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Genetics and Genomics

Acquired copy number variation in prostate tumours: a review of common somatic copy number alterations, how they are formed and their clinical utility

Abstract

Prostate cancer is one of the most commonly diagnosed cancers in men and unfortunately, disease will progress in up to a third of patients despite primary treatment. Currently, there is a significant lack of prognostic tests that accurately predict disease course; however, the acquisition of somatic chromosomal variation in the form of DNA copy number variants may help understand disease progression. Notably, studies have found that a higher burden of somatic copy number alterations (SCNA) correlates with more aggressive disease, recurrence after surgery and metastasis. Here we will review the literature surrounding SCNA formation, including the roles of key tumour suppressors and oncogenes (PTEN, BRCA2, NKX3.1, ERG and AR), and their potential to inform diagnostic and prognostic clinical testing to improve predictive value. Ultimately, SCNAs, or inherited germline alterations that predispose to SCNAs, could have significant clinical utility in diagnostic and prognostic tests, in addition to guiding therapeutic selection.

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Fig. 1: Somatic copy number alterations in prostate cancer focussed on in this review.
Fig. 2: Mechanisms of TMPRSS2-ERG formation.

References

  1. Sudmant PH, Rausch T, Gardner EJ, Handsaker RE, Abyzov A, Huddleston J, et al. An integrated map of structural variation in 2,504 human genomes. Nature. 2015;526:75–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Shao X, Lv N, Liao J, Long J, Xue R, Ai N, et al. Copy number variation is highly correlated with differential gene expression: a pan-cancer study. BMC Med Genet. 2019;20:175.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Li Y, Roberts ND, Wala JA, Shapira O, Schumacher SE, Kumar K, et al. Patterns of somatic structural variation in human cancer genomes. Nature. 2020;578:112–21.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  4. Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, Sun XW, et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science. 2005;310:644–8.

    Article  ADS  CAS  PubMed  Google Scholar 

  5. Attard G, Clark J, Ambroisine L, Fisher G, Kovacs G, Flohr P, et al. Duplication of the fusion of TMPRSS2 to ERG sequences identifies fatal human prostate cancer. Oncogene. 2008;27:253–63.

    Article  CAS  PubMed  Google Scholar 

  6. Mehra R, Tomlins SA, Yu J, Cao X, Wang L, Menon A, et al. Characterization of TMPRSS2-ETS gene aberrations in androgen-independent metastatic prostate cancer. Cancer Res. 2008;68:3584–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Perner S, Demichelis F, Beroukhim R, Schmidt FH, Mosquera JM, Setlur S, et al. TMPRSS2:ERG fusion-associated deletions provide insight into the heterogeneity of prostate cancer. Cancer Res. 2006;66:8337–41.

    Article  CAS  PubMed  Google Scholar 

  8. Tomlins SA, Laxman B, Varambally S, Cao X, Yu J, Helgeson BE, et al. Role of the TMPRSS2-ERG gene fusion in prostate cancer. Neoplasia. 2008;10:177–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Poniah P, Mohd Zain S, Abdul Razack AH, Kuppusamy S, Karuppayah S, Sian Eng H, et al. Genome-wide copy number analysis reveals candidate gene loci that confer susceptibility to high-grade prostate cancer. Urol Oncol. 2017;35:545.e1. e11.

    Article  CAS  PubMed  Google Scholar 

  10. Hastings PJ, Lupski JR, Rosenberg SM, Ira G. Mechanisms of change in gene copy number. Nat Rev Genet. 2009;10:551–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zhang F, Gu W, Hurles ME, Lupski JR. Copy number variation in human health, disease, and evolution. Annu Rev Genomics Hum Genet. 2009;10:451–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Blazek D, Kohoutek J, Bartholomeeusen K, Johansen E, Hulinkova P, Luo Z, et al. The Cyclin K/Cdk12 complex maintains genomic stability via regulation of expression of DNA damage response genes. Genes Dev. 2011;25:2158–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Nguyen B, Mota JM, Nandakumar S, Stopsack KH, Weg E, Rathkopf D, et al. Pan-cancer analysis of CDK12 alterations identifies a subset of prostate cancers with distinct genomic and clinical characteristics. Eur Urol. 2020;78:671–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Quigley DA, Dang HX, Zhao SG, Lloyd P, Aggarwal R, Alumkal JJ, et al. Genomic hallmarks and structural variation in metastatic prostate cancer. Cell. 2018;174:758–69.e9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wu YM, Cieślik M, Lonigro RJ, Vats P, Reimers MA, Cao X, et al. Inactivation of CDK12 delineates a distinct immunogenic class of advanced prostate cancer. Cell. 2018;173:1770–82.e14.

    Article  CAS  PubMed  Google Scholar 

  16. Hopkins BD, Hodakoski C, Barrows D, Mense SM, Parsons RE. PTEN function: the long and the short of it. Trends Biochem Sci. 2014;39:183–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. He J, Kang X, Yin Y, Chao KSC, Shen WH. PTEN regulates DNA replication progression and stalled fork recovery. Nat Commun. 2015;6:7620.

    Article  ADS  PubMed  Google Scholar 

  18. Williams JL, Greer PA, Squire JA. Recurrent copy number alterations in prostate cancer: an in silico meta-analysis of publicly available genomic data. Cancer Genet. 2014;207:474–88.

    Article  CAS  PubMed  Google Scholar 

  19. Vidotto T, Tiezzi DG, Squire JA. Distinct subtypes of genomic PTEN deletion size influence the landscape of aneuploidy and outcome in prostate cancer. Mol Cytogenet. 2018;11:1.

    Article  PubMed  PubMed Central  Google Scholar 

  20. He WW, Sciavolino PJ, Wing J, Augustus M, Hudson P, Meissner PS, et al. A novel human prostate-specific, androgen-regulated homeobox gene (NKX3.1) that maps to 8p21, a region frequently deleted in prostate cancer. Genomics. 1997;43:69–77.

    Article  CAS  PubMed  Google Scholar 

  21. Kluth M, Amschler NN, Galal R, Möller-Koop C, Barrow P, Tsourlakis MC, et al. Deletion of 8p is an independent prognostic parameter in prostate cancer. Oncotarget. 2017;8:379–92.

    Article  PubMed  Google Scholar 

  22. Zhang H, Muders MH, Li J, Rinaldo F, Tindall DJ, Datta K. Loss of NKX3.1 favors vascular endothelial growth factor-C expression in prostate cancer. Cancer Res. 2008;68:8770–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Bowen C, Ostrowski MC, Leone G, Gelmann EP. Loss of PTEN accelerates NKX3.1 degradation to promote prostate cancer progression. Cancer Res. 2019;79:4124–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Bowen C, Zheng T, Gelmann EP. NKX3.1 suppresses TMPRSS2-ERG gene rearrangement and mediates repair of androgen receptor-induced DNA damage. Cancer Res. 2015;75:2686–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zhang H, Zheng T, Chua CW, Shen M, Gelmann EP. Nkx3.1 controls the DNA repair response in the mouse prostate. Prostate. 2016;76:402–8.

    Article  CAS  PubMed  Google Scholar 

  26. Bubendorf L, Kononen J, Koivisto P, Schraml P, Moch H, Gasser TC, et al. Survey of gene amplifications during prostate cancer progression by high-throughout fluorescence in situ hybridization on tissue microarrays. Cancer Res. 1999;59:803–6.

    CAS  PubMed  Google Scholar 

  27. Grasso CS, Wu Y-M, Robinson DR, Cao X, Dhanasekaran SM, Khan AP, et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature. 2012;487:239–43.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  28. Koivisto P, Visakorpi T, Kallioniemi OP. Androgen receptor gene amplification: a novel molecular mechanism for endocrine therapy resistance in human prostate cancer. Scand J Clin Lab Invest Suppl. 1996;226:57–63.

    Article  CAS  PubMed  Google Scholar 

  29. Liu W, Xie CC, Zhu Y, Li T, Sun J, Cheng Y, et al. Homozygous deletions and recurrent amplifications implicate new genes involved in prostate cancer. Neoplasia. 2008;10:897–907.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Robinson D, Van Allen EM, Wu Y-M, Schultz N, Lonigro RJ, Mosquera J-M, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161:1215–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, et al. Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010;18:11–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Visakorpi T, Hyytinen E, Koivisto P, Tanner M, Keinänen R, Palmberg C, et al. In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat Genet. 1995;9:401–6.

    Article  CAS  PubMed  Google Scholar 

  33. Wyatt AW, Annala M, Aggarwal R, Beja K, Feng F, Youngren J, et al. Concordance of circulating tumor DNA and matched metastatic tissue biopsy in prostate cancer. J Natl Cancer Inst. 2017;109:djx118.

  34. Merson S, Yang ZH, Brewer D, Olmos D, Eichholz A, McCarthy F, et al. Focal amplification of the androgen receptor gene in hormone-naive human prostate cancer. Br J Cancer. 2014;110:1655–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Rubin MA, Demichelis F. The Genomics of Prostate Cancer: emerging understanding with technologic advances. Mod Pathol. 2018;31:S1–11.

    Article  PubMed  Google Scholar 

  36. Shafi AA, Yen AE, Weigel NL. Androgen receptors in hormone-dependent and castration-resistant prostate cancer. Pharm Ther. 2013;140:223–38.

    Article  CAS  Google Scholar 

  37. Koivisto P, Kononen J, Palmberg C, Tammela T, Hyytinen E, Isola J, et al. Androgen receptor gene amplification: a possible molecular mechanism for androgen deprivation therapy failure in prostate cancer. Cancer Res. 1997;57:314–9.

    CAS  PubMed  Google Scholar 

  38. Azad AA, Volik SV, Wyatt AW, Haegert A, Le Bihan S, Bell RH, et al. Androgen receptor gene aberrations in circulating cell-free DNA: biomarkers of therapeutic resistance in castration-resistant prostate cancer. Clin Cancer Res. 2015;21:2315–24.

    Article  CAS  PubMed  Google Scholar 

  39. Verhagen PC, Zhu XL, Rohr LR, Cannon-Albright LA, Tavtigian SV, Skolnick MH, et al. Microdissection, DOP-PCR, and comparative genomic hybridization of paraffin-embedded familial prostate cancers. Cancer Genet Cytogenet. 2000;122:43–8.

    Article  CAS  PubMed  Google Scholar 

  40. Chen Y, Sadasivan SM, She R, Datta I, Taneja K, Chitale D, et al. Breast and prostate cancers harbor common somatic copy number alterations that consistently differ by race and are associated with survival. BMC Med Genomics. 2020;13:116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Attard G, Parker C, Eeles RA, Schroder F, Tomlins SA, Tannock I, et al. Prostate cancer. Lancet. 2016;387:70–82.

    Article  PubMed  Google Scholar 

  42. Mitra A, Fisher C, Foster CS, Jameson C, Barbachanno Y, Bartlett J, et al. Prostate cancer in male BRCA1 and BRCA2 mutation carriers has a more aggressive phenotype. Br J Cancer. 2008;98:502–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Castro E, Goh C, Olmos D, Saunders E, Leongamornlert D, Tymrakiewicz M, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013;31:1748–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Shivji MK, Venkitaraman AR. DNA recombination, chromosomal stability and carcinogenesis: insights into the role of BRCA2. DNA Repair. 2004;3:835–43.

    Article  CAS  PubMed  Google Scholar 

  45. Castro E, Jugurnauth-Little S, Karlsson Q, Al-Shahrour F, Piñeiro-Yañez E, Van de Poll F, et al. High burden of copy number alterations and c-MYC amplification in prostate cancer from BRCA2 germline mutation carriers. Ann Oncol. 2015;26:2293–300.

    Article  CAS  PubMed  Google Scholar 

  46. Blackburn J, Vecchiarelli S, Heyer EE, Patrick SM, Lyons RJ, Jaratlerdsiri W, et al. TMPRSS2-ERG fusions linked to prostate cancer racial health disparities: a focus on Africa. Prostate. 2019;79:1191–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Faisal FA, Sundi D, Tosoian JJ, Choeurng V, Alshalalfa M, Ross AE, et al. Racial variations in prostate cancer molecular subtypes and androgen receptor signaling reflect anatomic tumor location. Eur Urol. 2016;70:14–7.

    Article  CAS  PubMed  Google Scholar 

  48. Koga Y, Song H, Chalmers ZR, Newberg J, Kim E, Carrot-Zhang J, et al. Genomic profiling of prostate cancers from men with African and European Ancestry. Clin Cancer Res. 2020;26:4651–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Magi-Galluzzi C, Tsusuki T, Elson P, Simmerman K, LaFargue C, Esgueva R, et al. TMPRSS2-ERG gene fusion prevalence and class are significantly different in prostate cancer of Caucasian, African-American and Japanese patients. Prostate. 2011;71:489–97.

    Article  CAS  PubMed  Google Scholar 

  50. Yuan J, Kensler KH, Hu Z, Zhang Y, Zhang T, Jiang J, et al. Integrative comparison of the genomic and transcriptomic landscape between prostate cancer patients of predominantly African or European genetic ancestry. PLoS Genet. 2020;16:e1008641–e.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Zhou CK, Young D, Yeboah ED, Coburn SB, Tettey Y, Biritwum RB, et al. TMPRSS2:ERG gene fusions in prostate cancer of West African men and a meta-analysis of racial differences. Am J Epidemiol. 2017;186:1352–61.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Hofer MD, Kuefer R, Maier C, Herkommer K, Perner S, Demichelis F, et al. Genome-wide linkage analysis of TMPRSS2-ERG fusion in familial prostate cancer. Cancer Res. 2009;69:640–6.

    Article  CAS  PubMed  Google Scholar 

  53. Luedeke M, Linnert CM, Hofer MD, Surowy HM, Rinckleb AE, Hoegel J, et al. Predisposition for TMPRSS2-ERG fusion in prostate cancer by variants in DNA repair genes. Cancer Epidemiol Biomark Prev. 2009;18:3030–5.

    Article  CAS  Google Scholar 

  54. FitzGerald LM, Agalliu I, Johnson K, Miller MA, Kwon EM, Hurtado-Coll A, et al. Association of TMPRSS2-ERG gene fusion with clinical characteristics and outcomes: results from a population-based study of prostate cancer. BMC Cancer. 2008;8:230.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Bhanushali A, Rao P, Raman V, Kokate P, Ambekar A, Mandva S, et al. Status of TMPRSS2-ERG fusion in prostate cancer patients from India: correlation with clinico-pathological details and TMPRSS2 Met160Val polymorphism. Prostate Int. 2018;6:145–50.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Luedeke M, Rinckleb AE, FitzGerald LM, Geybels MS, Schleutker J, Eeles RA, et al. Prostate cancer risk regions at 8q24 and 17q24 are differentially associated with somatic TMPRSS2:ERG fusion status. Hum Mol Genet. 2016;25:5490–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Penney KL, Pettersson A, Shui IM, Graff RE, Kraft P, Lis RT, et al. Association of prostate cancer risk variants with TMPRSS2:ERG status: evidence for distinct molecular subtypes. Cancer Epidemiol Biomark Prev. 2016;25:745–9.

    Article  CAS  Google Scholar 

  58. Kohaar I, Chen Y, Ravindranath L, Young D, Ali A, Li Q, et al. Association of common germline variants with TMPRSS2-ERG gene fusion status in prostate cancer. Cancer Res. 2018;78:1230.

    Article  Google Scholar 

  59. Robert G, Jannink S, Smit F, Aalders T, Hessels D, Cremers R, et al. Rational basis for the combination of PCA3 and TMPRSS2:ERG gene fusion for prostate cancer diagnosis. Prostate. 2013;73:113–20.

    Article  CAS  PubMed  Google Scholar 

  60. Velaeti S, Dimitriadis E, Kontogianni-Katsarou K, Savvani A, Sdrolia E, Pantazi G, et al. Detection of TMPRSS2-ERG fusion gene in benign prostatic hyperplasia. Tumour Biol. 2014;35:9597–602.

    Article  CAS  PubMed  Google Scholar 

  61. Cerveira N, Ribeiro FR, Peixoto A, Costa V, Henrique R, Jerónimo C, et al. TMPRSS2-ERG gene fusion causing ERG overexpression precedes chromosome copy number changes in prostate carcinomas and paired HGPIN lesions. Neoplasia. 2006;8:826–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Han B, Mehra R, Lonigro RJ, Wang L, Suleman K, Menon A, et al. Fluorescence in situ hybridization study shows association of PTEN deletion with ERG rearrangement during prostate cancer progression. Mod Pathol. 2009;22:1083–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Carver BS, Tran J, Chen Z, Carracedo-Perez A, Alimonti A, Nardella C, et al. ETS rearrangements and prostate cancer initiation. Nature. 2009;457:E1. discussion E2-3.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  64. Carver BS, Tran J, Gopalan A, Chen Z, Shaikh S, Carracedo A, et al. Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the prostate. Nat Genet. 2009;41:619–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Grubb RL 3rd, Pinsky PF, Greenlee RT, Izmirlian G, Miller AB, Hickey TP, et al. Prostate cancer screening in the prostate, lung, colorectal and ovarian cancer screening trial: update on findings from the initial four rounds of screening in a randomized trial. BJU Int. 2008;102:1524–30.

    Article  PubMed  Google Scholar 

  66. Schröder FH, Hugosson J, Roobol MJ, Tammela TL, Ciatto S, Nelen V, et al. Screening and prostate-cancer mortality in a randomized European study. New Engl J Med. 2009;360:1320–8.

    Article  PubMed  Google Scholar 

  67. Tomlins SA, Aubin SM, Siddiqui J, Lonigro RJ, Sefton-Miller L, Miick S, et al. Urine TMPRSS2:ERG fusion transcript stratifies prostate cancer risk in men with elevated serum PSA. Sci Transl Med. 2011;3:94ra72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Cani AK, Hu K, Liu CJ, Siddiqui J, Zheng Y, Han S, et al. Development of a whole-urine, multiplexed, next-generation RNA-sequencing assay for early detection of aggressive prostate cancer. Eur Urol Oncol. 2022;5:430–9.

    Article  PubMed  Google Scholar 

  69. Brezina S, Feigl M, Gumpenberger T, Staudinger R, Baierl A, Gsur A. Genome-wide association study of germline copy number variations reveals an association with prostate cancer aggressiveness. Mutagenesis. 2020;35:283–90.

    Article  CAS  PubMed  Google Scholar 

  70. Hieronymus H, Murali R, Tin A, Yadav K, Abida W, Moller H, et al. Tumor copy number alteration burden is a pan-cancer prognostic factor associated with recurrence and death. eLife. 2018;7:e37294.

  71. Hieronymus H, Schultz N, Gopalan A, Carver BS, Chang MT, Xiao Y, et al. Copy number alteration burden predicts prostate cancer relapse. Proc Natl Acad Sci USA. 2014;111:11139–44.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  72. Ryan MJ, Bose R. Genomic alteration burden in advanced prostate cancer and therapeutic implications. Front Oncol. 2019;9:1287.

    Article  PubMed  PubMed Central  Google Scholar 

  73. van Duin M, van Marion R, Vissers K, Watson JE, van Weerden WM, Schröder FH, et al. High-resolution array comparative genomic hybridization of chromosome arm 8q: evaluation of genetic progression markers for prostate cancer. Genes Chromosomes Cancer. 2005;44:438–49.

    Article  PubMed  Google Scholar 

  74. Fromont G, Godet J, Peyret A, Irani J, Celhay O, Rozet F, et al. 8q24 amplification is associated with Myc expression and prostate cancer progression and is an independent predictor of recurrence after radical prostatectomy. Hum Pathol. 2013;44:1617–23.

    Article  CAS  PubMed  Google Scholar 

  75. Sato H, Minei S, Hachiya T, Yoshida T, Takimoto Y. Fluorescence in situ hybridization analysis of c-myc amplification in stage TNM prostate cancer in Japanese patients. Int J Urol. 2006;13:761–6.

    Article  CAS  PubMed  Google Scholar 

  76. Wang Y, Li X, Liu W, Li B, Chen D, Hu F, et al. MicroRNA-1205, encoded on chromosome 8q24, targets EGLN3 to induce cell growth and contributes to risk of castration-resistant prostate cancer. Oncogene. 2019;38:4820–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Brusselaers N, Ekwall K, Durand-Dubief M. Copy number of 8q24.3 drives HSF1 expression and patient outcome in cancer: an individual patient data meta-analysis. Hum Genomics. 2019;13:54.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Le Magnen C, Virk RK, Dutta A, Kim JY, Panja S, Lopez-Bujanda ZA, et al. Cooperation of loss of NKX3.1 and inflammation in prostate cancer initiation. Dis Models Mechan. 2018;11:dmm035139.

  79. Asatiani E, Huang WX, Wang A, Rodriguez Ortner E, Cavalli LR, Haddad BR, et al. Deletion, methylation, and expression of the NKX3.1 suppressor gene in primary human prostate cancer. Cancer Res. 2005;65:1164–73.

    Article  CAS  PubMed  Google Scholar 

  80. Barnabas N, Xu L, Savera A, Hou Z, Barrack ER. Chromosome 8 markers of metastatic prostate cancer in African American men: gain of the MIR151 gene and loss of the NKX3-1 gene. Prostate. 2011;71:857–71.

    Article  CAS  PubMed  Google Scholar 

  81. Bowen C, Bubendorf L, Voeller HJ, Slack R, Willi N, Sauter G, et al. Loss of NKX3.1 expression in human prostate cancers correlates with tumor progression. Cancer Res. 2000;60:6111–5.

    CAS  PubMed  Google Scholar 

  82. Meng J, Wang LH, Zou CL, Dai SM, Zhang J, Lu Y. C10orf116 gene copy number loss in prostate cancer: clinicopathological correlations and prognostic significance. Med Sci Monit. 2017;23:5176–83.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Hamid AA, Gray KP, Shaw G, MacConaill LE, Evan C, Bernard B, et al. Compound genomic alterations of TP53, PTEN, and RB1 tumor suppressors in localized and metastatic prostate cancer. Eur Urol. 2019;76:89–97.

    Article  CAS  PubMed  Google Scholar 

  84. Hubbard GK, Mutton LN, Khalili M, McMullin RP, Hicks JL, Bianchi-Frias D, et al. Combined MYC activation and pten loss are sufficient to create genomic instability and lethal metastatic prostate cancer. Cancer Res. 2016;76:283–92.

    Article  CAS  PubMed  Google Scholar 

  85. Zafarana G, Ishkanian AS, Malloff CA, Locke JA, Sykes J, Thoms J, et al. Copy number alterations of c-MYC and PTEN are prognostic factors for relapse after prostate cancer radiotherapy. Cancer. 2012;118:4053–62.

    Article  CAS  PubMed  Google Scholar 

  86. Hernández-Llodrà S, Juanpere N, de Muga S, Lorenzo M, Gil J, Font-Tello A, et al. ERG overexpression plus SLC45A3 (prostein) and PTEN expression loss: Strong association of the triple hit phenotype with an aggressive pathway of prostate cancer progression. Oncotarget. 2017;8:74106–18.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Wang X, Grasso CS, Jordahl KM, Kolb S, Nyame YA, Wright JL, et al. Copy number alterations are associated with metastatic-lethal progression in prostate cancer. Prostate Cancer Prostatic Dis. 2020;23:494–506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Liu W, Hou J, Petkewicz J, Na R, Wang CH, Sun J, et al. Feasibility and performance of a novel probe panel to detect somatic DNA copy number alterations in clinical specimens for predicting prostate cancer progression. Prostate. 2020;80:1253–62.

    Article  CAS  PubMed  Google Scholar 

  89. Ross-Adams H, Lamb AD, Dunning MJ, Halim S, Lindberg J, Massie CM, et al. Integration of copy number and transcriptomics provides risk stratification in prostate cancer: a discovery and validation cohort study. EBioMedicine. 2015;2:1133–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Lalonde E, Ishkanian AS, Sykes J, Fraser M, Ross-Adams H, Erho N, et al. Tumour genomic and microenvironmental heterogeneity for integrated prediction of 5-year biochemical recurrence of prostate cancer: a retrospective cohort study. Lancet Oncol. 2014;15:1521–32.

    Article  PubMed  Google Scholar 

  91. Lalonde E, Alkallas R, Chua MLK, Fraser M, Haider S, Meng A, et al. Translating a prognostic DNA genomic classifier into the clinic: retrospective validation in 563 localized prostate tumors. Eur Urol. 2017;72:22–31.

    Article  CAS  PubMed  Google Scholar 

  92. Gajria D, Chandarlapaty S. HER2-amplified breast cancer: mechanisms of trastuzumab resistance and novel targeted therapies. Expert Rev Anticancer Ther. 2011;11:263–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Taplin ME, Bubley GJ, Shuster TD, Frantz ME, Spooner AE, Ogata GK, et al. Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer. N. Engl J Med. 1995;332:1393–8.

    Article  CAS  PubMed  Google Scholar 

  94. Ehsani M, David FO, Baniahmad A. Androgen receptor-dependent mechanisms mediating drug resistance in prostate cancer. Cancers. 2021;13:1534.

  95. Einstein DJ, Arai S, Balk SP. Targeting the androgen receptor and overcoming resistance in prostate cancer. Curr Opin Oncol. 2019;31:175–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Jernberg E, Bergh A, Wikström P. Clinical relevance of androgen receptor alterations in prostate cancer. Endocr Connect. 2017;6:R146–R61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R, et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med. 2004;10:33–9.

    Article  PubMed  Google Scholar 

  98. Chandrasekar T, Yang JC, Gao AC, Evans CP. Mechanisms of resistance in castration-resistant prostate cancer (CRPC). Transl Androl Urol. 2015;4:365–80.

    PubMed  PubMed Central  Google Scholar 

  99. Lolli C, De Lisi D, Conteduca V, Gurioli G, Scarpi E, Schepisi G, et al. Testosterone levels and androgen receptor copy number variations in castration-resistant prostate cancer treated with abiraterone or enzalutamide. Prostate. 2019;79:1211–20.

    Article  CAS  PubMed  Google Scholar 

  100. Salvi S, Conteduca V, Lolli C, Testoni S, Casadio V, Zaccheroni A, et al. AR copy number and AR signaling-directed therapies in castrationresistant prostate cancer. Curr Cancer Drug Targets. 2018;18:869–76.

    Article  CAS  PubMed  Google Scholar 

  101. Palmberg C, Koivisto P, Hyytinen E, Isola J, Visakorpi T, Kallioniemi OP, et al. Androgen receptor gene amplification in a recurrent prostate cancer after monotherapy with the nonsteroidal potent antiandrogen Casodex (bicalutamide) with a subsequent favorable response to maximal androgen blockade. Eur Urol. 1997;31:216–9.

    Article  CAS  PubMed  Google Scholar 

  102. Schiewer MJ, Knudsen KE. DNA damage response in prostate cancer. Cold Spring Harb Perspect Med. 2019;9:a030486.

  103. Annala M, Vandekerkhove G, Khalaf D, Taavitsainen S, Beja K, Warner EW, et al. Circulating tumor DNA genomics correlate with resistance to abiraterone and enzalutamide in prostate cancer. Cancer Discov. 2018;8:444–57.

    Article  CAS  PubMed  Google Scholar 

  104. Abida W, Campbell D, Patnaik A, Shapiro JD, Sautois B, Vogelzang NJ, et al. Non-BRCA DNA damage repair gene alterations and response to the PARP inhibitor rucaparib in metastatic castration-resistant prostate cancer: analysis from the phase II TRITON2 study. Clin Cancer Res. 2020;26:2487–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Ferraldeschi R, Nava Rodrigues D, Riisnaes R, Miranda S, Figueiredo I, Rescigno P, et al. PTEN protein loss and clinical outcome from castration-resistant prostate cancer treated with abiraterone acetate. Eur Urol. 2015;67:795–802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Stambolic V, Suzuki A, de la Pompa JL, Brothers GM, Mirtsos C, Sasaki T, et al. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell. 1998;95:29–39.

    Article  CAS  PubMed  Google Scholar 

  107. Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase–AKT pathway in human cancer. Nat Rev Cancer. 2002;2:489–501.

    Article  CAS  PubMed  Google Scholar 

  108. Carver BS, Chapinski C, Wongvipat J, Hieronymus H, Chen Y, Chandarlapaty S, et al. Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell. 2011;19:575–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. de Bono JS, De Giorgi U, Rodrigues DN, Massard C, Bracarda S, Font A, et al. Randomized Phase II study evaluating Akt blockade with ipatasertib, in combination with abiraterone, in patients with metastatic prostate cancer with and without PTEN loss. Clin Cancer Res. 2019;25:928–36.

    Article  PubMed  Google Scholar 

  110. Kolinsky MP, Rescigno P, Bianchini D, Zafeiriou Z, Mehra N, Mateo J, et al. A phase I dose-escalation study of enzalutamide in combination with the AKT inhibitor AZD5363 (capivasertib) in patients with metastatic castration-resistant prostate cancer. Ann Oncol. 2020;31:619–25.

    Article  CAS  PubMed  Google Scholar 

  111. Sweeney C, Bracarda S, Sternberg CN, Chi KN, Olmos D, Sandhu S, et al. Ipatasertib plus abiraterone and prednisolone in metastatic castration-resistant prostate cancer (IPATential150): a multicentre, randomised, double-blind, phase 3 trial. Lancet. 2021;398:131–42.

    Article  CAS  PubMed  Google Scholar 

  112. González-Billalabeitia E, Seitzer N, Song SJ, Song MS, Patnaik A, Liu XS, et al. Vulnerabilities of PTEN-TP53-deficient prostate cancers to compound PARP-PI3K inhibition. Cancer Discov. 2014;4:896–904.

    Article  PubMed  PubMed Central  Google Scholar 

  113. Kohaar I, Li Q, Chen Y, Ravindranath L, Young D, Ali A, et al. Association of germline genetic variants with TMPRSS2-ERG fusion status in prostate cancer. Oncotarget. 2020;11:1321–33.

    Article  PubMed  PubMed Central  Google Scholar 

  114. Pettersson A, Graff RE, Bauer SR, Pitt MJ, Lis RT, Stack EC, et al. The TMPRSS2:ERG rearrangement, ERG expression, and prostate cancer outcomes: a cohort study and meta-analysis. Cancer Epidemiol Biomark Prev. 2012;21:1497–509.

    Article  Google Scholar 

  115. St John J, Powell K, Conley-Lacomb MK, Chinni SR. TMPRSS2-ERG fusion gene expression in prostate tumor cells and its clinical and biological significance in prostate cancer progression. J Cancer Sci Ther. 2012;4:94–101.

    Google Scholar 

  116. Xu B, Chevarie-Davis M, Chevalier S, Scarlata E, Zeizafoun N, Dragomir A, et al. The prognostic role of ERG immunopositivity in prostatic acinar adenocarcinoma: a study including 454 cases and review of the literature. Hum Pathol. 2014;45:488–97.

    Article  CAS  PubMed  Google Scholar 

  117. Linn DE, Penney KL, Bronson RT, Mucci LA, Li Z. Deletion of Interstitial Genes between TMPRSS2 and ERG Promotes Prostate Cancer Progression. Cancer Res. 2016;76:1869–81.

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Funding

DEO is supported by a Research Training PhD scholarship, University of Tasmania (UTAS); KR is supported by a Cancer Council Tasmania Joy & Robert Coghlan/College of Health and Medicine UTAS Postdoctoral Research Fellowship; JLD is supported by a Select Foundation Cancer Research Fellowship, UTAS; LMF is supported by a Williams Oncology Royal Hobart Hospital Research Foundation grant and a Gerald Harvey UTAS Senior Research Fellowship.

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DEO: conceptualisation, investigation, writing original draft and writing review and editing; KR: writing review and editing; PM: writing review and editing and supervision; KPB: writing review and editing and supervision; JLD: writing review and editing and supervision; LMF: conceptualisation, writing review and editing, supervision and project administration.

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Correspondence to Liesel M. FitzGerald.

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O’Malley, D.E., Raspin, K., Melton, P.E. et al. Acquired copy number variation in prostate tumours: a review of common somatic copy number alterations, how they are formed and their clinical utility. Br J Cancer 130, 347–357 (2024). https://doi.org/10.1038/s41416-023-02485-7

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