Division of Research Oakland CA.

Background Fine particulate matter <2.5 µm in diameter (PM) has known effects on cardiovascular morbidity and mortality. However, no study has quantified and compared the risks of incident myocardial infarction, incident stroke, ischemic heart disease (IHD) mortality, and cerebrovascular mortality in relation to long-term PM exposure. Methods and Results We sought to quantitatively summarize studies of long-term PM exposure and risk of IHD and stroke events by conducting a review and meta-analysis of studies published by December 31, 2019. The main outcomes were myocardial infarction, stroke, IHD mortality, and cerebrovascular mortality. Random effects meta-analyses were used to estimate the combined risk of each outcome among studies. We reviewed 69 studies and included 42 studies in the meta-analyses. In meta-analyses, we found that a 10-µg/m increase in long-term PM exposure was associated with an increased risk of 23% for IHD mortality (95% CI, 15%-31%), 24% for cerebrovascular mortality (95% CI, 13%-36%), 13% for incident stroke (95% CI, 11%-15%), and 8% for incident myocardial infarction (95% CI, -1% to 18%). There were an insufficient number of studies of recurrent stroke and recurrent myocardial infarction to conduct meta-analyses. Conclusions Long-term PM exposure is associated with increased risks of IHD mortality, cerebrovascular mortality, and incident stroke. The relationship with incident myocardial infarction is suggestive of increased risk but not conclusive. More research is needed to understand the relationship with recurrent events.
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http://dx.doi.org/10.1161/JAHA.120.016890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955467PMC
January 2021

A Large-Scale Association Study Detects Novel Rare Variants, Risk Genes, Functional Elements, and Polygenic Architecture of Prostate Cancer Susceptibility.

Cancer Res 2021 04 8;81(7):1695-1703. Epub 2020 Dec 8.

Program in Biological and Medical Informatics, University of California San Francisco, San Francisco, California.

To identify rare variants associated with prostate cancer susceptibility and better characterize the mechanisms and cumulative disease risk associated with common risk variants, we conducted an integrated study of prostate cancer genetic etiology in two cohorts using custom genotyping microarrays, large imputation reference panels, and functional annotation approaches. Specifically, 11,984 men (6,196 prostate cancer cases and 5,788 controls) of European ancestry from Northern California Kaiser Permanente were genotyped and meta-analyzed with 196,269 men of European ancestry (7,917 prostate cancer cases and 188,352 controls) from the UK Biobank. Three novel loci, including two rare variants (European ancestry minor allele frequency < 0.01, at 3p21.31 and 8p12), were significant genome wide in a meta-analysis. Gene-based rare variant tests implicated a known prostate cancer gene (), as well as a novel candidate gene (), which encodes a receptor highly expressed in prostate tissue and is related to the B7/CD28 family of T-cell immune checkpoint markers. Haplotypic patterns of long-range linkage disequilibrium were observed for rare genetic variants at and other loci, reflecting their evolutionary history. In addition, a polygenic risk score (PRS) of 188 prostate cancer variants was strongly associated with risk (90th vs. 40th-60th percentile OR = 2.62, = 2.55 × 10). Many of the 188 variants exhibited functional signatures of gene expression regulation or transcription factor binding, including a 6-fold difference in log-probability of androgen receptor binding at the variant rs2680708 (17q22). Rare variant and PRS associations, with concomitant functional interpretation of risk mechanisms, can help clarify the full genetic architecture of prostate cancer and other complex traits. SIGNIFICANCE: This study maps the biological relationships between diverse risk factors for prostate cancer, integrating different functional datasets to interpret and model genome-wide data from over 200,000 men with and without prostate cancer..
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http://dx.doi.org/10.1158/0008-5472.CAN-20-2635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137514PMC
April 2021

Long-term follow-up of a racially and ethnically diverse population of men with localized prostate cancer who did not undergo initial active treatment.

Cancer Med 2020 11 23;9(22):8530-8539. Epub 2020 Sep 23.

Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA, USA.

Background: There is limited research on the racial/ethnic differences in long-term outcomes for men with untreated, localized prostate cancer.

Methods: Men diagnosed with localized, Gleason ≤7 prostate cancer who were not treated within 1 year of diagnosis from 1997-2007 were identified. Cumulative incidence rates of the following events were calculated; treatment initiation, metastasis, death due to prostate cancer and all-cause mortality, accounting for competing risks. The Cox model of all-cause mortality and Fine-Gray sub distribution model to account for competing risks were used to test for racial/ethnic differences in outcomes adjusted for clinical factors.

Results: There were 3925 men in the study, 749 Hispanic, 2415 non-Hispanic white, 559 non-Hispanic African American, and 202 non-Hispanic Asian/Pacific Islander (API). Median follow-up was 9.3 years. At 19 years, overall cumulative incidence of treatment, metastasis, death due to prostate cancer, and all-cause mortality was 25.0%, 14.7%, 11.7%, and 67.8%, respectively. In adjusted models compared to non-Hispanic whites, African Americans had higher rates of treatment (HR = 1.39, 95% CI = 1.15-1.68); they had an increased risk of metastasis beyond 10 years after diagnosis (HR = 4.70, 95% CI = 2.30-9.61); API and Hispanic had lower rates of all-cause mortality (HR = 0.66, 95% CI = 0.52-0.84, and HR = 0.72, 95% CI = 0.62-0.85, respectively), and API had lower rates of prostate cancer mortality in the first 10 years after diagnosis (HR = 0.29, 95% CI = 0.09-0.90) and elevated risks beyond 10 years (HR = 5.41, 95% CI = 1.39-21.11).

Conclusions: Significant risks of metastasis and prostate cancer mortality exist in untreated men beyond 10 years after diagnosis, but are not equally distributed among racial/ethnic groups.
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http://dx.doi.org/10.1002/cam4.3471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666755PMC
November 2020

Pan-cancer study detects genetic risk variants and shared genetic basis in two large cohorts.

Nat Commun 2020 09 4;11(1):4423. Epub 2020 Sep 4.

Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA.

Deciphering the shared genetic basis of distinct cancers has the potential to elucidate carcinogenic mechanisms and inform broadly applicable risk assessment efforts. Here, we undertake genome-wide association studies (GWAS) and comprehensive evaluations of heritability and pleiotropy across 18 cancer types in two large, population-based cohorts: the UK Biobank (408,786 European ancestry individuals; 48,961 cancer cases) and the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging cohorts (66,526 European ancestry individuals; 16,001 cancer cases). The GWAS detect 21 genome-wide significant associations independent of previously reported results. Investigations of pleiotropy identify 12 cancer pairs exhibiting either positive or negative genetic correlations; 25 pleiotropic loci; and 100 independent pleiotropic variants, many of which are regulatory elements and/or influence cross-tissue gene expression. Our findings demonstrate widespread pleiotropy and offer further insight into the complex genetic architecture of cross-cancer susceptibility.
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http://dx.doi.org/10.1038/s41467-020-18246-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473862PMC
September 2020

The 17-Gene Genomic Prostate Score Test as a Predictor of Outcomes in Men with Unfavorable Intermediate Risk Prostate Cancer.

Urology 2020 Sep 7;143:103-111. Epub 2020 Jun 7.

Division of Research, Kaiser Permanente Northern California, Oakland, CA.

Objectives: To evaluate the association of the Genomic Prostate Score (GPS) assay result with biochemical recurrence (BCR), distant metastases (DM), and prostate-specific death (PCD) in unfavorable intermediate (UFI) risk prostate cancer patients. The GPS assay is used to help guide management decisions for newly diagnosed low and favorable intermediate (FI) risk disease.

Methods: GPS results from 2 studies (Center for Prostate Disease Research [CPDR]; Kaiser Permanente Northern California [KPNC]) in men treated with radical prostatectomy were analyzed to determine associations of the GPS result with BCR, DM, and PCD in UFI risk disease. Analyses included 299 intermediate risk prostate patients, 175 of whom had UFI risk disease (KPNC = 103; CPDR = 72).

Results: The GPS result as a dichotomous value (≤40 vs >40) was a significant predictor of BCR in UFI patients in multivariate analyses (hazard ratio [HR] 6.0; 95% confidence interval [CI] 2.0-22.4; P = .0035; CPDR). The GPS result was a strong predictor of all 3 endpoints in multivariate analyses (BCR HR 7.1; 95% CI 5.7-8.8; P < .0001; DM HR 5.4; 95% CI 3.8-7.8; P < .0001; PCD HR 3.4; 95% CI 1.5-8.9; P = .006; KPNC). UFI patients with GPS >40 had outcomes consistent with high-risk disease, whereas UFI patients with GPS ≤40 had outcomes similar to FI risk patients (CPDR/KPNC).

Conclusions: The GPS result was a strong independent predictor of BCR, DM, and PCD in intermediate risk prostate cancer. UFI patients with GPS >40 have a poor prognosis and may benefit from additional therapeutic options.
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http://dx.doi.org/10.1016/j.urology.2020.05.045DOI Listing
September 2020

Prediagnostic serum polychlorinated biphenyl concentrations and primary liver cancer: A case-control study nested within two prospective cohorts.

Environ Res 2020 08 20;187:109690. Epub 2020 May 20.

Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA. Electronic address:

Background: Polychlorinated biphenyls (PCBs) were used in electrical equipment and a range of construction materials. Although banned in the United States and most of Europe in the 1970s, they are highly persistent in the environment and bioaccumulate. Whether PCBs are associated with liver cancer risk at general population levels is unknown.

Methods: This study consisted of 136 incident liver cancer cases and 408 matched controls from the Kaiser Permanente Northern California Multiphasic Health Checkup (MHC) cohort and 84 cases and 252 matched controls from the Norwegian Janus cohort. Sera collected in the 1960s-1980s were measured for 37 PCB congeners and markers of hepatitis B (HBV) and C (HCV) infection. Odds ratios (OR) and 95% confidence intervals (CI) for tertiles of each lipid-adjusted PCB were estimated from conditional logistic regression. We also examined the molar sum of congeners in groups: total PCBs; low, medium, and high chlorination; and Wolff functional groups.

Results: Concentrations of individual congeners from the 1960s/1970s sera ranged from 1.3-123.0 and 1.4-116.0 ng/g lipid among MHC cases and controls, respectively, and from 1.9-258.0 and 1.9-271.0 ng/g lipid among Janus cases and controls, respectively. Among MHC participants with sera from the 1960s, collected an average of 27 years before diagnosis among cases, the top tertile of PCBs 151, 170, 172, 177, 178, 180, and 195 was significantly associated with elevated odds of liver cancer (OR range = 2.01-2.38); most of these congeners demonstrated exposure-response trends. For example, OR = 2.38 (95% CI: 1.22-4.64, p-trend = 0.01) for PCB 180. As a group, Wolff group 1b congeners, which are biologically persistent and weak phenobarbital inducers, were associated with increased odds. In MHC participants, ever vs. never HBV or HCV infection modified the PCB-liver cancer associations. There was little evidence of an association between PCBs and odds of liver cancer among the Janus cohort.

Discussion: We observed associations between a number of PCB congeners and increased odds of liver cancer among MHC, but not Janus, participants with sera from the 1960s/1970s.
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http://dx.doi.org/10.1016/j.envres.2020.109690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317661PMC
August 2020

Associations between Genetically Predicted Blood Protein Biomarkers and Pancreatic Cancer Risk.

Cancer Epidemiol Biomarkers Prev 2020 07 21;29(7):1501-1508. Epub 2020 May 21.

Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota.

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with few known risk factors and biomarkers. Several blood protein biomarkers have been linked to PDAC in previous studies, but these studies have assessed only a limited number of biomarkers, usually in small samples. In this study, we evaluated associations of circulating protein levels and PDAC risk using genetic instruments.

Methods: To identify novel circulating protein biomarkers of PDAC, we studied 8,280 cases and 6,728 controls of European descent from the Pancreatic Cancer Cohort Consortium and the Pancreatic Cancer Case-Control Consortium, using genetic instruments of protein quantitative trait loci.

Results: We observed associations between predicted concentrations of 38 proteins and PDAC risk at an FDR of < 0.05, including 23 of those proteins that showed an association even after Bonferroni correction. These include the protein encoded by , which has been implicated as a potential target gene of PDAC risk variant. Eight of the identified proteins (LMA2L, TM11D, IP-10, ADH1B, STOM, TENC1, DOCK9, and CRBB2) were associated with PDAC risk after adjusting for previously reported PDAC risk variants (OR ranged from 0.79 to 1.52). Pathway enrichment analysis showed that the encoding genes for implicated proteins were significantly enriched in cancer-related pathways, such as STAT3 and IL15 production.

Conclusions: We identified 38 candidates of protein biomarkers for PDAC risk.

Impact: This study identifies novel protein biomarker candidates for PDAC, which if validated by additional studies, may contribute to the etiologic understanding of PDAC development.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334065PMC
July 2020

Pregnancy-related relapses and breastfeeding in a contemporary multiple sclerosis cohort.

Neurology 2020 05 13;94(18):e1939-e1949. Epub 2020 Apr 13.

From the Department of Neurology (A.L.-G.), Southern California Permanente Medical Group, Los Angeles Medical Center; Department of Research & Evaluation (J.B.S., A.H.X., J.W., E.G.G.), Kaiser Permanente Southern California; and Division of Research (K.B.A., E.H.K., K.M., A.D.L., S.K.V.D.E.), Kaiser Permanente Northern California, Los Angeles, CA.

Objective: To determine whether women with multiple sclerosis (MS) diagnosed according to current criteria are at an increased risk of postpartum relapses and to assess whether this risk is modified by breastfeeding or MS disease-modifying therapies (DMTs), we examined the electronic health records (EHRs) of 466 pregnancies among 375 women with MS and their infants.

Methods: We used prospectively collected information from the EHR at Kaiser Permanente Southern and Northern California between 2008 and 2016 of the mother and infant to identify treatment history, breastfeeding, and relapses. Multivariable models accounting for measures of disease severity were used.

Results: In the postpartum year, 26.4% relapsed, 87% breastfed, 36% breastfed exclusively for at least 2 months, and 58.8% did not use DMTs. At pregnancy onset, 67.2% had suboptimally controlled disease. Annualized relapse rates (ARRs) declined from 0.37 before pregnancy to 0.14-0.07 ( < 0.0001) during pregnancy, but in the postpartum period, we did not observe any rebound disease activity. The ARR was 0.27 in the first 3 months postpartum, returning to prepregnancy rates at 4-6 months (0.37). Exclusive breastfeeding reduced the risk of early postpartum relapses (adjusted hazard ratio = 0.37, = 0.009), measures of disease severity increased the risk, and resuming modestly effective DMTs had no effect (time-dependent covariate, = 0.62).

Conclusion: Most women diagnosed with MS today can have children without incurring an increased risk of relapses. Women with suboptimal disease control before pregnancy may benefit from highly effective DMTs that are compatible with pregnancy and lactation. Women with MS should be encouraged to breastfeed exclusively.
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http://dx.doi.org/10.1212/WNL.0000000000009374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274922PMC
May 2020

A Transcriptome-Wide Association Study Identifies Novel Candidate Susceptibility Genes for Pancreatic Cancer.

J Natl Cancer Inst 2020 10;112(10):1003-1012

Yale Cancer Center, New Haven, CT, USA.

Background: Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown.

Methods: To discover novel pancreatic cancer risk loci and possible causal genes, we performed a pancreatic cancer transcriptome-wide association study in Europeans using three approaches: FUSION, MetaXcan, and Summary-MulTiXcan. We integrated genome-wide association studies summary statistics from 9040 pancreatic cancer cases and 12 496 controls, with gene expression prediction models built using transcriptome data from histologically normal pancreatic tissue samples (NCI Laboratory of Translational Genomics [n = 95] and Genotype-Tissue Expression v7 [n = 174] datasets) and data from 48 different tissues (Genotype-Tissue Expression v7, n = 74-421 samples).

Results: We identified 25 genes whose genetically predicted expression was statistically significantly associated with pancreatic cancer risk (false discovery rate < .05), including 14 candidate genes at 11 novel loci (1p36.12: CELA3B; 9q31.1: SMC2, SMC2-AS1; 10q23.31: RP11-80H5.9; 12q13.13: SMUG1; 14q32.33: BTBD6; 15q23: HEXA; 15q26.1: RCCD1; 17q12: PNMT, CDK12, PGAP3; 17q22: SUPT4H1; 18q11.22: RP11-888D10.3; and 19p13.11: PGPEP1) and 11 at six known risk loci (5p15.33: TERT, CLPTM1L, ZDHHC11B; 7p14.1: INHBA; 9q34.2: ABO; 13q12.2: PDX1; 13q22.1: KLF5; and 16q23.1: WDR59, CFDP1, BCAR1, TMEM170A). The association for 12 of these genes (CELA3B, SMC2, and PNMT at novel risk loci and TERT, CLPTM1L, INHBA, ABO, PDX1, KLF5, WDR59, CFDP1, and BCAR1 at known loci) remained statistically significant after Bonferroni correction.

Conclusions: By integrating gene expression and genotype data, we identified novel pancreatic cancer risk loci and candidate functional genes that warrant further investigation.
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http://dx.doi.org/10.1093/jnci/djz246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566474PMC
October 2020

Interpersonal Trauma as a Marker of Risk for Urinary Tract Dysfunction in Midlife and Older Women.

Obstet Gynecol 2020 01;135(1):106-112

University of California, San Francisco, and the San Francisco Veterans Affairs Health Care System, San Francisco, the Kaiser Permanente Division of Research, Oakland, and Stanford University School of Medicine, Stanford, California.

Objective: To examine relationships between interpersonal trauma exposures and urinary symptoms in community-dwelling midlife and older women.

Methods: We analyzed cross-sectional data from a multiethnic cohort of women aged 40-80 years enrolled in an integrated health care system in California. Lifetime history of intimate partner violence (IPV) and sexual assault, current posttraumatic stress disorder (PTSD) symptoms, and current urinary symptoms were assessed using structured-item questionnaires. Multivariable-adjusted logistic regression models examined associations between traumatic exposures and PTSD symptoms with any weekly urinary incontinence, stress-type incontinence, urgency-type incontinence, and nocturia two or more times per night.

Results: Of the 1,999 participants analyzed, 21.7% women reported lifetime emotional IPV, 16.2% physical IPV, 19.7% sexual assault, and 22.6% reported clinically significant PTSD symptoms. Overall, 45% reported any weekly incontinence, 23% stress-type incontinence, 23% urgency-type incontinence, and 35% nocturia. Exposure to emotional IPV was associated with any weekly incontinence (odds ratio [OR] 1.33, 95% CI 1.04-1.70), stress-type incontinence (OR 1.30, 95% CI 1.00-1.65), urgency-type incontinence (OR 1.30, 95% CI 1.00-1.70), and nocturia (OR 1.73, 95% CI 1.36-2.19). Physical IPV exposure was associated with nocturia (OR 1.35, 95% CI 1.04-1.77), but not incontinence. Sexual assault history was not associated with weekly incontinence of any type or nocturia. Symptoms of PTSD were associated with all urinary symptoms assessed, including any weekly incontinence (OR 1.46, 95% CI 1.15-1.85), stress-type incontinence (OR 1.70, 95% CI 1.32-2.20), urgency-type incontinence (OR 1.60, 95% CI 1.24-2.06), and nocturia (OR 1.95, 95% CI 1.55-2.45).

Conclusion: More than 20% of women in this multiethnic, community-based cohort reported a history of IPV, PTSD symptoms, or both, which were associated with symptomatic urinary tract dysfunction. Findings highlight the need to provide trauma-informed care of midlife and older women presenting with urinary symptoms.
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http://dx.doi.org/10.1097/AOG.0000000000003586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6923600PMC
January 2020

Associations Between Prediagnostic Concentrations of Circulating Sex Steroid Hormones and Liver Cancer Among Postmenopausal Women.

Hepatology 2020 08;72(2):535-547

Division of Medical Oncology, National Cancer Centre Singapore, Singapore.

Background And Aims: In almost all countries, incidence rates of liver cancer (LC) are 100%-200% higher in males than in females. However, this difference is predominantly driven by hepatocellular carcinoma (HCC), which accounts for 75% of LC cases. Intrahepatic cholangiocarcinoma (ICC) accounts for 12% of cases and has rates only 30% higher in males. Hormones are hypothesized to underlie observed sex differences. We investigated whether prediagnostic circulating hormone and sex hormone binding globulin (SHBG) levels were associated with LC risk, overall and by histology, by leveraging resources from five prospective cohorts.

Approach And Results: Seven sex steroid hormones and SHBG were quantitated using gas chromatography/tandem mass spectrometry and competitive electrochemiluminescence immunoassay, respectively, from baseline serum/plasma samples of 191 postmenopausal female LC cases (HCC, n = 83; ICC, n = 56) and 426 controls, matched on sex, cohort, age, race/ethnicity, and blood collection date. Odds ratios (ORs) and 95% confidence intervals (CIs) for associations between a one-unit increase in log hormone value (approximate doubling of circulating concentration) and LC were calculated using multivariable-adjusted conditional logistic regression. A doubling in the concentration of 4-androstenedione (4-dione) was associated with a 50% decreased LC risk (OR = 0.50; 95% CI = 0.30-0.82), whereas SHBG was associated with a 31% increased risk (OR = 1.31; 95% CI = 1.05-1.63). Examining histology, a doubling of estradiol was associated with a 40% increased risk of ICC (OR = 1.40; 95% CI = 1.05-1.89), but not HCC (OR = 1.12; 95% CI = 0.81-1.54).

Conclusions: This study provides evidence that higher levels of 4-dione may be associated with lower, and SHBG with higher, LC risk in women. However, this study does not support the hypothesis that higher estrogen levels decrease LC risk. Indeed, estradiol may be associated with an increased ICC risk.
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http://dx.doi.org/10.1002/hep.31057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391790PMC
August 2020

Cervical dystonia incidence and diagnostic delay in a multiethnic population.

Mov Disord 2020 03 27;35(3):450-456. Epub 2019 Nov 27.

Department of Neurology, School of Medicine, University of California, San Francisco, California, USA.

Background: Current cervical dystonia (CD) incidence estimates are based on small numbers in relatively ethnically homogenous populations. The frequency and consequences of delayed CD diagnosis is poorly characterized.

Objectives: To determine CD incidence and characterize CD diagnostic delay within a large, multiethnic integrated health maintenance organization.

Methods: We identified incident CD cases using electronic medical records and multistage screening of more than 3 million Kaiser Permanente Northern California members from January 1, 2003, to December 31, 2007. A final diagnosis was made by movement disorders specialist consensus. Diagnostic delay was measured by questionnaire and health utilization data. Incidence rates were estimated assuming a Poisson distribution of cases and directly standardized to the 2000 U.S. census. Multivariate logistic regression models were employed to assess diagnoses and behaviors preceding CD compared with matched controls, adjusting for age, sex, and membership duration.

Results: CD incidence was 1.18/100,000 person-years (95% confidence interval [CI], 0.35-2.0; women, 1.81; men, 0.52) based on 200 cases over 15.4 million person-years. Incidence increased with age. Half of the CD patients interviewed reported diagnostic delay. Diagnoses more common in CD patients before the index date included essential tremor (odds ratio [OR] 68.1; 95% CI, 28.2-164.5), cervical disc disease (OR 3.83; 95% CI, 2.8-5.2), neck sprain/strain (OR 2.77; 95% CI, 1.99-3.62), anxiety (OR 2.24; 95% CI, 1.63-3.11) and depression (OR 1.94; 95% CI, 1.4-2.68).

Conclusions: CD incidence is greater in women and increases with age. Diagnostic delay is common and associated with adverse effects. © 2019 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27927DOI Listing
March 2020

Selecting Active Surveillance: Decision Making Factors for Men with a Low-Risk Prostate Cancer.

Med Decis Making 2019 11 21;39(8):962-974. Epub 2019 Oct 21.

Cancer Prevention and Control Program, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.

Men with a low-risk prostate cancer (PCa) should consider observation, particularly active surveillance (AS), a monitoring strategy that avoids active treatment (AT) in the absence of disease progression. To determine clinical and decision-making factors predicting treatment selection. Prospective cohort study. Kaiser Permanente Northern California (KPNC). Men newly diagnosed with low-risk PCa between 2012 and 2014 who remained enrolled in KPNC for 12 months following diagnosis. We used surveys and medical record abstractions to measure sociodemographic and clinical characteristics and psychological and decision-making factors. Men were classified as being on observation if they did not undergo AT within 12 months of diagnosis. We performed multivariable logistic regression analyses. The average age of the 1171 subjects was 61.5 years ( = 7.2 years), and 81% were white. Overall, 639 (57%) were managed with observation; in adjusted analyses, significant predictors of observation included awareness of low-risk status (odds ratio 1.75; 95% confidence interval 1.04-2.94), knowing that observation was an option (3.62; 1.62-8.09), having concerns about treatment-related quality of life (1.21, 1.09-1.34), reporting a urologist recommendation for observation (8.20; 4.68-14.4), and having a lower clinical stage (T1c v. T2a, 2.11; 1.16-3.84). Conversely, valuing cancer control (1.54; 1.37-1.72) and greater decisional certainty (1.66; 1.18-2.35) were predictive of AT. Results may be less generalizable to other types of health care systems and to more diverse populations. Many participants selected observation, and this was associated with tumor characteristics. However, nonclinical decisional factors also independently predicted treatment selection. Efforts to provide early decision support, particularly targeting knowledge deficits, and reassurance to men with low-risk cancers may facilitate better decision making and increase uptake of observation, particularly AS.
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http://dx.doi.org/10.1177/0272989X19883242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895433PMC
November 2019

Author Correction: Association of imputed prostate cancer transcriptome with disease risk reveals novel mechanisms.

Nat Commun 2019 Aug 28;10(1):3948. Epub 2019 Aug 28.

Program in Biological and Medical Informatics, University of California San Francisco, San Francisco, CA, 94158, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41467-019-11810-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713745PMC
August 2019

Association of imputed prostate cancer transcriptome with disease risk reveals novel mechanisms.

Nat Commun 2019 07 15;10(1):3107. Epub 2019 Jul 15.

Program in Biological and Medical Informatics, University of California San Francisco, San Francisco, CA, 94158, USA.

Here we train cis-regulatory models of prostate tissue gene expression and impute expression transcriptome-wide for 233,955 European ancestry men (14,616 prostate cancer (PrCa) cases, 219,339 controls) from two large cohorts. Among 12,014 genes evaluated in the UK Biobank, we identify 38 associated with PrCa, many replicating in the Kaiser Permanente RPGEH. We report the association of elevated TMPRSS2 expression with increased PrCa risk (independent of a previously-reported risk variant) and with increased tumoral expression of the TMPRSS2:ERG fusion-oncogene in The Cancer Genome Atlas, suggesting a novel germline-somatic interaction mechanism. Three novel genes, HOXA4, KLK1, and TIMM23, additionally replicate in the RPGEH cohort. Furthermore, 4 genes, MSMB, NCOA4, PCAT1, and PPP1R14A, are associated with PrCa in a trans-ethnic meta-analysis (N = 9117). Many genes exhibit evidence for allele-specific transcriptional activation by PrCa master-regulators (including androgen receptor) in Position Weight Matrix, Chip-Seq, and Hi-C experimental data, suggesting common regulatory mechanisms for the associated genes.
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http://dx.doi.org/10.1038/s41467-019-10808-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6629701PMC
July 2019

A genome-wide association study of prostate cancer in Latinos.

Int J Cancer 2020 04 3;146(7):1819-1826. Epub 2019 Jul 3.

Department of Preventative Medicine, Keck School of Medicine, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, CA.

Latinos represent <1% of samples analyzed to date in genome-wide association studies of cancer. The clinical value of genetic information in guiding personalized medicine in populations of non-European ancestry will require additional discovery and risk locus characterization efforts across populations. In the present study, we performed a GWAS of prostate cancer (PrCa) in 2,820 Latino PrCa cases and 5,293 controls to search for novel PrCa risk loci and to examine the generalizability of known PrCa risk loci in Latino men. We also conducted a genetic admixture-mapping scan to identify PrCa risk alleles associated with local ancestry. Genome-wide significant associations were observed with 84 variants all located at the known PrCa risk regions at 8q24 (128.484-128.548) and 10q11.22 (MSMB gene). In admixture mapping, we observed genome-wide significant associations with local African ancestry at 8q24. Of the 162 established PrCa risk variants that are common in Latino men, 135 (83.3%) had effects that were directionally consistent as previously reported, among which 55 (34.0%) were statistically significant with p < 0.05. A polygenic risk model of the known PrCa risk variants showed that, compared to men with average risk (25th-75th percentile of the polygenic risk score distribution), men in the top 10% had a 3.19-fold (95% CI: 2.65, 3.84) increased PrCa risk. In conclusion, we found that the known PrCa risk variants can effectively stratify PrCa risk in Latino men. Larger studies in Latino populations will be required to discover and characterize genetic risk variants for PrCa and improve risk stratification for this population.
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http://dx.doi.org/10.1002/ijc.32525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028127PMC
April 2020

Telomere length and socioeconomic status at neighborhood and individual levels among 80,000 adults in the Genetic Epidemiology Research on Adult Health and Aging cohort.

Environ Epidemiol 2019 Jun 1;3(3):e049. Epub 2019 May 1.

Division of Research, Oakland, Kaiser Permanente Northern California, Oakland, California.

Background: Telomere length (TL) may serve as a biologic marker of aging. We examined neighborhood and individual-level socioeconomic status (SES) in relation to TL.

Methods: The study included 84,996 non-Hispanic white subjects from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort, part of the Research Program on Genes, Environment and Health. Relative TL (T/S) was log transformed to improve normality and standardized to have mean 0 and variance 1. Neighborhood SES was measured using the Neighborhood Deprivation Index (NDI), and individual SES was measured by self-reported education level. We fit linear regression models of TL on age, sex, smoking, body mass index, comorbidities, NDI, and education level. We tested for differences in the associations by sex and nonlinearity in the association of NDI with TL.

Results: Each SD increase in NDI was associated with a decrease of 0.0192 in standardized TL, 95% confidence interval (CI) = -0.0306, -0.0078. There was no evidence of nonlinearity in the association of NDI with TL. We further found that less than high school education was associated with a decrease of 0.1371 in standardized TL, 95% CI = -0.1919, -0.0823 as compared to a college education. There were no differences in the associations by sex.

Conclusions: We found evidence that both lower neighborhood SES and lower individual-level SES are associated with shorter TL among non-Hispanic whites. Our findings suggest that socioeconomic factors may influence aging by contributing to shorter TL.
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http://dx.doi.org/10.1097/EE9.0000000000000049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7939422PMC
June 2019

Incorporation of a Molecular Prognostic Classifier Improves Conventional Non-Small Cell Lung Cancer Staging.

J Thorac Oncol 2019 07 5;14(7):1223-1232. Epub 2019 Apr 5.

University of California, San Francisco, San Francisco, California. Electronic address:

Introduction: Despite adoption of molecular biomarkers in the management of NSCLC, the recently adopted eighth edition of the TNM staging system utilized only clinicopathologic characteristics and validated improvement in risk stratification of early-stage disease has remained elusive. We therefore evaluated the integration of a clinically validated molecular prognostic classifier into conventional staging.

Methods: A novel staging system, the TNMB (with the B denoting biology) system, which integrates a 14-gene molecular prognostic classifier into the eighth edition of the TNM staging system, was developed by using data from 321 patients with NSCLC at the University of California, San Francisco. The TNMB staging system was subsequently validated in an independent, multicenter cohort of 1373 patients, and its implementation was compared with adoption of the seventh and eighth edition staging systems utilizing metrics of reclassification.

Results: Compared with staging according to the eighth edition of the TNM system, the TNMB staging system enhanced the identification of high-risk patients, with a net reclassification improvement of 0.33 (95% confidence interval [CI]: 0.24-0.41). It better predicted differences in survival, with a relative integrated discrimination improvement of 22.1% (95% CI: 8.8%-35.3%), and it improved agreement between observed and predicted survival, with a decrease in the reclassification calibration statistic of from 39 to 21. The seventh and eighth editions failed to change the net reclassification improvement (0.01 [95% CI: -0.04 to 0.03] and 0.03 [95% CI: 0.00 to 0.06], respectively) or relative integrated discrimination improvement (2.1% [95% CI: -5.8 to 9.9] and -2.5% [95% CI: -17.6 to 12.4], respectively); in addition, the eighth edition worsened calibration, with an increase in the reclassification calibration statistic from 23 to 25.

Conclusions: Incorporation of a molecular prognostic classifier significantly improved identification of high-risk patients and survival predictions compared with when conventional staging is used. The TNMB staging system may lead to improved survival of early-stage disease through more effective application of adjuvant therapy.
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http://dx.doi.org/10.1016/j.jtho.2019.03.015DOI Listing
July 2019
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