The CHEK2 Variant C.349A>G Is Associated with Prostate Cancer Risk and Carriers Share a Common Ancestor

The identification of recurrent founder variants in cancer predisposing genes may have important implications for implementing cost-effective targeted genetic screening strategies. In this study, we evaluated the prevalence and relative risk of the CHEK2 recurrent variant c.349A>G in a series of 462 Portuguese patients with early-onset and/or familial/hereditary prostate cancer (PrCa), as well as in the large multicentre PRACTICAL case–control study comprising 55,162 prostate cancer cases and 36,147 controls. Additionally, we investigated the potential shared ancestry of the carriers by performing identity-by-descent, haplotype and age estimation analyses using high-density SNP data from 70 variant carriers belonging to 11 different populations included in the PRACTICAL consortium. The CHEK2 missense variant c.349A>G was found significantly associated with an increased risk for PrCa (OR 1.9; 95% CI: 1.1–3.2). A shared haplotype flanking the variant in all carriers was identified, strongly suggesting a common founder of European origin. Additionally, using two independent statistical algorithms, implemented by DMLE+2.3 and ESTIAGE, we were able to estimate the age of the variant between 2300 and 3125 years. By extending the haplotype analysis to 14 additional carrier families, a shared core haplotype was revealed among all carriers matching the conserved region previously identified in the high-density SNP analysis. These findings are consistent with CHEK2 c.349A>G being a founder variant associated with increased PrCa risk, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families.

Download Full-text

Social Jetlag and Prostate Cancer Incidence in Alberta’s Tomorrow Project: A Prospective Cohort Study

Cancers ◽

10.3390/cancers12123873 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3873

Author(s):

Liang Hu ◽

Andrew Harper ◽

Emily Heer ◽

Jessica McNeil ◽

Chao Cao ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Risk ◽

Cancer Incidence ◽

Repeated Measures ◽

Prospective Cohort ◽

Prostate Cancer Risk ◽

Absolute Difference ◽

Prostate Cancer Incidence ◽

Social Jetlag ◽

Increased Risk

We investigated the association of social jetlag (misalignment between the internal clock and socially required timing of activities) and prostate cancer incidence in a prospective cohort in Alberta, Canada. Data were collected from 7455 cancer-free men aged 35–69 years enrolled in Alberta’s Tomorrow Project (ATP) from 2001–2007. In the 2008 survey, participants reported usual bed- and wake-times on weekdays and weekend days. Social jetlag was defined as the absolute difference in waking time between weekday and weekend days, and was categorized into three groups: 0–<1 h (from 0 to anything smaller than 1), 1–<2 h (from 1 to anything smaller than 2), and 2+ h. ATP facilitated data linkage with the Alberta Cancer Registry in June 2018 to determine incident prostate cancer cases (n = 250). Hazard ratios (HR) were estimated using Cox proportional hazards regressions, adjusting for a range of covariates. Median follow-up was 9.57 years, yielding 68,499 person-years. Baseline presence of social jetlag of 1–<2 h (HR = 1.52, 95% CI: 1.10 to 2.01), and 2+ hours (HR = 1.69, 95% CI: 1.15 to 2.46) were associated with increased prostate cancer risk vs. those reporting no social jetlag (p for trend = 0.004). These associations remained after adjusting for sleep duration (p for trend = 0.006). With respect to chronotype, the association between social jetlag and prostate cancer risk remained significant in men with early chronotypes (p for trend = 0.003) but attenuated to null in men with intermediate (p for trend = 0.150) or late chronotype (p for trend = 0.381). Our findings suggest that greater than one hour of habitual social jetlag is associated with an increased risk of prostate cancer. Longitudinal studies with repeated measures of social jetlag and large samples with sufficient advanced prostate cancer cases are needed to confirm these findings.

Download Full-text

CHEK2∗1100delC Mutation and Risk of Prostate Cancer

Prostate Cancer ◽

10.1155/2014/294575 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 24

Author(s):

Victoria Hale ◽

Maren Weischer ◽

Jong Y. Park

Keyword(s):

Prostate Cancer ◽

Current Knowledge ◽

Prostate Cancer Screening ◽

Critical Role ◽

Prostate Cancer Risk ◽

Conclusive Evidence ◽

Increased Risk ◽

History Of ◽

Cancer Studies

Although the causes of prostate cancer are largely unknown, previous studies support the role of genetic factors in the development of prostate cancer.CHEK2plays a critical role in DNA replication by responding to double-stranded breaks. In this review, we provide an overview of the current knowledge of the role of a genetic variant, 1100delC, ofCHEK2on prostate cancer risk and discuss the implication for potential translation of this knowledge into clinical practice. Currently, twelve articles that discussedCHEK2∗1100delC and its association with prostate cancer were identified. Of the twelve prostate cancer studies, five studies had independent data to draw conclusive evidence from. The pooled results of OR and 95% CI were 1.98 (1.23–3.18) for unselected cases and 3.39 (1.78–6.47) for familial cases, indicating thatCHEK2∗1100delC mutation is associated with increased risk of prostate cancer. Screening for CHEK2∗1100delC should be considered in men with a familial history of prostate cancer.

Download Full-text

O8A.4 Asbestos exposure and prostate cancer, really?

Occupational and Environmental Medicine ◽

10.1136/oem-2019-epi.190 ◽

2019 ◽

Vol 76 (Suppl 1) ◽

pp. A71.1-A71

Author(s):

Marie-Elise Parent ◽

M Hugues Richard

Keyword(s):

Prostate Cancer ◽

Cancer Risk ◽

Asbestos Exposure ◽

Large Population ◽

Prostate Cancer Risk ◽

Cumulative Exposure ◽

Population Exposure ◽

Specific Information ◽

Chrysotile Asbestos ◽

Increased Risk

BackgroundGeneral population exposure to asbestos from residential insulation and from environmental sources during childhood have recently been associated with prostate cancer. While asbestos fibers can be found in the prostate of workplace-exposed men at autopsy, few occupational studies have reported on asbestos exposure and prostate cancer incidence. We examined the association between lifetime occupational exposure to chrysotile asbestos and prostate cancer risk in a large population-based case-control study.MethodsCases were 1933 men with histologically-confirmed incident prostate cancer, aged ≤75 years, diagnosed in 2005–2009 in Montreal. Concurrently, 1994 population controls from the same residential area and age distribution were randomly selected from electoral lists. In-person interviews elicited detailed socio-demographics, lifestyle and work histories. Industrial hygienists used job-specific information to provide semi-quantitative evaluations of intensity and frequency of exposure to 345 chemical agents, including asbestos, and a measure of confidence in the evaluation. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer risk associated with exposure to chrysotile asbestos.ResultsAfter restriction to probable and definite exposure, and application of a 5 year lag, 12.5% of cases and 11.8% of controls were ever exposed to asbestos (OR=1.1, 95% CI 0.9–1.3). For duration of exposure, there was no increase in risk of overall prostate cancer in the lower tertiles of exposure but risk was elevated in the upper tertile (OR=1.6, 95% CI 1.2–2.2). Similarly, for cumulative exposure, risk was elevated in the upper tertile only (OR=1.5, 95% CI 1.1–2.1). Analyses considering tumor grades also showed a higher risk in the upper tertile of cumulative exposure for non-aggressive (OR=1.5, 95% CI 1.1–2.2) and especially aggressive (OR=1.9, 95% CI 1.2–3.0) cancers.ConclusionOur findings are consistent with an increased risk of prostate cancer with prolonged and high cumulative exposure to chrysotile asbestos, and particularly for the aggressive form of the disease.

Download Full-text

Evaluation of prostate cancer risk in men with PSA < 1.5.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.6_suppl.64 ◽

2018 ◽

Vol 36 (6_suppl) ◽

pp. 64-64

Author(s):

Whitney N. Stanton ◽

E. David Crawford ◽

Paul Arangua ◽

John Hoenemeyer ◽

Francisco G. La Rosa ◽

...

Keyword(s):

Prostate Cancer ◽

Specific Antigen ◽

Prostate Cancer Risk ◽

Clinical Information ◽

Mrna Levels ◽

Protein Biomarkers ◽

Cancer Awareness ◽

Free Psa ◽

Increased Risk ◽

Total Psa

64 Background: Prostate Specific Antigen (PSA) screening remains controversial primarily because of over detection and treatment. There is an unmet clinical need to identify patients at increased risk for high-grade (HG – Gleason Score ≥7) prostate cancer (PCa) since PSA has low sensitivity. Combining PSA with well-validated prostate cancer biomarkers (PCM) can improve risk assessment. We investigated the performance of three PCMs (phi – prostate health index, 4KScore, and SelectMDx) on patients with PSA levels < 1.5 ng/mL that represent a “safe zone” where risk of any PCa is rare Methods: 652 men were screened for PCa during the annual Prostate Cancer Awareness Week at the University of Colorado Hospital. This study was supported by Prostate Condition Education Council and the Schramm Foundation. phi is evaluated using p2PSA, total PSA, and free PSA in serum. Phi < 52.7 suggests absence of HG PCa. 4KScore incorporates four kallikrein protein biomarkers: total PSA, free PSA, intact PSA, human kallikrein protein, and clinical information. A 4KScore < 20% suggests absence of HG PCa. The SelectMDx post-DRE urine test measures mRNA levels of the homeobox C6 and distal-less homeobox 1 biomarkers. SelectMDx score of 0% indicates absence of HG PCa. Results: No patients with a PSA < 1.5 had SelectMDx > 0% and/or phi > 52.7. One patient had a 4KScore of 27%, indicating a risk for HG PCa. For patients with PSA between 1.5-3.99, 2.9% (4/135), 7.4% (4/54), and 2.3% (2/85) had positive phi, 4KScore, and SelectMDx results, respectively. Conclusions: Men with PSA <1.5 ng/mL are at very low risk for HG PCa. Men with PSA between 1.5-3.99 with positive PCM results may be referred for further evaluation. [Table: see text]

Download Full-text

Vasectomy and Risk of Aggressive Prostate Cancer: A 24-Year Follow-Up Study

Journal of Clinical Oncology ◽

10.1200/jco.2013.54.8446 ◽

2014 ◽

Vol 32 (27) ◽

pp. 3033-3038 ◽

Cited By ~ 31

Author(s):

Mohummad Minhaj Siddiqui ◽

Kathryn M. Wilson ◽

Mara M. Epstein ◽

Jennifer R. Rider ◽

Neil E. Martin ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Treatment ◽

Specific Antigen ◽

Prostate Cancer Risk ◽

The United States ◽

Low Grade ◽

High Grade ◽

Follow Up Study ◽

Increased Risk

Purpose Conflicting reports remain regarding the association between vasectomy, a common form of male contraception in the United States, and prostate cancer risk. We examined prospectively this association with extended follow-up and an emphasis on advanced and lethal disease. Patients and Methods Among 49,405 US men in the Health Professionals Follow-Up Study, age 40 to 75 years at baseline in 1986, 6,023 patients with prostate cancer were diagnosed during the follow-up to 2010, including 811 lethal cases. In total, 12,321 men (25%) had vasectomies. We used Cox proportional hazards models to estimate the relative risk (RR) and 95% CIs of total, advanced, high-grade, and lethal disease, with adjustment for a variety of possible confounders. Results Vasectomy was associated with a small increased risk of prostate cancer overall (RR, 1.10; 95% CI, 1.04 to 1.17). Risk was elevated for high-grade (Gleason score 8 to 10; RR, 1.22; 95% CI, 1.03 to 1.45) and lethal disease (death or distant metastasis; RR, 1.19; 95% CI, 1.00 to 1.43). Among a subcohort of men receiving regular prostate-specific antigen screening, the association with lethal cancer was stronger (RR, 1.56; 95% CI, 1.03 to 2.36). Vasectomy was not associated with the risk of low-grade or localized disease. Additional analyses suggested that the associations were not driven by differences in sex hormone levels, sexually transmitted infections, or cancer treatment. Conclusion Our data support the hypothesis that vasectomy is associated with a modest increased incidence of lethal prostate cancer. The results do not appear to be due to detection bias, and confounding by infections or cancer treatment is unlikely.

Download Full-text

Meta-Analysis of the Relationship between XRCC1-Arg399Gln and Arg280His Polymorphisms and the Risk of Prostate Cancer

Scientific Reports ◽

10.1038/srep09905 ◽

2015 ◽

Vol 5 (1) ◽

Cited By ~ 10

Author(s):

Jie Yan ◽

Xiantao Wang ◽

Hui Tao ◽

Zengfu Deng ◽

Wang Yang ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Risk ◽

Meta Analysis ◽

Prostate Cancer Risk ◽

Recessive Model ◽

Dominant Model ◽

Xrcc1 Arg399gln ◽

Increased Risk ◽

Arg399gln Polymorphism ◽

The Relationship

Abstract Prostate cancer is one of the most common noncutaneous malignancies in Western countries. Because there has been a debate regarding the relationship between the XRCC1-Arg399Gln and Arg280His polymorphisms and prostate cancer risk, we therefore performed this meta-analysis. The electronic databases PubMed, EMBASE and Medline were searched prior to October 1, 2014. An odds ratio and 95% confidence interval were used to calculate association. Heterogeneity was tested by both a chi-square test and I2statistic. Funnel plots and Egger’s test were used to assess publication bias. All statistical analyses were performed using STATA 12.0 software. A significant association between the XRCC1-Arg399Gln polymorphism and prostate cancer risk was found under a homozygote model and a recessive model. A significant association between XRCC1-Arg280His and prostate cancer risk was found under a heterozygote model and a dominant model. Overall, the results of this meta-analysis show that the XRCC1-Arg399Gln polymorphism may be associated with an increased risk for prostate cancer under the homozygote model and the recessive model. And XRCC1-Arg280His polymorphism is likely to be related with prostate cancer risk under the heterozygote model and the dominant model. Additional larger well-designed studies are needed to validate our results.

Download Full-text

Mendelian randomization does not support serum calcium in prostate cancer risk

10.1101/297721 ◽

2018 ◽

Author(s):

James Yarmolinsky ◽

Katie Berryman ◽

Ryan Langdon ◽

Carolina Bonilla ◽

George Davey Smith ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Risk ◽

Causal Inference ◽

Serum Calcium ◽

Observational Studies ◽

Advanced Prostate Cancer ◽

Mendelian Randomization ◽

Prostate Cancer Risk ◽

A Genome ◽

Increased Risk

AbstractBackground: Observational studies suggest that dietary and serum calcium are risk factors for prostate cancer. However, such studies suffer from residual confounding (due to unmeasured or imprecisely measured confounders), undermining causal inference. Mendelian randomization uses randomly assigned (hence unconfounded and pre-disease onset) germline genetic variation to proxy for phenotypes and strengthen causal inference in observational studies.Objective: We tested the hypothesis that serum calcium is associated with an increased risk of overall and advanced prostate cancer.Design: A genetic instrument was constructed using 5 single nucleotide polymorphisms robustly associated with serum calcium in a genome-wide association study (N ≤ 61,079). This instrument was then used to test the effect of a 0.5 mg/dL increase (1 standard deviation, SD) in serum calcium on risk of prostate cancer in 72,729 men in the PRACTICAL (Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome) Consortium (44,825 cases, 27,904 controls) and risk of advanced prostate cancer in 33,498 men (6,263 cases, 27,235 controls).Results: We found weak evidence for a protective effect of serum calcium on prostate cancer risk (odds ratio [OR] per 0.5 mg/dL increase in calcium: 0.83, 95% CI: 0.63-1.08; P=0.12). We did not find strong evidence for an effect of serum calcium on advanced prostate cancer (OR per 0.5 mg/dL increase in calcium: 0.98, 95% CI: 0.57-1.70; P=0.93).Conclusions: Our Mendelian randomization analysis does not support the hypothesis that serum calcium increases risk of overall or advanced prostate cancer.

Download Full-text

Genetic polymorphisms in CDH1 and Exo1 genes elevate the prostate cancer risk in Bangladeshi population

Tumor Biology ◽

10.1177/1010428319830837 ◽

2019 ◽

Vol 41 (3) ◽

pp. 101042831983083 ◽

Cited By ~ 2

Author(s):

Hasnain Imtiaz ◽

Sharmin Afroz ◽

Md Amir Hossain ◽

Sm Faysal Bellah ◽

Md Mostafizur Rahman ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Risk ◽

Confidence Interval ◽

Genetic Polymorphisms ◽

Odds Ratio ◽

Prostate Cancer Risk ◽

Polymorphism Analysis ◽

Increased Risk ◽

Bangladeshi Population ◽

Increased Susceptibility

The polymorphisms of invasion suppressor gene CDH1 and DNA mismatch repair gene Exo1 have been reported to play critical role in the development, tumorigenesis, and progression of several kinds of cancers including prostate cancer. This study was designed to analyze the contribution of single-nucleotide polymorphisms of the CDH1 (-160C/A) and Exo1 (K589E) to prostate cancer susceptibility in Bangladeshi population. The study included 100 prostate cancer cases and age-matched 100 healthy controls. Polymerase chain reaction-restriction fragment length polymorphism analysis was used to determine the genetic polymorphisms. A significant association was found between CDH1 -160C/A (rs16260) and Exo1 (rs1047840, K589E) polymorphisms and prostate cancer risk. In case of CDH1 -160C/A polymorphism, the frequencies of the three genotypes C/C,C/A, and A/A were 45%, 48%, and 7% in cases and 63%, 32%, and 5% in controls, respectively. The heterozygote C/A genotype and combined C/A + A/A genotypes showed 2.10-fold (odds ratio = 2.1000, 95% confidence interval = 1.2956–4.0905, p = 0.013) and 2.08-fold (odds ratio = 2.0811, 95% confidence interval = 1.1820–3.6641, p = 0.011) increased risk of prostate cancer, respectively, when compared with homozygous C/C genotypes. The variant A allele also was associated with increased risk of prostate cancer (odds ratio = 1.6901, 95% confidence interval = 1.0740–2.6597, p = 0.0233). In case of Exo1 (K589E) polymorphism, G/A heterozygote, A/A homozygote, and combined G/A + A/A genotypes were found to be associated with 2.30-, 4.85-, and 3.04-fold higher risk of prostate cancer, respectively (odds ratio = 2.3021, 95% confidence interval = 2.956–4.0905, p = 0.0031; odds ratio = 4.8462, 95% confidence interval = 1.0198–23.0284, p = 0.0291; OR = 3.0362, 95% confidence interval = 1.7054–5.4053, p = 0.0001, respectively). The “A” allele showed significant association with increased susceptibility (2.29-fold) to prostate cancer (odds ratio = 2.2955, 95% confidence interval = 1.4529–3.6270, p = 0.0004). Our results suggest that CDH1 -160C/A and Exo1 K589E polymorphisms are associated with increased susceptibility to prostate cancer in Bangladeshi population.

Download Full-text

Profile study: Genetic prostate cancer risk stratification for targeted screening.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.5054 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 5054-5054

Author(s):

Elena Castro ◽

Elizabeth Bancroft ◽

Natalie Taylor ◽

Tokhir Dadaev ◽

Elizabeth Page ◽

...

Keyword(s):

Prostate Cancer ◽

Genetic Model ◽

Genetic Risk Score ◽

Prostate Cancer Risk ◽

Screening Tools ◽

Risk Scores ◽

Severe Side Effect ◽

Cancer Worry ◽

Increased Risk

5054 Background: Prostate cancer (PC) screening is controversial and better approaches are needed, including a better assessment of individualized PC risk. Several studies have identified a number of common single nucleotide polymorphisms (SNPs) that confer a cumulative risk of PC. We have explored the potential role of genetic markers in identifying men who should be selectively targeted for screening in a population with increased risk of PC due to family history (FH) of the disease. Methods: PROFILE has been developed as a pilot study. The primary aim is to determine the feasibility of targeted PC screening using prostatic biopsy (PB) and its association with specific genetic profiles in men with FH. Secondary aims are to evaluate the role of PSA and Diffusion Weighted MRI (DW-MRI) as screening tools in this population. From December 2010 men aged 40-69 with FH of PC were invited into the study until 100 men were enrolled. Blood samples were provided for PSA and DNA extraction. The cumulative SNP risk scores for each patient were calculated by summing 59 risk alleles for each locus using the weighted effect as estimated in previous studies (log-additive model). DW-MRI was performed in 50 patients. All participants were asked to undergo a 10 core PB regardless of baseline PSA. Those who declined PB have been excluded from this analysis. Data on side effects and cancer worry were also collected. Results: 35% of invited men entered the study. Median age was 53 yrs (40-69) and median PSA was 1.15. Ninety men accepted to undergo a PB as primary PC screening. Twenty-two tumours were found and 45% of them were clinically significant [Median age 64yrs (47-69), median PSA 5.4 (0.91-9.3)]. The predictive performance of DW-MRI, PSA, genetic model and genetic model plus PSA measured by AUC were: 0.85, 0.73, 0.57 and 0.74, respectively. The genetic model performed better in men with PSA<3(AUC 0.63). No severe side effect or adverse psychosocial variables were noted. Conclusions: Our results indicate that PB is acceptable as a means of PC screening in men with FH of PC. Overall, DW-MRI and PSA were more predictive of PC than the genetic risk score. As more SNPs are found, a larger study is warranted to evaluate their role in the PC screening algorithm.

Download Full-text

Precision prevention of TMPRSS2:ERG prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.2_suppl.78 ◽

2016 ◽

Vol 34 (2_suppl) ◽

pp. 78-78

Author(s):

Lorelei A. Mucci ◽

Thomas Ahearn ◽

Kathryn Penney ◽

Andreas Pettersson ◽

Rebecca E Graff ◽

...

Keyword(s):

Prostate Cancer ◽

Molecular Subtype ◽

Prostate Cancer Risk ◽

Health Study ◽

Tumor Biomarker ◽

Common Disease ◽

Study Cohort ◽

Increased Risk ◽

Biomarker Data

78 Background: Increased integration of tumor biomarker data into prostate cancer epidemiology studies is needed to identify molecular subtypes that underlie its etiology and progression. We hypothesize that the TMPRSS2:ERG gene fusion is a unique prostate cancer subtype that is etiologically distinct from cancers lacking TMPRSS2:ERG. Methods: We leveraged the Physicians’ Health Study and Health Professionals Follow-up Study cohort data on pre- and post-diagnostic lifestyle factors, inherited genetic variants, circulating biomarkers, and clinical data and follow-up for 30 years. We have a tumor repository of men with prostate cancer and tumor tissue microarrays. Using immunohistochemistry, we characterized TMPRSS2:ERG status for 1,491 incident prostate cancer cases in these cohorts, and also have biomarker data on a range of additional markers from immunohistochemistry and mRNA expression profiling. Results: Fifty percent of prostate cancer cases were ERG-positive. ERG-positive cancers show much higher expression of insulin/IGF signaling, PTEN loss, higher VDR expression, as well as expression of mismatch repair genes. In contrast, ERG-negative prostate cancer is characterized by increased presence of chronic inflammation and atrophy. We found higher pre-diagnostic free testosterone levels, but not other sex hormones, were associated with increased risk of ERG-positive (OR = 1.4, 95% CI = 1.0-1.8) but not ERG-negative disease (OR = 0.9, 95% CI = 0.7-1.2). Of 39 known genetic risk loci, six were significantly associated (p < 0.05) with ERG+ versus ERG- cancer (2 expected by chance). Prostate cancer risk factors such as taller height (an indicator of growth factors in puberty) are uniquely associated with ERG-positive prostate cancer. Moreover, we observe a complex interaction of components of insulin/IGF and ERG-status on prostate cancer mortality. Conclusions: TMPRSS2:ERG is a highly prevalent somatic event in prostate cancer that likely defines a unique molecular subtype of this common disease. Understanding the differences between these two prostate cancer subtypes may enhance opportunities for prevention.

Download Full-text