Abstract Introduction: Men with a first degree relative with prostate cancer (PC) have twice the general population risk. This risk is greater amongst young cases and amongst men with more affected relatives. Genome Wide Association studies have identified a number of common single nucleotide polymorphisms (SNPs) that confer small but cumulatively substantial risks of PC. These findings open the possibility for exploring the use of SNPs in PC risk stratification for targeted screening. Objectives: PROFILE has been developed as a pilot study; the primary aim is to determine the acceptability and feasibility of targeted PC screening using prostatic biopsy in men with a family history and its association with specific genetic profiles. The secondary aims are to: (1) determine PC risk related SNPs signatures in men with a family history; (2) study the correlation between specific PC risk related SNP signatures and prostate biopsy (PB) outcomes; (3) estimate the sensitivity and specificity of PSA screening and the optimal PSA threshold for PB in men with a family history of PC; (4) to assess the value of Diffusion Weighted Magnetic Resonance Imaging (DW-MRI) as a PC screening tool in men with a family history of PC. Method: Eligible men were aged 40-69 years with i) first degree relative (FDR) with PC <70 years, or ii) two relatives FDR or second degree relatives (SDR) with PC, at least one <70 years, or iii) 3 relatives (FDR or SDR) with PC at any age. After informed consent, patients provided blood samples to measure PSA level and for DNA extraction. All participants were asked to undergo a ten core trans-rectal ultrasound guided PB regardless of baseline PSA result. Participants without previous PB or who underwent PB >1 year ago were offered a DW-MRI prior to biopsy. Blood DNA from each participant was analysed for a panel of 39 SNPs associated with increased risk of PC using iPLEX Sequenom technology. The results were fed back to participants and an associated psycho-social study has collected data on cancer worry, anxiety and depression and illness perceptions. We aim to enrol 100 men Results: 70 men had been recruited by 1st November 2011. 45 PB have been performed, finding 10 (22.2%) PC, 5 (11.1%) ASAP and 2 (4.4%) high grade PIN. The results of SNP profiling, risk prediction modelling and clinical parameters will be presented alongside the outcome of the baseline psychosocial measures Conclusions: Our preliminary results indicate that PB as a means of PC screening is feasible and acceptable in men with a family history of the disease. The incidence of PC and ASAP in this group of men is higher than expected in the general population. No adverse psychosocial variables were noted. These results support the development of a larger national study. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2612. doi:1538-7445.AM2012-2612