• Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci.

      Schumacher, F; Al Olama, A; Berndt, S; Benlloch, S; Ahmed, M; Saunders, E; Dadaev, T; Leongamornlert, D; Anokian, E; Cieza-Borrella, C; et al. (2018-06-11)
      Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P < 5.0 × 10-8) with PrCa and one locus significantly associated with early-onset PrCa (≤55 years). Our findings include missense variants rs1800057 (odds ratio (OR) = 1.16; P = 8.2 × 10-9; G>C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 10-9; T>G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55-2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04-6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa 1 .
    • Common genetic variation associated with increased susceptibility to prostate cancer does not increase risk of radiotherapy toxicity.

      Ahmed, M; Dorling, L; Kerns, S; Fachal, L; Elliott, Rebecca M; Parliament, M; Rosenstein, B; Vega, A; Gómez-Caamaño, A; Barnett, G; et al. (2016-05-10)
      Numerous germline single-nucleotide polymorphisms increase susceptibility to prostate cancer, some lying near genes involved in cellular radiation response. This study investigated whether prostate cancer patients with a high genetic risk have increased toxicity following radiotherapy.
    • Contribution of common SNPs to variability in late radiation therapy toxicity in prostate cancer.

      Kerns, S; Hao, K; Stahl, E; Rosenstein, B; CaamaNo, A; Carballo, A; Peleteiro, P; Fachal, L; Vega, A; Dunning, A; et al. (2017-10)
    • Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes

      Fachal, L; Aschard, H; Beesley, J; Barnes, DR; Allen, J; Kar, S; Pooley, KA; Dennis, J; Michailidou, K; Turman, C; et al. (2020)
      Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.
    • A genome wide association study (GWAS) providing evidence of an association between common genetic variants and late radiotherapy toxicity.

      Barnett, G; Thompson, D; Fachal, L; Kerns, S; Talbot, C; Elliott, Rebecca M; Dorling, L; Coles, C; Dearnaley, D; Rosenstein, B; et al. (2014-04-28)
      This study was designed to identify common single nucleotide polymorphisms (SNPs) associated with toxicity 2years after radiotherapy.
    • GWAS identifies new susceptibility loci for late toxicity following prostate cancer radiotherapy

      West, Catharine ML; Kerns, S; Dorling, L; Barnett, G; Dearnaley, D; Fachal, L; Veldeman, L; Parliament, M; Vega, A; Dunning, A; et al. (2019)
    • Individual patient data meta-analysis shows a significant association between the ATM rs1801516 SNP and toxicity after radiotherapy in 5456 breast and prostate cancer patients.

      Andreassen, C; Rosenstein, B; Kerns, S; Ostrer, H; De Ruysscher, D; Cesaretti, J; Barnett, G; Dunning, A; Dorling, L; West, Catharine M L; et al. (2016-07-18)
      Several small studies have indicated that the ATM rs1801516 SNP is associated with risk of normal tissue toxicity after radiotherapy. However, the findings have not been consistent. In order to test this SNP in a well-powered study, an individual patient data meta-analysis was carried out by the International Radiogenomics Consortium.
    • Meta-analysis of Genome Wide Association Studies Identifies Genetic Markers of Late Toxicity Following Radiotherapy for Prostate Cancer.

      Kerns, S; Dorling, L; Fachal, L; Bentzen, S; Pharoah, P; Barnes, D; Gómez-Caamaño, A; Carballo, A; Dearnaley, D; Peleteiro, P; et al. (2016-08)
      Nearly 50% of cancer patients undergo radiotherapy. Late radiotherapy toxicity affects quality-of-life in long-term cancer survivors and risk of side-effects in a minority limits doses prescribed to the majority of patients. Development of a test predicting risk of toxicity could benefit many cancer patients. We aimed to meta-analyze individual level data from four genome-wide association studies from prostate cancer radiotherapy cohorts including 1564 men to identify genetic markers of toxicity. Prospectively assessed two-year toxicity endpoints (urinary frequency, decreased urine stream, rectal bleeding, overall toxicity) and single nucleotide polymorphism (SNP) associations were tested using multivariable regression, adjusting for clinical and patient-related risk factors. A fixed-effects meta-analysis identified two SNPs: rs17599026 on 5q31.2 with urinary frequency (odds ratio [OR] 3.12, 95% confidence interval [CI] 2.08-4.69, p-value 4.16×10(-8)) and rs7720298 on 5p15.2 with decreased urine stream (OR 2.71, 95% CI 1.90-3.86, p-value=3.21×10(-8)). These SNPs lie within genes that are expressed in tissues adversely affected by pelvic radiotherapy including bladder, kidney, rectum and small intestine. The results show that heterogeneous radiotherapy cohorts can be combined to identify new moderate-penetrance genetic variants associated with radiotherapy toxicity. The work provides a basis for larger collaborative efforts to identify enough variants for a future test involving polygenic risk profiling.
    • Meta-analysis of Genome-Wide Association Studies (GWAS) of late toxicity in 3,874 men treated with radiation for prostate cancer.

      Kerns, SL; Fachal, L; Dorling, L; Barnett, G; Burnet, N; Sydes, M; Dearnaley, D; Dunning, A; Pharoah, P; Parliament, MB; et al. (2018)
    • Radiogenomics consortium genome-wide association study meta-analysis of late toxicity after prostate cancer radiotherapy

      Kerns, S; Fachal, L; Dorling, L; Barnett, G; Baran, A; Peterson, D; Hollenberg, M; Hao, K; Narzo, A; Ahsen, M; et al. (2019)
      BACKGROUND: 10-20% of patients develop long-term toxicity following radiotherapy for prostate cancer. Identification of common genetic variants associated with susceptibility to radiotoxicity might improve risk prediction and inform functional mechanistic studies. METHODS: We conducted an individual patient data meta-analysis of six genome-wide association studies (n?=?3,871) in men with European ancestry who underwent radiotherapy for prostate cancer. Radiotoxicities (increased urinary frequency, decreased urinary stream, hematuria, rectal bleeding) were graded prospectively. Grouped relative risk models tested associations with ?6 million genotyped/imputed variants (time to first ?grade 2 toxicity event). Variants with two-sided Pmeta<5x10-8 were considered statistically significant. Bayesian false discovery probability provided an additional measure of confidence. Statistically significant variants were evaluated in three Japanese cohorts (n?=?962). All statistical tests were two-sided. RESULTS: Meta-analysis of the European ancestry cohorts identified three genomic signals: single nucleotide polymorphism (SNP) rs17055178 with rectal bleeding (Pmeta=6.2x10-10), rs10969913 with decreased urinary stream (Pmeta=2.9x10-10) and rs11122573 with hematuria (Pmeta=1.8x10-8). Fine scale mapping of these three regions identified another independent signal (rs147121532) associated with hematuria (Pconditional=4.7x10-6). Credible causal variants at these four signals lie in gene-regulatory regions, some modulating expression of nearby genes. Previously identified variants showed consistent associations (rs17599026 with increased urinary frequency, rs7720298 with decreased urinary stream, rs1801516 with overall toxicity) in new cohorts. rs10969913 and rs17599026 had similar effects in the photon-treated Japanese cohorts. CONCLUSIONS: This study increases understanding of the architecture of common genetic variants affecting radiotoxicity, points to novel radio-pathogenic mechanisms, and develops risk models for testing in clinical studies. Further multi-national radiogenomics studies in larger cohorts are worthwhile.
    • Updated polygenic risk score in breast cancer patients is not associated with increased radiotherapy toxicity

      Barnett, C; Dorling, L; Fachal, L; Brothwell, M; Coles, E; Yarnold, R; Burnet, Neil G; Pharoah, P; West, Catharine ML; Dunning, M; et al. (2018)