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Whole-exome sequencing of Indian prostate cancer reveals a novel therapeutic target: POLQ

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Abstract

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.

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Data availability

The datasets generated for this study are available in the NCBI BioProject database with accession number: PRJNA838939.

References

  • Arnedo-Pac C, Mularoni L, Muiños F, Gonzalez-Perez A, Lopez-Bigas N (2019) Oncodrive CLUSTL: a sequence-based clustering method to identify cancer drivers. Bioinformatics [internet] 35(22):4788–4790

    Article  CAS  PubMed  Google Scholar 

  • Arnold K, Bordoli L, Kopp J, Schwede T (2006) The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling. Bioinformatics [internet] 22(2):195–201

    Article  CAS  PubMed  Google Scholar 

  • Barbieri CE, Baca SC, Lawrence MS, Demichelis F, Blattner M, Theurillat JP et al (2012) Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nat Genet 44(6):685–689

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bawa PS, Ravi S, Paul S, Chaudhary B, Srinivasan S (2018) A novel molecular mechanism for a long non-coding RNA PCAT92 implicated in prostate cancer. Oncotarget [internet] 9(65):32419–32434

    Article  PubMed  PubMed Central  Google Scholar 

  • Bian X, Zhu B, Wang M, Hu Y, Chen Q, Nguyen C et al (2018) Comparing the performance of selected variant callers using synthetic data and genome segmentation. BMC Bioinformatics 19(1):429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brooke GN, Bevan CL (2009) The role of androgen receptor mutations in prostate cancer progression. Curr Genomics 10(1):18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cancer today [Internet]. [Cited 2021 Dec 29]. Available from: http://gco.iarc.fr/today/home

  • Capriotti E, Fariselli P, Casadio R (2005) I-Mutant20: predicting stability changes upon mutation from the protein sequence or structure. Nucleic Acids Res 33(Web Server):W306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chang TC, Yang Y, Yasue H, Bharti AK, Retzel EF, Liu WS (2011) The expansion of the PRAME gene family in eutheria. PLoS ONE 6(2):e16867

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cingolani P, Platts A, Wang LL, Coon M, Nguyen T, Wang L et al (2012a) A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of drosophila melanogaster strain w1118; iso-2; iso-3. Fly 6(2):80

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cingolani P, Patel VM, Coon M, Nguyen T, Land SJ, Ruden DM et al (2012b) Using drosophila melanogaster as a model for genotoxic chemical mutational studies with a new program SnpSift. Front Genet. https://doi.org/10.3389/fgene.2012.00035

    Article  PubMed  PubMed Central  Google Scholar 

  • Dorsam RT, Gutkind JS (2007) G-protein-coupled receptors and cancer. Nat Rev Cancer 7(2):79–94

    Article  CAS  PubMed  Google Scholar 

  • Dzamba M, Ramani AK, Buczkowicz P, Jiang Y, Yu M, Hawkins C et al (2017) Identification of complex genomic rearrangements in cancers using CouGaR. Genome Res 27(1):107–117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eliasziw M, Donner A (1991) Application of the McNemar test to non-independent matched pair data. Stat Med [internet] 10(12):1981–1991

    Article  CAS  PubMed  Google Scholar 

  • Giri VN, Beebe-Dimmer JL (2016) Familial prostate cancer. Semin Oncol [internet] 43(5):560–565

    Article  PubMed  Google Scholar 

  • Grasso CS, Wu YM, Robinson DR, Cao X, Dhanasekaran SM, Khan AP et al (2012) The mutational landscape of lethal castrate resistant prostate cancer. Nature 487(7406):239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gupta A, Shukla N, Nehra M, Gupta S, Malik B, Mishra AK et al (2020) A pilot study on the whole exome sequencing of prostate cancer in the Indian phenotype reveals distinct polymorphisms. Front Genet 11:874

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hieronymus H, Schultz N, Gopalan A, Carver BS, Chang MT, Xiao Y et al (2014) Copy number alteration burden predicts prostate cancer relapse. Proc Natl Acad Sci USA 111(30):11139–11144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang FW, Mosquera JM, Garofalo A, Oh C, Baco M, Amin-Mansour A et al (2017a) Exome sequencing of African-American prostate cancer reveals loss-of-function ERF mutations. Cancer Discov 7:73–83. https://doi.org/10.1158/2159-8290.cd-16-0960

    Article  Google Scholar 

  • Huang FW, Mosquera JM, Garofalo A, Oh C, Baco M, Amin-Mansour A et al (2017b) Exome sequencing of African-American prostate cancer reveals loss-of-function mutations. Cancer Discov 7(9):973–983

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang MY, Liu XY, Shao Q, Zhang X, Miao L, Wu XY et al (2022) Phosphoserine phosphatase as a prognostic biomarker in patients with gastric cancer and its potential association with immune cells. BMC Gastroenterol 22(1):1–10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huey R, Morris GM, Olson AJ, Goodsell DS (2007) A semi empirical free energy force field with charge-based desolvation. J Comput Chem 28(6):1145–1152

    Article  CAS  PubMed  Google Scholar 

  • Jain S, Saxena S, Kumar A (2014) Epidemiology of prostate cancer in India. Meta Gene 2:596

    Article  PubMed  PubMed Central  Google Scholar 

  • Jiang Z, Zhang Y, Chen X, Wu P, Chen D (2019) Inactivation of the Wnt/β-catenin signaling pathway underlies inhibitory role of microRNA-129–5p in epithelial–mesenchymal transition and angiogenesis of prostate cancer by targeting ZIC2. Cancer Cell Int. https://doi.org/10.1186/s12935-019-0977-9

    Article  PubMed  PubMed Central  Google Scholar 

  • Jillson LK, Yette GA, Laajala TD, Tilley WD, Costello JC, Cramer SD (2021) Androgen receptor signalling in prostate cancer genomic subtypes. Cancers [internet] 13(13):3272. https://doi.org/10.3390/cancers13133272

    Article  CAS  PubMed  Google Scholar 

  • Kaneko A (2013) The neural basis of early vision. Springer Science and Business Media.

  • Kazutoshi Fujita NN (2019) Role of androgen receptor in prostate cancer: a review. World J Mens Health 37(3):288

    Article  PubMed  Google Scholar 

  • Khazaei Z, Sohrabivafa M, Momenabadi V, Moayed L, Goodarzi E (2019) Global cancer statistics 2018: Globocan estimates of incidence and mortality worldwide prostate cancers and their relationship with the human development index. Adv Human Biol 9(3):245

    Article  Google Scholar 

  • Kim DE, Chivian D, Baker D (2004) Protein structure prediction and analysis using the Robetta server. Nucleic Acids Res 32(Web Server):W526

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Krishnamoorthy Hariharan VP (2016) Demography and disease characteristics of prostate cancer in India. Indian J Urol 32(2):103

    Article  PubMed  PubMed Central  Google Scholar 

  • Kuei CH, Lin HY, Lin MH et al (2020) DNA polymerase theta repression enhances the docetaxel responsiveness in metastatic castration-resistant prostate cancer. Biochimica Et Biophysica Acta (BBA) - Mol Basis Dis 1866(12):165954

    Article  CAS  Google Scholar 

  • Langmead B, Salzberg SL (2012) Fast gapped-read alignment with Bowtie 2. Nat Methods 9(4):357–359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Laskowski RA, Swindells MB (2011) LigPlot+: multiple ligand-protein interaction diagrams for drug discovery. J Chem Inf Model [internet] 51(10):2778–2786

    Article  CAS  PubMed  Google Scholar 

  • Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N et al (2009) The sequence alignment/map format and SAM tools. Bioinformatics [internet] 25(16):2078–2079

    Article  PubMed  Google Scholar 

  • Liang C, Niu L, Xiao Z, Zheng C, Shen Y, Shi Y et al (2020) Whole-genome sequencing of prostate cancer reveals novel mutation-driven processes and molecular subgroups. Life Sci 254:117218

    Article  CAS  PubMed  Google Scholar 

  • Liao C, Wang Q, An J, Zhang M, Chen J, Li X et al (2022) SPINKs in tumors: potential therapeutic targets. Front Oncol [internet]. https://doi.org/10.3389/fonc.2022.833741

    Article  PubMed  PubMed Central  Google Scholar 

  • Liu W (2016) DNA alterations in the tumor genome and their associations with clinical outcome in prostate cancer. Asian J Androl 18(4):533–542

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu J, Yan J, Mao R, Ren G, Liu X, Zhang Y et al (2020) Exome sequencing identified six copy number variations as a prediction model for recurrence of primary prostate cancers with distinctive prognosis. Transl Cancer Res [internet] 9(4):2231–2242

    Article  CAS  PubMed  Google Scholar 

  • Liu C, Tu C, Wang L, Wu H, Houston BJ et al (2021) Deleterious variants in X-linked CFAP47 induce asthenoteratozoospermia and primary male infertility. Am J Hum Genet 108(2):309–323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Love MI, Myšičková A, Sun R, Kalscheuer V, Vingron M, Haas SA (2011) Modeling read counts for CNV detection in exome sequencing data. Stat Appl Genet Mol Biol. https://doi.org/10.2202/1544-6115.1732

    Article  PubMed  PubMed Central  Google Scholar 

  • Lu WC, Saha A, Yan W, Garrison K, Lamb C, Pandey R et al (2020) Enzyme-mediated depletion of serum l-Met abrogates prostate cancer growth via multiple mechanisms without evidence of systemic toxicity. Proc Natl Acad Sci USA 117(23):13000–13011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lv Z, Qi L, Hu X, Mo M, Jiang H, Fan B et al (2021) Zic family Member 2 (ZIC2): a potential diagnostic and prognostic biomarker for pan-cancer. Front Mol Biosci [internet]. https://doi.org/10.3389/fmolb.2021.631067

    Article  PubMed  PubMed Central  Google Scholar 

  • McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A et al (2010) The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 20(9):1297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Obinata D, Lawrence MG, Takayama K, Choo N, Risbridger GP, Takahashi S et al (2020) Recent discoveries in the androgen receptor pathway in castration-resistant prostate cancer. Front Oncol [internet]. https://doi.org/10.3389/fonc.2020.581515

    Article  PubMed  Google Scholar 

  • Ogbu SC, Rojas S, Weaver J, Musich PR, Zhang J, Yao ZQ et al (2021) DSTYK enhances chemo resistance in triple-negative breast cancer cells. Cells 11(1):97

    Article  PubMed  PubMed Central  Google Scholar 

  • Piovesan D, Minervini G, Tosatto SCE (2016) The RING 2.0 web server for high quality residue interaction networks. Nucleic Acids Res 44(W1):W367–W374

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Quinlan AR, Hall IM (2010) BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26(6):841–842

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Richard D, Wood SD (2016) DNA polymerase θ (POLQ), double-strand break repair, and cancer. DNA Repair 44:22

    Article  Google Scholar 

  • Ruan X, Tian M, Kang N, Ma W, Zeng Y, Zhuang G et al (2021) Genome-wide identification of m6A-associated functional SNPs as potential functional variants for thyroid cancer. Am J Cancer Res 11(11):5402

    CAS  PubMed  PubMed Central  Google Scholar 

  • Schrempf A, Slyskova J, Loizou JI (2021) Targeting the DNA repair enzyme polymerase θ in cancer therapy. Trends Cancer Res 7(2):98–111

    Article  CAS  Google Scholar 

  • Seki M, Marini F, Wood RD (2003) POLQ (Pol θ), a DNA polymerase and DNA-dependent ATPase in human cells. Nucleic Acids Res 31(21):6117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D et al (2003) Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 13(11):2498–2504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Skidmore ZL, Wagner AH, Lesurf R, Campbell KM, Kunisaki J, Griffith OL et al (2016) GenVisR: Genomic visualizations in R. Bioinformatics [internet] 32(19):3012–3014

    Article  CAS  PubMed  Google Scholar 

  • Song C, Chen H (2018) Predictive significance of TMRPSS2-ERG fusion in prostate cancer: a meta-analysis. Cancer Cell Int 18(1):1–12

    Article  CAS  Google Scholar 

  • Sun X, Wang L, Li H, Jin C, Yu Y, Hou L et al (2021) Identification of microenvironment related potential biomarkers of biochemical recurrence at 3 years after prostatectomy in prostate adenocarcinoma. Aging [internet] 13(12):16024–16042

    Article  CAS  PubMed  Google Scholar 

  • Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z (2017) GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res 45(W1):W98-102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tang R, Liu X, Pan L, Chen R (2019) Novel mutation in FTHL17 gene in pedigree with 46. XY Pure Gonadal Dysgenesis Fertil Steril 111(6):1226–35.e1

    Article  CAS  PubMed  Google Scholar 

  • The Cancer Genome Atlas Research Network (2015) The molecular taxonomy of primary prostate cancer. Cell 163(4):1011

    Article  PubMed Central  Google Scholar 

  • The human protein Atlas [Internet]. [Cited 2022 May 21]. Available from: https://www.proteinatlas.org

  • Therneau TM, Grambsch PM (2000) Modeling survival data: extending the cox model. Stat Biol Health. https://doi.org/10.1007/978-1-4757-3294-8

    Article  Google Scholar 

  • Uhlen M, Zhang C, Lee S, Sjöstedt E, Fagerberg L, Bidkhori G et al (2017) A pathology atlas of the human cancer transcriptome. Science. https://doi.org/10.1126/science.aan2507

    Article  PubMed  Google Scholar 

  • Wang L, Jin G, He C, Guo X, Zhou X, Li M et al (2014) Gαs protein expression is an independent predictor of recurrence in prostate cancer. J Immunol Res 2014:1–9

    Article  Google Scholar 

  • Wang W, Chen ZX, Guo DY, Tao YX (2018) Regulation of prostate cancer by hormone-responsive G protein-coupled receptors. Pharmacol Ther 191:135–147

    Article  CAS  PubMed  Google Scholar 

  • Website [Internet]. Available from: https://saves.mbi.ucla.edu/

  • Website [Internet] (2014) Available from: Eng J. ROC analysis: web-based calculator for ROC curves. Baltimore: Johns Hopkins University [updated 2014 March 19]. Available from: http://www.jrocfit.org

  • Wedge DC, Gundem G, Mitchell T, Woodcock DJ, Martincorena I, Ghori M et al (2018) Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets. Nat Genet 50(5):682–692

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yazdani B, Jazini M, Jabbari N, Karami M et al (2021) Altered expression level of ACSM5 in breast cancer: an integrative analysis of tissue biomarkers with diagnostic potential. Gene Rep 22:100992

    Article  CAS  Google Scholar 

  • Zhou J, Gelot C, Pantelidou C, Li A, Yücel H, Davis RE et al (2021) A first-in-class polymerase theta inhibitor selectively targets homologous-recombination-deficient tumors. Nature Cancer 2(6):598–610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank the sequencing facility and BIO-IT center of IBAB, Bangalore, Karnataka, India for conducting this study.

Funding

This work was supported by the Department of Science & Technology Fund for Improvement of S&T Infrastructure in Higher Educational Institutions (No. SR/FST/LSI-5361/2012), and The Departments of Information Technology, Biotechnology, and Science and Technology, Government of Karnataka, India. SD is supported by the Department of Biotechnology (Ref. no BT/PR13458/COE/34/33/2015 and BT/PR13616/GET/119/9/2015), Govt. of India, India.

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Author notes

  1. Febina Ravindran and Anika Jain contributed equally to the study and were the co-first authors.

Authors and Affiliations

  1. Institute of Bioinformatics and Applied Biotechnology, Electronic City Phase 1, Bangalore, Karnataka, India

    Febina Ravindran, Anika Jain, Sagar Desai, Navjoth Menon, Kriti Srivastava, Pushpinder Singh Bawa, Subhashini Srinivasan & Bibha Choudhary

  2. Manipal Academy of Higher Education, Manipal, India

    Sagar Desai

  3. Healthcare Global Enterprises Ltd, Cancer Centre, Bangalore, India

    K. Sateesh, N. Srivatsa & S. K. Raghunath

Authors
  1. Febina Ravindran
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  2. Anika Jain
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  3. Sagar Desai
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Contributions

FR: investigation, methodology, formal analysis, design, and writing—original draft; AJ: investigation, formal analysis, and bioinformatic analysis; SD: bioinformatic analysis; NM: bioinformatic analysis; KS: bioinformatic analysis; PSB: methodology and investigation; SK: resources; SN: resources; RSK: resources and data curation; SS: formal analysis; BC: conceptualization, design, formal analysis, supervision, and writing—review and editing. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to Bibha Choudhary.

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Conflict of interest

The authors declare no competing interests.

Ethical approval

The study was approved by the Institutional Ethics Committee HCG (HCG Institute Ethics Committee/41/21/08). Informed consent from all the patients was obtained for this study.

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Ravindran, F., Jain, A., Desai, S. et al. Whole-exome sequencing of Indian prostate cancer reveals a novel therapeutic target: POLQ. J Cancer Res Clin Oncol 149, 2451–2462 (2023). https://doi.org/10.1007/s00432-022-04111-0

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