| 1. |
- Gusev, A, et al.
(författare)
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Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation
- 2016
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7, s. 10979-
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Tidskriftsartikel (refereegranskat)abstract
- Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.
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| 2. |
- Wang, Zhaoming, et al.
(författare)
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Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33
- 2014
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:24, s. 6616-6633
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
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| 3. |
- Wang, Anqi, et al.
(författare)
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Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants
- 2023
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 55:12, s. 2065-2074
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Tidskriftsartikel (refereegranskat)abstract
- The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.
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| 7. |
- Kang, D, et al.
(författare)
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Benign prostatic hyperplasia and subsequent risk of bladder cancer
- 2007
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Ingår i: British Journal of Cancer. - London : Harcourt Publishers. - 0007-0920 .- 1532-1827. ; 96:9, s. 1475-1479
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Tidskriftsartikel (refereegranskat)abstract
- We evaluated the risk of bladder cancer in a cohort of 79,280 Swedish men hospitalised for benign prostatic hyperplasia (BPH), identified in the Swedish Inpatient Register between 1964 and 1983 and followed until 1989 via multiple record linkages with nationwide data on cancer registry, death and emigration. Standardised incidence ratios (SIRs), the ratios of the observed to the expected numbers of incident bladder cancers, were used to calculate the risk associated with BPH. The expected number was calculated by multiplying the number of person-years by the age-specific cancer incidence rates in Sweden for each 5-year age group and calendar year of observation. Analyses were stratified by BPH treatment, latency, calendar year and presence of genitourinary (GU) comorbid conditions. After excluding the first 3 years of follow-up after the index hospitalisation, we observed 506 incident bladder cancer cases during follow-up in the cohort. No overall increased risk of bladder cancer was apparent in our main analysis involving the entire BPH cohort. However, among BPH patients with transurethral resection of the prostate (TURP), there was an increased risk in all follow-up periods; SIRs of bladder cancer during years 4-6 of follow-up was 1.22 (95% confidence interval=1.02-1.46), 1.32 for 7-9 years of follow-up, and 1.47 for 10-26 years of follow-up. SIRs of bladder cancer among TURP-treated BPH patients were particularly elevated among those with comorbid conditions of the GU tract (e.g., stone, infection, etc.); 1.72, 1.74 and 2.01 for 4-6, 7-9, 10-26 years of follow-up, respectively, and also for those whose diagnoses occurred before 1975, when TURP was more likely to be performed by a urologist than a general practitioner: 1.87, 1.90 and 1.74, respectively. These findings suggest that BPH overall is not associated with bladder cancer risk. However, among men treated with TURP, particularly those with other comorbid GU tract conditions, risk of bladder cancer was elevated.
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