Molecular Evolution of Early-Onset Prostate Cancer Identifies Molecular Risk Markers and Clinical Trajectories.
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ABSTRACT:
SUBMITTER: Gerhauser C
PROVIDER: S-EPMC7444093 | biostudies-literature | 2018 Dec
REPOSITORIES: biostudies-literature
Publications
Molecular Evolution of Early-Onset Prostate Cancer Identifies Molecular Risk Markers and Clinical Trajectories.
Gerhauser Clarissa C Favero Francesco F Risch Thomas T Simon Ronald R Feuerbach Lars L Assenov Yassen Y Heckmann Doreen D Sidiropoulos Nikos N Waszak Sebastian M SM Hübschmann Daniel D Urbanucci Alfonso A Girma Etsehiwot G EG Kuryshev Vladimir V Klimczak Leszek J LJ Saini Natalie N Stütz Adrian M AM Weichenhan Dieter D Böttcher Lisa-Marie LM Toth Reka R Hendriksen Josephine D JD Koop Christina C Lutsik Pavlo P Matzk Sören S Warnatz Hans-Jörg HJ Amstislavskiy Vyacheslav V Feuerstein Clarissa C Raeder Benjamin B Bogatyrova Olga O Schmitz Eva-Maria EM Hube-Magg Claudia C Kluth Martina M Huland Hartwig H Graefen Markus M Lawerenz Chris C Henry Gervaise H GH Yamaguchi Takafumi N TN Malewska Alicia A Meiners Jan J Schilling Daniela D Reisinger Eva E Eils Roland R Schlesner Matthias M Strand Douglas W DW Bristow Robert G RG Boutros Paul C PC von Kalle Christof C Gordenin Dmitry D Sültmann Holger H Brors Benedikt B Sauter Guido G Plass Christoph C Yaspo Marie-Laure ML Korbel Jan O JO Schlomm Thorsten T Weischenfeldt Joachim J
Cancer cell 20181201 6
Identifying the earliest somatic changes in prostate cancer can give important insights into tumor evolution and aids in stratifying high- from low-risk disease. We integrated whole genome, transcriptome and methylome analysis of early-onset prostate cancers (diagnosis ≤55 years). Characterization across 292 prostate cancer genomes revealed age-related genomic alterations and a clock-like enzymatic-driven mutational process contributing to the earliest mutations in prostate cancer patients. Our ...[more]
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Project description:Recent admixture mapping and linkage/association studies have implicated an approximately 1 Mb region on chromosome 8q24 in prostate cancer susceptibility. In a subsequent follow-up investigation, Haiman et al. (Nat Genet 2007;39:638-44) observed significant, independent associations between 7 markers within this region and sporadic prostate cancer risk in a multi-ethnic sample. To clarify the risk associated with hereditary prostate cancer, we tested for prostate cancer association with 6 of these 7 markers in a sample of 1,015 non-Hispanic white men with and without prostate cancer from 403 familial and early-onset prostate cancer families. Single nucleotide polymorphisms (SNPs) rs6983561 and rs6983267 showed the strongest evidence of prostate cancer association. Using a family-based association test, the minor ("C") allele of rs6983561 and the major ("G") allele of rs6983267 were preferentially transmitted to affected men (p < 0.05), with estimated odds ratios (ORs) of 2.26 (95% confidence interval of 1.06-4.83) and 1.30 (95% confidence interval of 0.99-1.71), respectively, for an additive model. Notably, rs6983561 was significantly associated with prostate cancer among men diagnosed at an early (<50 years) but not later age (p = 0.03 versus p = 0.21). Similarly, the association with rs6983267 was (not) statistically significant among men with(out) clinically aggressive disease (p = 0.007 versus p = 0.34). Our results confirm the association of prostate cancer with several of the SNPs on chromosome 8q24 initially reported by Haiman et al. In addition, our results suggest that the increased risk associated with these SNPs is approximately doubled in individuals predisposed to develop early onset or clinically aggressive disease.
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Project description:Men with familial prostate cancer and African American men are at risk for developing prostate cancer at younger ages. Genetic markers predicting early-onset prostate cancer may provide clinically useful information to guide screening strategies for high-risk men. We evaluated clinical information from six polymorphisms associated with early-onset prostate cancer in a longitudinal cohort of high-risk men enrolled in prostate cancer early detection with significant African American participation.Eligibility criteria include ages 35 to 69 with a family history of prostate cancer or African American race. Participants undergo screening and biopsy per study criteria. Six markers associated with early-onset prostate cancer [rs2171492 (7q32), rs6983561 (8q24), rs10993994 (10q11), rs4430796 (17q12), rs1799950 (17q21), and rs266849 (19q13)] were genotyped. Cox models were used to evaluate time to prostate cancer diagnosis and prostate-specific antigen (PSA) prediction for prostate cancer by genotype. Harrell's concordance index was used to evaluate predictive accuracy for prostate cancer by PSA and genetic markers.Four hundred and sixty participants with complete data and ? 1 follow-up visit were included. Fifty-six percent were African American. Among African American men, rs6983561 genotype was significantly associated with earlier time to prostate cancer diagnosis (P = 0.005) and influenced prediction for prostate cancer by the PSA (P < 0.001). When combined with PSA, rs6983561 improved predictive accuracy for prostate cancer compared with PSA alone among African American men (PSA = 0.57 vs. PSA + rs6983561 = 0.75, P = 0.03).Early-onset marker rs6983561 adds potentially useful clinical information for African American men undergoing prostate cancer risk assessment. Further study is warranted to validate these findings.Genetic markers of early-onset prostate cancer have potential to refine and personalize prostate cancer early detection for high-risk men.
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Project description:In a recent genome-wide association study by Gudmundsson and colleagues, two prostate cancer susceptibility loci were identified on chromosome 17q. The first locus, at 17q12, was distinguished by two intronic single-nucleotide polymorphisms (SNPs) in the TCF2 gene (rs4430796 and rs7501939). The second locus was in a gene-poor region of 17q24, where the strongest evidence of association was for SNP rs1859962. To determine if these loci were also associated with hereditary prostate cancer, we genotyped them in a family-based association sample of 403 non-Hispanic white families, including 1,015 men with and without prostate cancer. SNPs rs4430796 and rs7501939, which were in strong linkage disequilibrium (r(2) = 0.68), showed the strongest evidence of prostate cancer association. Using a family-based association test, the A allele of SNP rs4430796 was overtransmitted to affected men (P = 0.006), with an odds ratio of 1.40 (95% confidence interval, 1.09-1.81) under an additive genetic model. Notably, rs4430796 was significantly associated with prostate cancer among men diagnosed at an early (<50 years) but not later age (P = 0.006 versus P = 0.118). Our results confirm the prostate cancer association with SNPs on chromosome 17q12 initially reported by Gudmundsson and colleagues. In addition, our results suggest that the increased risk associated with these SNPs is approximately doubled in individuals predisposed to develop early-onset disease. Importantly, these SNPs do not account for a significant portion of our prior prostate cancer linkage evidence on chromosome 17. Thus, there likely exist one or more additional independent prostate cancer susceptibility loci in this region.
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Project description:BackgroundColorectal cancer (CRC) incidence is increasing in adults younger than 50 years. This study evaluated clinical and molecular features to identify those features unique to early-onset CRC that differentiate these patients from patients 50 years old or older.MethodsBaseline characteristics were evaluated according to the CRC onset age with 3 independent cohorts. A fourth cohort was used to describe the impact of age on the consensus molecular subtype (CMS) prevalence.ResultsThis retrospective review of more than 36,000 patients with CRC showed that early-onset patients were more likely to have microsatellite instability (P = .038), synchronous metastatic disease (P = .009), primary tumors in the distal colon or rectum (P < .0001), and fewer BRAF V600 mutations (P < .001) in comparison with patients 50 years old or older. Patients aged 18 to 29 years had fewer adenomatous polyposis coli (APC) mutations (odds ratio [OR], 0.56; 95% confidence interval [CI], 0.35-0.90; P = .015) and an increased prevalence of signet ring histology (OR, 4.89; 95% CI, 3.23-7.39; P < .0001) in comparison with other patients younger than 50 years. In patients younger than 40 years, CMS1 was the most common subtype, whereas CMS3 and CMS4 were uncommon (P = .003). CMS2 was relatively stable across age groups. Early-onset patients with inflammatory bowel disease were more likely to have mucinous or signet ring histology (OR, 5.54; 95% CI, 2.24-13.74; P = .0004) and less likely to have APC mutations (OR, 0.24; 95% CI, 0.07-0.75; P = .019) in comparison with early-onset patients without predisposing conditions.ConclusionsEarly-onset CRC is not only distinct from traditional CRC: special consideration should be given to and further investigations should be performed for both very young patients with CRC (18-29 years) and those with predisposing conditions. The etiology of the high rate of CMS1 in patients younger than 40 years deserves further exploration.
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Project description:ImportanceDepression often first manifests in adolescence. Thereafter, individual trajectories vary substantially, but it is not known what shapes depression trajectories in youth. Adult studies suggest that genetic risk for schizophrenia, a psychiatric disorder with a neurodevelopmental component, may contribute to an earlier onset of depression.ObjectiveTo test the hypothesis that there are distinct trajectories of depressive symptoms and that genetic liability for neurodevelopmental psychiatric disorders (eg, schizophrenia, attention deficit/hyperactivity disorder [ADHD]), as well as for major depressive disorder (MDD), contribute to early-onset depression.Design, setting, and participantsThe Avon Longitudinal Study of Parents and Children is an ongoing, prospective, longitudinal, population-based cohort that has been collecting data since September 6, 1990, including data on 7543 adolescents with depressive symptoms at multiple time points. The present study was conducted between November 10, 2017, and August 14, 2018.Main outcomes and measuresTrajectories based on self-reported depressive symptoms dichotomized by the clinical cutpoint; MDD, schizophrenia, and ADHD polygenic risk score (PRS) were predictors.ResultsIn 7543 adolescents with depression data on more than 1 assessment point between a mean (SD) age of 10.64 (0.25) years and 18.65 (0.49) years (3568 [47.3%] male; 3975 [52.7%] female), 3 trajectory classes were identified: persistently low (73.7%), later-adolescence onset (17.3%), and early-adolescence onset (9.0%). The later-adolescence-onset class was associated with MDD genetic risk only (MDD PRS: odds ratio [OR], 1.27; 95% CI, 1.09-1.48; P = .003). The early-adolescence-onset class was also associated with MDD genetic risk (MDD PRS: OR, 1.24; 95% CI, 1.06-1.46; P = .007) but additionally with genetic risk for neurodevelopmental disorders (schizophrenia PRS: OR, 1.22; 95% CI, 1.04-1.43; P = .01; ADHD PRS: OR, 1.32; 95% CI, 1.13-1.54; P < .001) and childhood ADHD (χ21 = 6.837; P = .009) and neurodevelopmental traits (pragmatic language difficulties: OR, 1.31; P = .004; social communication difficulties: OR, 0.68; P < .001).Conclusions and relevanceThe findings of this study appear to demonstrate evidence of distinct depressive trajectories, primarily distinguished by age at onset. The more typical depression trajectory with onset of clinically significant symptoms at age 16 years was associated with MDD genetic risk. The less-common depression trajectory, with a very early onset, was particularly associated with ADHD and schizophrenia genetic risk and, phenotypically, with childhood ADHD and neurodevelopmental traits. Findings are consistent with emerging evidence for a neurodevelopmental component in some cases of depression and suggest that the presence of this component may be more likely when the onset of depression is very early.
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Project description:Prostate cancer (PCa) is one of the most common cancers among men in Western developed countries and its incidence has increased considerably in many other parts of the world, including China. The etiology of PCa is largely unknown but is thought to be multifactorial, where inherited genetics plays an important role. In this article, we first briefly review results from studies of familial aggregation and genetic susceptibility to PCa. We then recap key findings of rare and high-penetrance PCa susceptibility genes from linkage studies in PCa families. We devote a significant portion of this article to summarizing discoveries of common and low-penetrance PCa risk-associated single-nucleotide polymorphisms (SNPs) from genetic association studies in PCa cases and controls, especially those from genome-wide association studies (GWASs). A strong focus of this article is to review the literature on the potential clinical utility of these implicated genetic markers. Most of these published studies described PCa risk estimation using a genetic score derived from multiple risk-associated SNPs and its utility in determining the need for prostate biopsy. Finally, we comment on the newly proposed concept of genetic score; the notion is to treat it as a marker for genetic predisposition, similar to family history, rather than a diagnostic marker to discriminate PCa patients from non-cancer patients. Available evidence to date suggests that genetic score is an objective and better measurement of inherited risk of PCa than family history. Another unique feature of this article is the inclusion of genetic association studies of PCa in Chinese and Japanese populations.
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Project description:OBJECTIVE:Twin studies suggest that genetic factors contribute to continuity in mental health problems and that environmental factors are the major contributor to developmental change. The authors investigated the influence of psychiatric risk alleles on early-onset mental health trajectories and whether the trajectories were subsequently modified by exposure to childhood victimization. METHODS:The sample was a prospective U.K. population-based cohort, the Avon Longitudinal Study of Parents and Children. The developmental trajectories of emotional problems were estimated in childhood (approximately ages 4-8 years) and adolescence (approximately ages 12-17 years). Psychiatric risk alleles were indexed by polygenic risk scores (PRS) for schizophrenia using genome-wide association study results from the Psychiatric Genomics Consortium. Chronic peer victimization in late childhood (ages 8.5 and 10.5 years) was assessed as an index of environmental exposure. Individuals with sufficient data on emotional problems, the PRS, and victimization were included in the main analyses (N=3,988). RESULTS:Higher schizophrenia PRSs were associated with a trajectory of early-onset increasing emotional problems (odds ratio=1.18, 95% CI=1.02-1.36) compared with a trajectory of low-stable emotional problems. Subsequent exposure to victimization increased the likelihood of transitioning from a trajectory of low-stable emotional problems during childhood (before exposure) to an increasing trajectory in adolescence (after exposure) (odds ratio=2.59, 95% CI=1.48-4.53). CONCLUSIONS:While the early development of emotional problems was associated with genetic risk (schizophrenia risk alleles), the subsequent course of emotional problems for those who might otherwise have remained on a more favorable trajectory was altered by exposure to peer victimization, which is a potentially modifiable environmental exposure.
| S-EPMC6314438 | biostudies-literature
Project description:BACKGROUND:Early-onset prostate cancer is often more aggressive and may have a different aetiology than later-onset prostate cancer, but has been relatively little studied to date. We evaluated occupation in relation to early- and later-onset prostate cancer in a large pooled study. METHODS:We used occupational information from census data in five Nordic countries from 1960 to 1990. We identified prostate cancer cases diagnosed from 1961 to 2005 by linkage of census information to national cancer registries and calculated standardised incidence ratios (SIRs) separately for men aged 30-49 and those aged 50 or older. We also conducted separate analyses by period of follow-up, 1961-1985 and 1986-2005, corresponding to pre- and post-prostate-specific antigen (PSA) screening. RESULTS:For early-onset prostate cancer (n = 1521), we observed the highest SIRs for public safety workers (e.g. firefighters) (SIR = 1.71, 95% confidence interval [CI]: 1.23-2.31) and military personnel (SIR = 1.97, 95% CI: 1.31-2.85). These SIRs were significantly higher than the SIRs for later-onset disease (for public safety workers, SIR = 1.10, 95% CI: 1.07-1.14 and for military personnel, SIR = 1.09, 95% CI: 1.05-1.13; pheterogeneity = 0.005 and 0.002, respectively). Administrators and technical workers also demonstrated significantly increased risks for early-onset prostate cancer, but the SIRs did not differ from those of later-onset disease (pheterogeneity >0.05). While our early-onset finding for public safety workers was restricted to the post-PSA period, that for military personnel was restricted to the pre-PSA period. CONCLUSION:Our results suggest that occupational exposures, particularly for military personnel, may be associated with early-onset prostate cancer. Further evaluation is needed to explain these findings.
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Project description:Carboxypeptidase 4 (CPA4) is a zinc-dependent metallocarboxypeptidase on chromosome 7q32 in a region linked to prostate cancer aggressiveness. CPA4 is involved in the histone hyperacetylation pathway and may modulate the function of peptides that affect the growth and regulation of prostate epithelial cells. We examined the association between genetic variation in CPA4 and intermediate-to-high risk prostate cancer.We studied 1012 men (506 cases and 506 controls) from Cleveland, Ohio. All cases had Gleason > or = 7, clinical stage > or = T2c, or PSA > or = 10 ng/mL at diagnosis. Six CPA4 single-nucleotide polymorphisms were genotyped, and evaluated for their relation to prostate cancer. We also evaluated whether CPA4 variants influence risk of disease among men diagnosed at an earlier age (< 66 years).The nonsynonymous coding SNP (rs2171492, Cys303Gly) in CPA4 was associated with an increased risk of aggressive prostate cancer among younger patients (< 66 years). Specifically, men carrying the TT genotype had an approximately two-fold increased risk for being diagnosed with intermediate-to-high risk disease (Odds Ratio = 1.83, p = 0.04). In the overall population (all ages) none of the CPA4 SNPs demonstrated a statistically significant association with prostate cancer.Coding variation in CPA4 may confer increased risk of intermediate-to-high risk prostate cancer among younger patients. Further work is needed to identify the functional aspects of this variation and understand its biological effects on prostate cancer. Such work may translate into more precise screening of higher risk individuals as well as guiding clinicians and patients toward earlier and more definitive treatment modalities in patients genetically identified as higher risk.
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