PURPOSE: Prostate cancer is the second most common cancer diagnosed worldwide and the third most common cancer among men in India. This study's objective was to characterise the mutational landscape of Indian prostate cancer using whole-exome sequencing to identify population-specific polymorphisms. METHODS: Whole-exome sequencing was performed of 58 treatment-naive primary prostate tumors of Indian origin. Multiple computational and statistical analyses were used to profile the known common mutations, other deleterious mutations, driver genes, prognostic biomarkers, and gene signatures unique to each clinical parameter. Cox analysis was performed to validate survival-associated genes. McNemar test identified genes significant to recurrence and receiver-operating characteristic (ROC) analysis was conducted to determine its accuracy. OncodriveCLUSTL algorithm was used to deduce driver genes. The druggable target identified was modeled with its known inhibitor using Autodock. RESULTS: TP53 was the most commonly mutated gene in our cohort. Three novel deleterious variants unique to the Indian prostate cancer subtype were identified: POLQ, FTHL17, and OR8G1. COX regression analysis identified ACSM5, a mitochondrial gene responsible for survival. CYLC1 gene, which encodes for sperm head cytoskeletal protein, was identified as an unfavorable prognostic biomarker indicative of recurrence. The novel POLQ mutant, also identified as a driver gene, was evaluated as the druggable target in this study. POLQ, a DNA repair enzyme implicated in various cancer types, is overexpressed and is associated with a poor prognosis. The mutant POLQ was subjected to structural analysis and modeled with its known inhibitor novobiocin resulting in decreased binding efficiency necessitating the development of a better drug. CONCLUSION: In this pilot study, the molecular profiling using multiple computational and statistical analyses revealed distinct polymorphisms in the Indian prostate cancer cohort. The mutational signatures identified provide a valuable resource for prognostic stratification and targeted treatment strategies for Indian prostate cancer patients. The DNA repair enzyme, POLQ, was identified as the druggable target in this study.
PURPOSE: Prostate cancer is the second most common cancer diagnosed worldwide and the third most common cancer among men in India. This study's objective was to characterise the mutational landscape of Indian prostate cancer using whole-exome sequencing to identify population-specific polymorphisms. METHODS: Whole-exome sequencing was performed of 58 treatment-naive primary prostate tumors of Indian origin. Multiple computational and statistical analyses were used to profile the known common mutations, other deleterious mutations, driver genes, prognostic biomarkers, and gene signatures unique to each clinical parameter. Cox analysis was performed to validate survival-associated genes. McNemar test identified genes significant to recurrence and receiver-operating characteristic (ROC) analysis was conducted to determine its accuracy. OncodriveCLUSTL algorithm was used to deduce driver genes. The druggable target identified was modeled with its known inhibitor using Autodock. RESULTS: TP53 was the most commonly mutated gene in our cohort. Three novel deleterious variants unique to the Indian prostate cancer subtype were identified: POLQ, FTHL17, and OR8G1. COX regression analysis identified ACSM5, a mitochondrial gene responsible for survival. CYLC1 gene, which encodes for sperm head cytoskeletal protein, was identified as an unfavorable prognostic biomarker indicative of recurrence. The novel POLQ mutant, also identified as a driver gene, was evaluated as the druggable target in this study. POLQ, a DNA repair enzyme implicated in various cancer types, is overexpressed and is associated with a poor prognosis. The mutant POLQ was subjected to structural analysis and modeled with its known inhibitor novobiocin resulting in decreased binding efficiency necessitating the development of a better drug. CONCLUSION: In this pilot study, the molecular profiling using multiple computational and statistical analyses revealed distinct polymorphisms in the Indian prostate cancer cohort. The mutational signatures identified provide a valuable resource for prognostic stratification and targeted treatment strategies for Indian prostate cancer patients. The DNA repair enzyme, POLQ, was identified as the druggable target in this study.
Authors: Christopher E Barbieri; Sylvan C Baca; Michael S Lawrence; Francesca Demichelis; Mirjam Blattner; Jean-Philippe Theurillat; Thomas A White; Petar Stojanov; Eliezer Van Allen; Nicolas Stransky; Elizabeth Nickerson; Sung-Suk Chae; Gunther Boysen; Daniel Auclair; Robert C Onofrio; Kyung Park; Naoki Kitabayashi; Theresa Y MacDonald; Karen Sheikh; Terry Vuong; Candace Guiducci; Kristian Cibulskis; Andrey Sivachenko; Scott L Carter; Gordon Saksena; Douglas Voet; Wasay M Hussain; Alex H Ramos; Wendy Winckler; Michelle C Redman; Kristin Ardlie; Ashutosh K Tewari; Juan Miguel Mosquera; Niels Rupp; Peter J Wild; Holger Moch; Colm Morrissey; Peter S Nelson; Philip W Kantoff; Stacey B Gabriel; Todd R Golub; Matthew Meyerson; Eric S Lander; Gad Getz; Mark A Rubin; Levi A Garraway Journal: Nat Genet Date: 2012-05-20 Impact factor: 38.330
Authors: Ti-Cheng Chang; Yang Yang; Hiroshi Yasue; Arvind K Bharti; Ernest F Retzel; Wan-Sheng Liu Journal: PLoS One Date: 2011-02-10 Impact factor: 3.240
Authors: Catherine S Grasso; Yi-Mi Wu; Dan R Robinson; Xuhong Cao; Saravana M Dhanasekaran; Amjad P Khan; Michael J Quist; Xiaojun Jing; Robert J Lonigro; J Chad Brenner; Irfan A Asangani; Bushra Ateeq; Sang Y Chun; Javed Siddiqui; Lee Sam; Matt Anstett; Rohit Mehra; John R Prensner; Nallasivam Palanisamy; Gregory A Ryslik; Fabio Vandin; Benjamin J Raphael; Lakshmi P Kunju; Daniel R Rhodes; Kenneth J Pienta; Arul M Chinnaiyan; Scott A Tomlins Journal: Nature Date: 2012-07-12 Impact factor: 49.962
Authors: Pablo Cingolani; Viral M Patel; Melissa Coon; Tung Nguyen; Susan J Land; Douglas M Ruden; Xiangyi Lu Journal: Front Genet Date: 2012-03-15 Impact factor: 4.599