Secondary prevention of prostate cancer (PCa) is not standardized and high-risk groups at the time of diagnosis are not well defined. Hereditary susceptibility which is reported in about 10% of men is one important risk factor for PCa development but the absolute risk and clinical importance is fairly unknown. The population risk for developing PCa is estimated to be 11%. If men carry a mutation in BRCA2 or HOXB13, the lifetime risk is 2 to 10-fold increased. "ProFam-Risk" is a prospective cohort analysis not only to validate the known genetic risk scores but also to establish recommendations for follow of high risk populations based on a combination of clinical parameters, imaging (magnetic resonance imaging of the prostate), and genetic profile. Aim of this individualized recommendation is on the one hand to early detect PCa before developing of advanced disease and on the other hand to counsel men at low risk in order to prevent overdiagnosis and overtreatment. Overall, "ProFam-Risk" aims to create a best possible counseling and clinical care for men with familial risk to develop PCa. In this pilot study, about 100 men per year will be included for a total period of 3 years. In addition to the registration of clinical, imaging, and genetic information, liquids and tissue (if available) will be sampled for analysis in the above mentioned research questions.

Prostate cancer (PCA) is common in men. If men carry a mutation in BRCA2 or HOXB13, the lifetime risk is 2 to 10-fold increased. Germline testing is used for individualized risk prediction. In the context of the precision medicine era, different multigene panels are used for hereditary cancer syndromes, including hereditary breast and ovarian cancer (HBOC), Lynch syndrome and hereditary prostate cancer . In addition, targeted therapy with e.g. PARP inhibitors and immunotherapeutic drugs is based on the presence of mutations in DNA repair genes such as BRCA1 and BRCA2, ATM or mismatch repair genes . Furthermore, polygenic risk scores (PRS) are associated with the risk to develop prostate cancer in European and multi-ethnic ancestries with HRs of 1.6 to 5 . Trans-ancestry genome-wide association studies have revealed 269 risk variants from tissue related to prostate cancer including known tumor-related genes like TP53 and CHEK2 .

To more precisely tailor screening for prostate cancer, risk groups with a higher prevalence of clinically significant PCA (csPCA) need to be defined.

Current NCCN guidelines recommend e. g. genetic testing for men with a positive family history of PCA. The prevalence of germline variants in these men diagnosed with PCA at age 60 was 17.2% of which about 30% were BRCA1 or BRCA2 mutations and 4.5% were HOXB13. The absolute risk to develop PCA up to the age of 80 years in BRCA2 carriers is supposed to be 27% - 60%.

Limited data are available concerning the mutational landscape of PCA and somatic oncogenic drivers. To date, studies predominantly focused on known tumor genes with potential clinical actionability and their underlying pathways to guide clinical management in advanced tumor diseases. Systematic mutational profiling in different stages of tumor disease and correlation with germline findings are urgently needed for an in depth understanding of the prostate cancer pathogenesis and identifying promising drug candidates as well as early detection of driver mutations for lethal cancers.

First attempts to combine clinical and genetic data are currently tested in the PROFILE and BARCODE 1 studies. Men with a positive family history of PCA at age 40-69 years were recommended to undergo prostate biopsy regardless of prostate specific antigen (PSA) levels and 25% of those had PCA. The succeeding BARCODE 1 trial is currently recruiting men at ages 55-69 years who are offered genotyping by 130 germline PCA risk single nucleotide polymorphisms (SNPs) from saliva. After calculating a polygenic risk score (PRS), participants above the 90% percentile are offered screening by magnetic resonance imaging (MRI) followed by prostate biopsy. Prostate cancer detection was about 40% of all men screened within the pilot study.

Multiparametric MRI (mpMRI) was developed and explored in prospective and randomized trials also within the group in Düsseldorf to personalize the indication for a prostate biopsy. In collaboration with international partners, mpMRI was shown to improve the accuracy of PCA detection. In addition, the Düsseldorf branch of the hereditary breast and ovarian cancer (HBOC) consortium was part of an international analysis of non-HBOC cancer risks in BRCA1 and BRCA2 mutation carriers. By this analysis, more than 50 men with BRCA2 mutation were identified in the Düsseldorf cohort alone.

Within the National Cancer Prevention Graduate School, the German Cancer Aid (DKH) lately funded the newly established Prostate Cancer Prevention Clinic for men with familial risk at Düsseldorf University. This is a unique and first of its kind outpatient clinic which will include about 100 men at risk for PCA per year and offer specialized diagnostics as a combination of multiparametric MRI, psychometric tests, and genetic analysis to establish an individualized risk score with consecutive risk-adapted monitoring. Men with family history or already known BRCA1 or BRCA2 mutation and their family members will be offered a combined clinical, imaging and genetic profiling to tailor their risk to develop PCA. In addition, men with prostate cancer and positive family history will be offered genetic testing and mutational profiling of tumor tissue in order to exclude or detect hereditary cancer syndromes.

The overarching goal of this project is to identify novel cancer signaling pathways based on the identification of previously unreported genes causative for PCA and to extract preventive and therapeutic approaches for PCA . The groundwork is the establishment of a prospective cohort of unaffected men with a higher risk for PCA due to PCA affected family members ("index patients") (group 1) and/or a mutation in the BRCA1/2 genes (group 2) and PCA-affected men (group 3) . Besides the mutation positive men (group 2) , all will receive multigene panel analysis in a patient care setting and if negative, whole exome sequencing (WES), whole genome sequencing and transcriptome analyses. In PCA-affected men (group 3), additional mutational analysis will be performed on formalin-fixed paraffin embedded (FFPE) - and fresh frozen (FF) tumor tissue from biobanked radical prostatectomy specimens using FFPE panel analysis or WES if FF samples are available.

The investigators propose the following aims:

1. Assembly and clinical characterization of a prospective PCA cohort
2. Identification of PCA-related gene alterations in novel genes
3. Genotype-phenotype correlations and prevention of overdiagnosis/overtreatment by risk-adapted individualized follow-up investigations

Inclusion criteria:

• Healthy men with familial risk ( ≥ 2 first-degree relatives with PCA diagnosed at any age oder ≥ 1 first-degree relative with PCA diagnosed at the age <60)
• healthy men with genetic risk (BRCA1/2 Germline mutation)
• Men with PCA and genetic oder familial risk (familial risk = ≥ 2 first-degree relatives with PCA diagnosed at any age oder ≥ 1 first-degree relative with PCA diagnosed at the age <60; genetic risk= BRCA1/2 Germline mutation)

Exclusion criteria:

• <18 years
• no consent

Prostate cancer is only observed in men