Yishuo Wu1,2, Hongjie Yu2, Siqun Lilly Zheng2, Bingjian Feng3,4, Ashley L Kapron5, Rong Na2,6, Julie L Boyle5, Sameep Shah2, Zhuqing Shi2,7, Charles M Ewing8, Kathleen E Wiley8, Jun Luo8, Patrick C Walsh8, Herbert Ballentine Carter8, Brian T Helfand2, Kathleen A Cooney5, Jianfeng Xu1,2,7, William B Isaacs8. 1. Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China. 2. Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, Illinois. 3. Department of Dermatology, University of Utah, Salt Lake City, Utah. 4. Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah. 5. Department of Internal Medicine, University of Utah, Salt Lake City, Utah. 6. Department of Urology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. 7. State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China. 8. Department of Urology and the James Buchanan Brady Urologic Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Abstract
BACKGROUND: Few genes have germline mutations which predispose men to more aggressive prostate cancer (PCa). This study evaluated the contribution of germline loss of function (LOF) variants in PPFIBP2 to risk of lethal PCa. METHODS: A case-case study of 1414 PCa patients with lethal PCa and low-risk localized PCa was performed. Germline DNA samples from these patients were sequenced for PPFIBP2. Mutation carrier rates and association with lethal PCa were analyzed using the Fisher exact test, logistic regression, and Kaplan-Meier survival analysis. RESULTS: In the entire study population, eight patients, all of European ancestry, were identified as carrying PPFIBP2 pathogenic or likely pathogenic mutations. Seven (1.52%) of 462 lethal PCa patients were carriers compared with only one (0.12%) carrier in 810 low-risk PCa patients, P = 0.0029. The estimated Odds Ratio (OR) of carrying PPFIBP2 mutation for lethal PCa was 13.8 in European American population. The PPFIBP2 loss-of-function mutation carrier rate in lethal PCa cases was also higher than in 33 370 non-Finnish European individuals from the Exome Aggregation Consortium (ExAC) (carrier rate of 0.17%, P = 1.92 × 10-5 ) and in 498 men with localized PCa from The Cancer Genome Atlas cohort (TCGA) cohort (carrier rate of 0%, P = 0.0058). Survival analysis in European American lethal cases revealed PPFIBP2 mutation status as an independent predictor of shorter survival after adjusting for age at diagnosis, PSA at diagnosis, and genetic background (hazard ratio = 2.62, P = 0.034). CONCLUSIONS: While larger studies are needed, germline mutations in a novel gene, PPFIBP2, differentiated risk for lethal PCa from low-risk cases and were associated with shorter survival times after diagnosis.
BACKGROUND: Few genes have germline mutations which predispose men to more aggressive prostate cancer (PCa). This study evaluated the contribution of germline loss of function (LOF) variants in PPFIBP2 to risk of lethal PCa. METHODS: A case-case study of 1414 PCa patients with lethal PCa and low-risk localized PCa was performed. Germline DNA samples from these patients were sequenced for PPFIBP2. Mutation carrier rates and association with lethal PCa were analyzed using the Fisher exact test, logistic regression, and Kaplan-Meier survival analysis. RESULTS: In the entire study population, eight patients, all of European ancestry, were identified as carrying PPFIBP2 pathogenic or likely pathogenic mutations. Seven (1.52%) of 462 lethal PCa patients were carriers compared with only one (0.12%) carrier in 810 low-risk PCa patients, P = 0.0029. The estimated Odds Ratio (OR) of carrying PPFIBP2 mutation for lethal PCa was 13.8 in European American population. The PPFIBP2 loss-of-function mutation carrier rate in lethal PCa cases was also higher than in 33 370 non-Finnish European individuals from the Exome Aggregation Consortium (ExAC) (carrier rate of 0.17%, P = 1.92 × 10-5 ) and in 498 men with localized PCa from The Cancer Genome Atlas cohort (TCGA) cohort (carrier rate of 0%, P = 0.0058). Survival analysis in European American lethal cases revealed PPFIBP2 mutation status as an independent predictor of shorter survival after adjusting for age at diagnosis, PSA at diagnosis, and genetic background (hazard ratio = 2.62, P = 0.034). CONCLUSIONS: While larger studies are needed, germline mutations in a novel gene, PPFIBP2, differentiated risk for lethal PCa from low-risk cases and were associated with shorter survival times after diagnosis.
Authors: Nima C Emami; Taylor B Cavazos; Sara R Rashkin; Clinton L Cario; Rebecca E Graff; Caroline G Tai; Joel A Mefford; Linda Kachuri; Eunice Wan; Simon Wong; David Aaronson; Joseph Presti; Laurel A Habel; Jun Shan; Dilrini K Ranatunga; Chun R Chao; Nirupa R Ghai; Eric Jorgenson; Lori C Sakoda; Mark N Kvale; Pui-Yan Kwok; Catherine Schaefer; Neil Risch; Thomas J Hoffmann; Stephen K Van Den Eeden; John S Witte Journal: Cancer Res Date: 2020-12-08 Impact factor: 13.312