Dataset Information

Assessing the Cumulative Contribution of New and Established Common Genetic Risk Factors to Early-Onset Prostate Cancer.

ABSTRACT: We assessed the evidence for association between 23 recently reported prostate cancer variants and early-onset prostate cancer and the aggregate value of 63 prostate cancer variants for predicting early-onset disease using 931 unrelated men diagnosed with prostate cancer prior to age 56 years and 1,126 male controls.Logistic regression models were used to test the evidence for association between the 23 new variants and early-onset prostate cancer. Weighted and unweighted sums of total risk alleles across these 23 variants and 40 established variants were constructed. Weights were based on previously reported effect size estimates. Receiver operating characteristic curves and forest plots, using defined cut-points, were constructed to assess the predictive value of the burden of risk alleles on early-onset disease.Ten of the 23 new variants demonstrated evidence (P < 0.05) for association with early-onset prostate cancer, including four that were significant after multiple test correction. The aggregate burden of risk alleles across the 63 variants was predictive of early-onset prostate cancer (AUC = 0.71 using weighted sums), especially in men with a high burden of total risk alleles.A high burden of risk alleles is strongly associated with early-onset prostate cancer.Our results provide the first formal replication for several of these 23 new variants and demonstrate that a high burden of common-variant risk alleles is a major risk factor for early-onset prostate cancer. Cancer Epidemiol Biomarkers Prev; 25(5); 766-72. ©2015 AACR.

SUBMITTER: Lange EM

PROVIDER: S-EPMC4873425 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Assessing the Cumulative Contribution of New and Established Common Genetic Risk Factors to Early-Onset Prostate Cancer.

Lange Ethan M EM Ribado Jessica V JV Zuhlke Kimberly A KA Johnson Anna M AM Keele Gregory R GR Li Jin J Wang Yunfei Y Duan Qing Q Li Ge G Gao Zhengrong Z Li Yun Y Xu Jianfeng J Zheng S Lilly SL Cooney Kathleen A KA

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20151215 5

<h4>Background</h4>We assessed the evidence for association between 23 recently reported prostate cancer variants and early-onset prostate cancer and the aggregate value of 63 prostate cancer variants for predicting early-onset disease using 931 unrelated men diagnosed with prostate cancer prior to age 56 years and 1,126 male controls.<h4>Methods</h4>Logistic regression models were used to test the evidence for association between the 23 new variants and early-onset prostate cancer. Weighted and ...[more]

PMID: 26671023

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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.

Project description:Background & aimsEarly-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC.MethodsWe studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants.ResultsOverall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (P for interaction = .01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI 3.28-4.24) vs 2.9-fold for late-onset CRC (95% CI 2.80-3.04). This association was strongest for participants without a first-degree family history of CRC (P for interaction = 5.61 × 10-5). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI 2.70-3.00). Sensitivity analyses were consistent with these findings.ConclusionsIn an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early-onset than late-onset cancer, particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventive measures.

Dataset Information

Assessing the Cumulative Contribution of New and Established Common Genetic Risk Factors to Early-Onset Prostate Cancer.

Publications

Assessing the Cumulative Contribution of New and Established Common Genetic Risk Factors to Early-Onset Prostate Cancer.

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