Common Genetic Variation Associated with Increased Susceptibility to Prostate Cancer Does Not Increase Risk of Radiotherapy Toxicity

Overview

Journal Br J Cancer

Specialty Oncology

Date 2016 Apr 13

PMID 27070714

Citations 8

Authors

Mahbubl Ahmed

Leila Dorling

Sarah Kerns

Laura Fachal

Rebecca Elliott

Matt Partliament

Barry S Rosenstein

Ana Vega

Antonio Gomez-Caamano

Gill Barnett

David P Dearnaley

Emma Hall

Matt Sydes

Neil Burnet

Paul D P Pharoah

Ros Eeles

Catharine M L West

Affiliations

Soon will be listed here.

Abstract

Background: 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.

Methods: The study included 1560 prostate cancer patients from four radiotherapy cohorts: RAPPER (n=533), RADIOGEN (n=597), GenePARE (n=290) and CCI (n=150). Data from genome-wide association studies were imputed with the 1000 Genomes reference panel. Individuals were genetically similar with a European ancestry based on principal component analysis. Genetic risks were quantified using polygenic risk scores. Regression models tested associations between risk scores and 2-year toxicity (overall, urinary frequency, decreased stream, rectal bleeding). Results were combined across studies using standard inverse-variance fixed effects meta-analysis methods.

Results: A total of 75 variants were genotyped/imputed successfully. Neither non-weighted nor weighted polygenic risk scores were associated with late radiation toxicity in individual studies (P>0.11) or after meta-analysis (P>0.24). No individual variant was associated with 2-year toxicity.

Conclusion: Patients with a high polygenic susceptibility for prostate cancer have no increased risk for developing late radiotherapy toxicity. These findings suggest that patients with a genetic predisposition for prostate cancer, inferred by common variants, can be safely treated using current standard radiotherapy regimens.

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References

Howie B, Marchini J, Stephens M . Genotype imputation with thousands of genomes. G3 (Bethesda). 2012; 1(6):457-70. PMC: 3276165. DOI: 10.1534/g3.111.001198. View

Merino D, Malkin D . p53 and hereditary cancer. Subcell Biochem. 2014; 85:1-16. DOI: 10.1007/978-94-017-9211-0_1. View

Bentzen S, Constine L, Deasy J, Eisbruch A, Jackson A, Marks L . Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC): an introduction to the scientific issues. Int J Radiat Oncol Biol Phys. 2010; 76(3 Suppl):S3-9. PMC: 3431964. DOI: 10.1016/j.ijrobp.2009.09.040. View

Fachal L, Gomez-Caamano A, Sanchez-Garcia M, Carballo A, Peleteiro P, Lobato-Busto R . TGFβ1 SNPs and radio-induced toxicity in prostate cancer patients. Radiother Oncol. 2012; 103(2):206-9. DOI: 10.1016/j.radonc.2012.01.015. View

Olama A, Kote-Jarai Z, Schumacher F, Wiklund F, Berndt S, Benlloch S . A meta-analysis of genome-wide association studies to identify prostate cancer susceptibility loci associated with aggressive and non-aggressive disease. Hum Mol Genet. 2012; 22(2):408-15. PMC: 3526158. DOI: 10.1093/hmg/dds425. View

Kote-Jarai Z, Saunders E, Leongamornlert D, Tymrakiewicz M, Dadaev T, Jugurnauth-Little S . Fine-mapping identifies multiple prostate cancer risk loci at 5p15, one of which associates with TERT expression. Hum Mol Genet. 2013; 22(12):2520-8. PMC: 3658165. DOI: 10.1093/hmg/ddt086. View

Kerns S, Kundu S, Oh J, Singhal S, Janelsins M, Travis L . The Prediction of Radiotherapy Toxicity Using Single Nucleotide Polymorphism-Based Models: A Step Toward Prevention. Semin Radiat Oncol. 2015; 25(4):281-91. PMC: 4576690. DOI: 10.1016/j.semradonc.2015.05.006. View

Clement F, Camenisch U, Fei J, Kaczmarek N, Mathieu N, Naegeli H . Dynamic two-stage mechanism of versatile DNA damage recognition by xeroderma pigmentosum group C protein. Mutat Res. 2009; 685(1-2):21-8. DOI: 10.1016/j.mrfmmm.2009.08.005. View

Martin N, DAmico A . Progress and controversies: Radiation therapy for prostate cancer. CA Cancer J Clin. 2014; 64(6):389-407. DOI: 10.3322/caac.21250. View

10.

Rosenstein B, West C, Bentzen S, Alsner J, Andreassen C, Azria D . Radiogenomics: radiobiology enters the era of big data and team science. Int J Radiat Oncol Biol Phys. 2014; 89(4):709-13. PMC: 5119272. DOI: 10.1016/j.ijrobp.2014.03.009. View

11.

Feltes B, Bonatto D . Overview of xeroderma pigmentosum proteins architecture, mutations and post-translational modifications. Mutat Res Rev Mutat Res. 2015; 763:306-20. DOI: 10.1016/j.mrrev.2014.12.002. View

12.

Kerns S, West C, Andreassen C, Barnett G, Bentzen S, Burnet N . Radiogenomics: the search for genetic predictors of radiotherapy response. Future Oncol. 2014; 10(15):2391-406. DOI: 10.2217/fon.14.173. View

13.

Ohri N, Dicker A, Showalter T . Late toxicity rates following definitive radiotherapy for prostate cancer. Can J Urol. 2012; 19(4):6373-80. PMC: 3808959. View

14.

Abecasis G, Altshuler D, Auton A, Brooks L, Durbin R, Gibbs R . A map of human genome variation from population-scale sequencing. Nature. 2010; 467(7319):1061-73. PMC: 3042601. DOI: 10.1038/nature09534. View

15.

Fachal L, Gomez-Caamano A, Barnett G, Peleteiro P, Carballo A, Calvo-Crespo P . A three-stage genome-wide association study identifies a susceptibility locus for late radiotherapy toxicity at 2q24.1. Nat Genet. 2014; 46(8):891-4. DOI: 10.1038/ng.3020. View

16.

Eeles R, Olama A, Benlloch S, Saunders E, Leongamornlert D, Tymrakiewicz M . Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array. Nat Genet. 2013; 45(4):385-91, 391e1-2. PMC: 3832790. DOI: 10.1038/ng.2560. View

17.

Peeters S, Heemsbergen W, van Putten W, Slot A, Tabak H, Mens J . Acute and late complications after radiotherapy for prostate cancer: results of a multicenter randomized trial comparing 68 Gy to 78 Gy. Int J Radiat Oncol Biol Phys. 2005; 61(4):1019-34. DOI: 10.1016/j.ijrobp.2004.07.715. View

18.

Kerns S, De Ruysscher D, Andreassen C, Azria D, Barnett G, Chang-Claude J . STROGAR - STrengthening the Reporting Of Genetic Association studies in Radiogenomics. Radiother Oncol. 2013; 110(1):182-8. PMC: 4786020. DOI: 10.1016/j.radonc.2013.07.011. View

19.

Talbot C, Tanteles G, Barnett G, Burnet N, Chang-Claude J, Coles C . A replicated association between polymorphisms near TNFα and risk for adverse reactions to radiotherapy. Br J Cancer. 2012; 107(4):748-53. PMC: 3419947. DOI: 10.1038/bjc.2012.290. View

20.

Dearnaley D, Syndikus I, Sumo G, Bidmead M, Bloomfield D, Clark C . Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: preliminary safety results from the CHHiP randomised controlled trial. Lancet Oncol. 2011; 13(1):43-54. DOI: 10.1016/S1470-2045(11)70293-5. View