Whole-exome sequencing of Indian prostate cancer reveals a novel therapeutic target: POLQ
Febina Ravindran1, Anika Jain1, Sagar Desai1,2
1Institute of Bioinformatics and Applied Biotechnology, Electronic City Phase 1, Bangalore, Karnataka, India.
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.
Insights
This study characterized Indian prostate cancer mutations using whole-exome sequencing, identifying novel variants and the DNA repair enzyme POLQ as a potential drug target for improved patient outcomes.
Area of Science:
- Genomics
- Oncology
- Molecular Biology
Background:
- Prostate cancer is a significant global health concern, ranking as the third most common cancer in men in India.
- Understanding the specific genetic mutations in Indian prostate cancer is crucial for developing effective treatments.
Purpose of the Study:
- To characterize the mutational landscape of Indian prostate cancer.
- To identify population-specific polymorphisms using whole-exome sequencing.
- To discover novel driver genes and prognostic biomarkers.
Main Methods:
- Whole-exome sequencing of 58 treatment-naive primary prostate tumors from Indian patients.
- Computational and statistical analyses for mutation profiling, driver gene identification, and biomarker discovery.
- Cox regression and ROC analysis for survival and recurrence association; Autodock for drug target modeling.
Main Results:
- TP53 was the most frequently mutated gene; three novel deleterious variants (POLQ, FTHL17, OR8G1) were identified in the Indian cohort.
- ACSM5 identified as a survival-associated gene; CYLC1 identified as an unfavorable prognostic biomarker for recurrence.
- The novel POLQ mutant, a DNA repair enzyme, was identified as a driver gene and a druggable target, though initial modeling showed limited binding efficiency with novobiocin.
Conclusions:
- Molecular profiling revealed distinct polymorphisms in Indian prostate cancer, offering a resource for prognostic stratification.
- Identified mutational signatures can guide targeted treatment strategies for Indian patients.
- The DNA repair enzyme POLQ emerged as a key druggable target for further therapeutic development.
