Frequent germline mutations in DNA repair genes in familial prostate cancer cases. D. Leongamornlert1, E. Saunders1, T. Dadaev1, M. Tymrakiewicz1, C. Goh1, S. Jugurnauth-Little1, I. Kozarewa2, K. Fenwick2, I. Assiotis2, D. Barrowdale3, K. Govindasami1, M. Guy1, E. Sawyer1, R. Wilkinson1, A. Antoniou3, R. Eeles1, 4, Z. Kote-Jarai1 1) Oncogenetics, The Institute of Cancer Research, Sutton, Surrey, United Kingdom; 2) Gene Function, The Institute of Cancer Research, London, United Kingdom; 3) University of Cambridge, Cambridge, United Kingdom; 4) The Royal Marsden Fundation Trust, Sutton and London, United Kingdom.

   Prostate cancer (PrCa) is one of the most common diseases to affect men worldwide and the underlying aetiology is poorly understood compared with other complex diseases. Many common variants have been identified over the last few years which are associated with PrCa risk but very few rare, higher risk alleles have been found. To investigate if rare variants in 22 DNA repair genes have a role in PrCa predisposition, we analysed these genes in a UK collection of familial prostate cancer cases. Germline DNA samples were obtained from 191 PrCa cases which had 3 or more relatives affected with PrCa. These samples were deeply re-sequenced using Agilent SureSelect target capture and Illumina HiSeq systems. The exonic and intronic sequences of 22 tumour suppressor DNA repair genes were analysed for genomic variation using a pipeline consisting of BWA, GATK and Annovar. We identified 14 loss-of-function (LoF) mutations (7.3%) with the highest fraction contributed by BRCA2 (4 mutations). Mutations were also found in ATM, CHEK2, BRIP1, BRCA1, MUTYH, PALB2 and PMS2. In addition, 13 missense variants which are likely to modify protein function were also identified. LoF mutation carriers had significantly higher odds of nodal involvement, metastasis or death from PrCa OR 11.32 (95% CI: 2.27-69.56; P=0.00421). Using a modified segregation analysis approach, we estimate that LoF mutations in any of the studied genes confer a relative risk of PrCa of 4.64, (95% confidence interval 3.84-5.61). In summary we present evidence that mutations in DNA repair genes may have a significant role in familial PrCa predisposition and that carriers of LoF mutations in these genes are more likely to have aggressive disease. This may have clinical utility in the implementation of new screening and treatment strategies.