The IMPACT Study - Identification of Men With a Genetic Predisposition to ProstAte Cancer: Targeted Screening in Men at Higher Genetic Risk and Controls

Prostate cancer is a significant public health problem. In the EU approximately 200,000 men are diagnosed annually with prostate cancer. There are 24,000 cases per year in England and Wales and 10,000 deaths. The incidence is increasing, even when screen-detected cancers are considered, and within the next few years it will become the most common cancer in UK men.

that an alteration in the breast cancer predisposition genes BRCA1 and BRCA2, may predispose to prostate cancer (PC) and this study will increase this evidence-base. There is some evidence, at least in BRCA2 carriers, that the prostate cancer in these men may be more aggressive and so earlier detection could theoretically reduce mortality. It has been reported that unaffected individuals from families with multiple cases of PC show an increased percentage of raised PSA levels, but the use of PSA level and its predictive value in healthy males with BRCA1/2 mutations has not been studied. If PSA were to be used as a screening tool in BRCA1/2 mutation carriers, we would need to gain a better understanding of the pathogenesis of PC in these men and determine whether they have a different baseline PSA profile compared with controls.

The high prevalence of hormone-dependent/secreting tumours such as breast, ovary and prostate in BRCA1/2 carriers suggests an important role of hormones and their receptors in the development of cancer. Androgens and androgen receptors are considered crucial elements in PC pathogenesis. Therefore male sex hormones will be measured to determine the hormone profile in BRCA1/2 carriers compared with a control group. There is strong evidence that BRCA1/2 play an important role in DNA repair and cell cycling. Therefore, we will investigate abnormalities of the metabolic processes in individuals with a BRCA1/2 mutation where cell cycling may be abnormal. Analysis of proteins (proteomics) and metabolites (metabonomics) are powerful approaches to identifying proteins and metabolites involved in cancer formation. The analysis of the proteins and metabolites will enable us to investigate the effect of the presence of a BRCA1/2 mutation and aid in the identification of new biomarkers for prostate cancer.

The target population is a group of 850 males who carry a known pathogenic mutation in the BRCA1/2 genes (500 BRCA1 and 350 BRCA2). These men will be recruited through genetics clinics across the UK and the world. A control group of men who have tested negative for a known pathogenic mutation that is running in their family will also be recruited through the genetics clinics.

All participants will be invited to attend annually for 5 years for an appointment lasting approximately 30 minutes during which they will discuss the study in detail before giving their written consent agreeing to participate. They will have a 50ml blood sample taken and be asked to provide a urine sample every year. They will also be required to complete a short family and medical history questionnaire. These appointments will either take place at the centre they are registered at, at the Royal Marsden Hospital, or in their own home depending on the arrangements made with the collaborating consultant and patient preference.