Germline Genetic Variants Associated with Prostate Cancer and Potential Relevance to Clinical Practice
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The inherited link of prostate cancer predisposition has been supported using data from early epidemiological studies, as well as from familial and twin studies. Early linkage analyses and candidate gene approaches to identify these variants yielded mixed results. Since then, multiple genetic variants associated with prostate cancer susceptibility have now been found from genome-wide association studies (GWAS). Their clinical utility, however, remains unknown. It is recognised that collaborative efforts are needed to ensure adequate sample sizes are available to definitively investigate the genetic–clinical interactions. These could have important implications for public health as well as individualised prostate cancer management strategies. With the costs of genotyping decreasing and direct-to-consumer testing already offered for these common variants, it is envisaged that a lot of attention will be focussed in this area. These results will enable more refined risk stratification which will be important for targeting screening and prevention to higher risk groups. Ascertaining their clinical role remains an important goal for the GWAS community with international consortia now established, pooling efforts and resources to move this field forward.
KeywordsProstate cancer Genetic variants Genome-wide association studies (GWAS) Clinical application Risk profiling
This work was funded by the Genetic Associations and Mechanisms in Oncology (GAME-ON) Initiative (NIH ELLIPSE grant: U19CA148537) and CRUK (Cancer Research United Kingdom) C5047/A10692 PRACTICAL grant. We are grateful for the support from The Ronald and Rita McAulay Foundation, The Institute of Cancer Research Everyman Campaign and Prostate Action. We acknowledge support from the NIHR (National Institute for Health Research) to the Biomedical Research Centre at The Institute of Cancer Research and Royal Marsden Foundation NHS Trust.
RAE is the principal investigator of PRACTICAL and the CEC, and both CLG and RAE are members of the ELLIPSE consortium. RAE has received an honorarium from Succinct Communications and educational grants from Vista Diagnostics, Illumina, Tepnel (now GenProbe) and Janssen-Cilag.
- Amin Al Olama AA, Kote-Jarai Z, Schumacher FR et al (2013) A meta-analysis of genome-wide association studies to identify prostate cancer susceptibility loci associated with aggressive and non-aggressive disease. Hum Mol Genet 22:408–415Google Scholar
- Audet-Walsh E, Bellemare J, Nadeau G et al (2011) SRD5A Polymorphisms and Biochemical Failure After Radical Prostatectomy. Eur Urol 60:1226–1234Google Scholar
- Castro E, Goh CL, Olmos D et al (2013) Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis and poor survival outcomes in prostate cancer. J Clin Oncol 31:1748–1757Google Scholar
- Chang CF, Pao JB, Yu CC, et al (2013) Common variants in IGF1 pathway genes and clinical outcomes after radical prostatectomy. Ann Surg Oncol 20:2446–2452Google Scholar
- Easton DF (2004) From families to chromosomes: genetic linkage and association studies for finding cancer-predisposition genes. In: Eeles RA, Easton DF, Ponder BA, Eng C (eds) Genetic predisposition to cancer, London, ArnoldGoogle Scholar
- Eeles R, Kote-Jarai Z, Guy M, et al (2010) The identification of rare and common variants which predispose to prostate cancer. In: Foulkes WD, Cooney KA (eds) Male reproductive cancers; epidemiology, pathology and genetics, Springer, New YorkGoogle Scholar
- Goh CL, Saunders EJ, Leongamornlert DA et al (2013) Clinical implications of family history of prostate cancer and genetic risk single nucleotide polymorphism (SNP) profiles in an active surveillance cohort. BJU Int 112:666–673Google Scholar
- Haiman CA, Stram DO, Vickers AJ et al (2013) Levels of beta-microseminoprotein in blood and risk of prostate cancer in multiple populations. J Natl Cancer Inst 105:237–243Google Scholar
- Hindroff LA, Junkins HA, Hall PN, et al (2009) A catalog of published genome-wide association studies [Online]. Available www.genome.gov/gwastudies. Accessed March 28 2013
- Houlston RS, Peto J (2004) Genetics and common cancers. In: Ra E, Easton DF, Ponder BA, Eng C (eds) Genetic predisposition to prostate cancer, Arnold, LondonGoogle Scholar
- Kerns SL, Ostrer H, Stock R et al (2010) Genome-wide association study to identify single nucleotide polymorphisms (SNPs) associated with the development of erectile dysfunction in African-American men after radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 78:1292–1300PubMedCentralPubMedCrossRefGoogle Scholar
- Kerns SL, Stock R, Stone N et al (2013a) A 2-stage genome-wide association study to identify single nucleotide polymorphisms associated with development of erectile dysfunction following radiation therapy for prostate cancer. Int J Radiat Oncol Biol Phys 85:e21–e28PubMedCentralPubMedCrossRefGoogle Scholar
- Kerns SL, Stone NN, Stock RG et al (2013b) A two-stage genome-wide association study to identify single nucleotide polymorphisms associated with development of urinary symptoms after radiotherapy for prostate cancer. J Urol 190:102–108Google Scholar
- Lange EM (2010) Identification of genetic risk factors for prostate cancer: analytic approaches using hereditary prostate cancer families. In: Foulkes WD, Cooney KA (eds) Male reproductive cancers; epidemilogy, pathology and genetics, Springer, New YorkGoogle Scholar
- National Institute of Health (2010) ELLIPSE (Elucidating Loci Involved in Prostate Cancer Susceptibility) [Online]. Available http://epi.grants.cancer.gov/pgwas/personnel.html#ellipse. Accessed 1 July 2012
- PRACTICAL (2008) PRACTICAL (Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome) [Online]. Available http://www.srl.cam.ac.uk/consortia/practical/index.html. Accessed 1 July 2012
- Shang Z, Zhu S, Zhang H, et al (2013) Germline homeobox B13 (HOXB13) G84E mutation and prostate cancer risk in european descendants: a meta-analysis of 24 213 cases and 73 631 controls. Eur Urol 64:173–176Google Scholar
- Yu CC, Lin VC, Huang CY et al (2013) Prognostic significance of cyclin D1 polymorphisms on prostate-specific antigen recurrence after radical prostatectomy. Ann Surg Oncol 20 Suppl 3:492–499Google Scholar