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A Review of Prostate Cancer Genome-Wide Association Studies (GWAS).

ABSTRACT: Prostate cancer is the most common cancer in men in Europe and the United States. The genetic heritability of prostate cancer is contributed to by both rarely occurring genetic variants with higher penetrance and moderate to commonly occurring variants conferring lower risks. The number of identified variants belonging to the latter category has increased dramatically in the last 10 years with the development of the genome-wide association study (GWAS) and the collaboration of international consortia that have led to the sharing of large-scale genotyping data. Over 40 prostate cancer GWAS have been reported, with approximately 170 common variants now identified. Clinical utility of these variants could include strategies for population-based risk stratification to target prostate cancer screening to men with an increased genetic risk of disease development, while for those who develop prostate cancer, identifying genetic variants could allow treatment to be tailored based on a genetic profile in the early disease setting. Functional studies of identified variants are needed to fully understand underlying mechanisms of disease and identify novel targets for treatment. This review will outline the GWAS carried out in prostate cancer and the common variants identified so far, and how these may be utilized clinically in the screening for and management of prostate cancer. Cancer Epidemiol Biomarkers Prev; 27(8); 845-57. ©2018 AACR.

SUBMITTER: Benafif S

PROVIDER: S-EPMC6051932 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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A Review of Prostate Cancer Genome-Wide Association Studies (GWAS).

Benafif Sarah S Kote-Jarai Zsofia Z Eeles Rosalind A RA

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20180118 8

Prostate cancer is the most common cancer in men in Europe and the United States. The genetic heritability of prostate cancer is contributed to by both rarely occurring genetic variants with higher penetrance and moderate to commonly occurring variants conferring lower risks. The number of identified variants belonging to the latter category has increased dramatically in the last 10 years with the development of the genome-wide association study (GWAS) and the collaboration of international cons ...[more]

PMID: 29348298

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Project description:Genome-wide association studies have identified multiple common alleles associated with prostate cancer risk in populations of European ancestry. Testing these variants in other populations is needed to assess the generalizability of the associations and may guide fine-mapping efforts. We examined 13 of these risk variants in a multiethnic sample of 2,768 incident prostate cancer cases and 2,359 controls from the Multiethnic Cohort (African Americans, European Americans, Latinos, Japanese Americans, and Native Hawaiians). We estimated ethnic-specific and pooled odds ratios and tested for ethnic heterogeneity of effects using logistic regression. In ethnic-pooled analyses, 12 of the 13 variants were positively associated with risk, with statistically significant associations (P < 0.05) noted with six variants: JAZF1, rs10486567 [odds ratio (OR), 1.23; 95% confidence interval (95% CI, 1.12-1.35); Xp11.2, rs5945572 (OR, 1.31; 95% CI, 1.13-1.51); HNF1B, rs4430796 (OR, 1.15; 95% CI, 1.06-1.25); MSMB, rs10993994 (OR, 1.13; 95% CI, 1.04-1.23); 11q13.2, rs7931342 (OR, 1.13; 95% CI, 1.03-1.23); 3p12.1, rs2660753 (OR, 1.11; 95% CI, 1.01-1.21); SLC22A3, rs9364554 (OR, 1.10; 95% CI, 1.00-1.21); CTBP2, rs12769019 (OR, 1.11; 95% CI, 0.99-1.25); HNF1B, rs11649743 (OR, 1.10; 95% CI, 0.99-1.22); EHBP1, rs721048 (OR, 1.08; 95% CI, 0.94-1.25); KLK2/3, rs2735839 (OR, 1.06; 95% CI, 0.97-1.16); 17q24.3, rs1859962 (OR, 1.04; 95% CI, 0.96-1.13); and LMTK2, rs6465657 (OR, 0.99; 95% CI, 0.89-1.09). Significant ethnic heterogeneity of effects was noted for four variants (EHBP1, P(het) = 3.9 x 10(-3); 11q13, P(het) = 0.023; HNF1B (rs4430796), P(het) = 0.026; and KLK2/3, P(het) = 2.0 x 10(-3)). Although power was limited in some ethnic/racial groups due to variation in sample size and allele frequencies, these findings suggest that a large fraction of prostate cancer variants identified in populations of European ancestry are global markers of risk. For many of these regions, fine-mapping in non-European samples may help localize causal alleles and better determine their contribution to prostate cancer risk in the population.

Project description:Genome-wide Association Studies (GWAS) revealed novel genetic markers for breast cancer susceptibility. But little is known about the risk factors and molecular events associated with breast cancer in Arab Population. Therefore, we designed a broad study to investigate the susceptibility and prognostic implications of the GWAS breast cancer loci in the Tunisian population. In a cohort of 640 unrelated patients with breast cancer and 371 healthy control subjects, we characterized the variation of 9 single nucleotide polymorphisms (SNPs), namely rs1219648, rs2981582; rs8051542, rs12443621, and rs3803662; rs889312; rs3817198; rs13387042 and rs13281615. Only 5 out of 9 GWAS breast cancer loci were found to be significantly associated with breast cancer in Tunisians: The rs1219648 (G vs. A allele: OR = 1.36, P = 1 × 10(-3)) and rs2981582 (A vs. G allele: OR = 1.55, P = 3 × 10(-6)) of FGFR2 gene; the rs8051542 of the TNRC9 gene (T vs. C allele: OR = 1.40, P = 4 × 10(-4)); the rs889312 of the MAP3K1 gene (C vs. A allele: OR = 1.33, P = 3 × 10(-3)) and the rs13281615 located on 8q24 (G vs. A allele: OR = 1.21, P = 0.03). Homozygous variant genotypes of rs2981582 were strongly related to lymph node negative breast cancer (OR = 3.33, P = 6 × 10(-7)) and the minor allele of rs2981582 was associated with increased risk of ER+ tumors (OR = 1.57, P = 0.02; OR = 2.15, P = 0.001, for heterozygous and homozygous variant genotypes, respectively) and increased risk of distant metastasis development (OR = 2.30, P = 4 × 10(-3); OR = 3.57, P = 6 × 10(-5), for heterozygous and homozygous variant genotypes, respectively) in a dose dependent manner. The association for rs8051542 was stronger for high-grade SBR tumors (OR = 2.54, P = 2 × 10(-4)). GG genotype of rs13387042 on 2q35 showed a significant association with the risk of developing distant metastasis (OR = 1.94, P = 0.02). The G allele of rs1219648 in FGFR2 and the A allele of rs13387042 on 2q35 indicated a better prognosis by showing a significantly higher overall survival rates (P = 0.013 and P = 0.005, respectively). In conclusion, GWAS breast cancer FGFR2, TNRC9, MAP3K1, and 8q24 loci are associated with an increased risk of breast cancer and genetic variation in FGFR2 gene may predict the aggressiveness of breast cancer in Tunisians.

Dataset Information

A Review of Prostate Cancer Genome-Wide Association Studies (GWAS).

Publications

A Review of Prostate Cancer Genome-Wide Association Studies (GWAS).

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