BERKELEY, CA (UroToday.com) - Prostate cancer (PrCa) remains a significant public health burden for countries in the Western world. Among men worldwide, it is the second most common cancer and causes over 250 000 deaths annually.[1] However, very little is known regarding the underlying aetiology. Age, race, and family history of PrCa remain the main risk factors for PrCa.[2] Incidence rates for men of African ancestry are nearly twice the incidence rates of their European and Asian counterparts.[3] PrCa has been shown to be one of the most heritable cancers,[4, 5] and a positive family history of PrCa increases risk to first degree relatives by > 2-fold.[5] This familial relative risk is greater amongst young cases, being > 4-fold for first degree relatives of PrCa cases diagnosed at < 60 years. Analyses based on the Nordic twin registries have found 50% higher risks in monozygotic compared with dizygotic twins, supporting the hypothesis that much of this familial aggregation is due to genetic rather than shared lifestyle factors.[4, 6] It has been estimated that about 58% (95% CI 52%-63%) of the risk of developing PrCa could be due to genetic factors.[7] However, identifying genetic variants associated with PrCa has proved a challenge.
Germline genetic variants and prostate cancer risk
The model of PrCa susceptibility is a polygenic model. The risk conferred by rare variants is high (more than 4-fold), and the risk conferred by multiple loci is low (up to 2-fold). Several rare variants of genes involved in the DNA repair pathway have been identified including the BRCA genes, as well as genes involved in mismatch repair (MSH2). Another gene of interest is HOXB13. We have so far identified 78 single nucleotide polymorphisms (SNPs) which are common variants conferring a low PrCa risk.
The clinical application of the PrCa susceptibility loci identified from GWAS remains undefined. We don’t yet know the clinical significance of the recently discovered rare susceptibility variant HOXB13G84E for British men. New rare susceptibility variants in the DNA repair pathway have been identified,[8] and there is a need to correlate these with PrCa risk. Several metabolites could be future biomarkers, and they could be discovered using mass spectrometry in urine and plasma samples of men with a known genetic predisposition to PrCa.
Incorporating genetics in clinic
This is an exciting time to be part of PrCa genetic research. We are looking into ways to apply a genetic signature consisting of the known predisposition SNPs in our cancer screening strategies. Within the next few years we hope to be able to identify those men at higher risk and offer PSA screening accordingly. With the cost of sequencing dropping rapidly, we will be able to offer genetic testing as a bedside or office test. Genetic testing has the potential to inform screening and clinical treatment decisions by risk stratifying patients. Genetic signatures could also highlight those patients who would benefit from surgery or radiotherapy. Targeted agents could be offered based on specific genetic targets, such as PARP-inhibitors in BRCA carriers (so-called ‘precision medicine’).
References:
- Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM: Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 127(12), 2893-2917 (2010).
- Crawford ED: Epidemiology of prostate cancer. Urology 62(6 Suppl 1), 3-12 (2003).
- Altekruse SF, Huang L, Cucinelli JE, Mcneel TS, Wells KM, Oliver MN: Spatial patterns of localized-stage prostate cancer incidence among white and black men in the southeastern United States, 1999-2001. Cancer Epidemiol Biomarkers Prev 19(6), 1460-1467 (2010).
- Lichtenstein P, Holm NV, Verkasalo PK et al. Environmental and heritable factors in the causation of cancer--analyses of cohorts of twins from Sweden, Denmark, and Finland. The New England Journal of Medicine 343(2), 78-85 (2000).
- Schaid DJ: The complex genetic epidemiology of prostate cancer. Hum Mol Genet 13 Spec No 1, R103-121 (2004).
- Hemminki K, Vaittinen P: Familial breast cancer in the family-cancer database. Int J Cancer 77(3), 386-391 (1998).
- Hjelmborg JB, Scheike T, Holst K et al. The Heritability of Prostate Cancer in the Nordic Twin Study of Cancer. Cancer Epidemiology, Biomarkers & Prevention: A publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, (2014).
- Leongamornlert D, Saunders E, Dadaev T et al. Frequent germline deleterious mutations in DNA repair genes in familial prostate cancer cases are associated with advanced disease. British Journal of Cancer 110(6), 1663-1672 (2014).
Written by:
Christos Mikropoulos as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
The Institute of Cancer Research, Sutton, Surrey UK
Translating genetic risk factors for prostate cancer to the clinic: 2013 and beyond - Abstract