Genomic Evolution Shapes Prostate Cancer Disease Type

The development of cancer is an evolutionary process involving the sequential acquisition of genetic alterations that disrupt normal biological processes, enabling tumor cells to rapidly proliferate and eventually invade and metastasize to other tissues. We investigated the genomic evolution of prostate cancer through the application of three separate classification methods, each designed to investigate a different aspect of tumor evolution. Integrating the results revealed the existence of two distinct types of prostate cancer that arise from divergent evolutionary trajectories, designated as the Canonical and Alternative evolutionary disease types. We therefore propose the evotype model for prostate cancer evolution wherein Alternative-evotype tumors diverge from those of the Canonical-evotype through the stochastic accumulation of genetic alterations associated with disruptions to androgen receptor DNA binding. Our model unifies many previous molecular observations, providing a powerful new framework to investigate prostate cancer disease progression.

Citing Articles

Spatial Genomics Identifies Heat Shock Proteins as Key Molecular Changes Associated to Adipose Periprostatic Space Invasion in Prostate Cancer.

Cussenot O, Poupel L, Mousset C, Lavergne J, Bruyere F, Fontaine A Cancers (Basel). 2025; 17(1.

PMID: 39796635 PMC: 11718861. DOI: 10.3390/cancers17010002.

Unsupervised self-organising map classification of Raman spectra from prostate cell lines uncovers substratified prostate cancer disease states.

West D, Stepney S, Hancock Y Sci Rep. 2025; 15(1):773.

PMID: 39755726 PMC: 11700215. DOI: 10.1038/s41598-024-83708-6.

References

Rodrigues L, Rider L, Nieto C, Romero L, Karimpour-Fard A, Loda M . Coordinate loss of MAP3K7 and CHD1 promotes aggressive prostate cancer. Cancer Res. 2015; 75(6):1021-34. PMC: 4531265. DOI: 10.1158/0008-5472.CAN-14-1596. View

Lee D, Seung H . Learning the parts of objects by non-negative matrix factorization. Nature. 1999; 401(6755):788-91. DOI: 10.1038/44565. View

Augello M, Liu D, Deonarine L, Robinson B, Huang D, Stelloo S . CHD1 Loss Alters AR Binding at Lineage-Specific Enhancers and Modulates Distinct Transcriptional Programs to Drive Prostate Tumorigenesis. Cancer Cell. 2019; 35(5):817-819. DOI: 10.1016/j.ccell.2019.04.012. View

Li H, Durbin R . Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics. 2010; 26(5):589-95. PMC: 2828108. DOI: 10.1093/bioinformatics/btp698. View

Boysen G, Barbieri C, Prandi D, Blattner M, Chae S, Dahija A . SPOP mutation leads to genomic instability in prostate cancer. Elife. 2015; 4. PMC: 4621745. DOI: 10.7554/eLife.09207. View

Gerhauser C, Favero F, Risch T, Simon R, Feuerbach L, Assenov Y . Molecular Evolution of Early-Onset Prostate Cancer Identifies Molecular Risk Markers and Clinical Trajectories. Cancer Cell. 2018; 34(6):996-1011.e8. PMC: 7444093. DOI: 10.1016/j.ccell.2018.10.016. View

Cooper C, Eeles R, Wedge D, Van Loo P, Gundem G, Alexandrov L . Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue. Nat Genet. 2015; 47(4):367-372. PMC: 4380509. DOI: 10.1038/ng.3221. View

Ortmann C, Kent D, Nangalia J, Silber Y, Wedge D, Grinfeld J . Effect of mutation order on myeloproliferative neoplasms. N Engl J Med. 2015; 372(7):601-612. PMC: 4660033. DOI: 10.1056/NEJMoa1412098. View

Liu W, Lindberg J, Sui G, Luo J, Egevad L, Li T . Identification of novel CHD1-associated collaborative alterations of genomic structure and functional assessment of CHD1 in prostate cancer. Oncogene. 2011; 31(35):3939-48. PMC: 3667348. DOI: 10.1038/onc.2011.554. View

10.

Mollica C, Tardella L . Bayesian Plackett-Luce Mixture Models for Partially Ranked Data. Psychometrika. 2016; 82(2):442-458. DOI: 10.1007/s11336-016-9530-0. View

11.

Gerstung M, Jolly C, Leshchiner I, Dentro S, Gonzalez S, Rosebrock D . The evolutionary history of 2,658 cancers. Nature. 2020; 578(7793):122-128. PMC: 7054212. DOI: 10.1038/s41586-019-1907-7. View

12.

Gel B, Diez-Villanueva A, Serra E, Buschbeck M, Peinado M, Malinverni R . regioneR: an R/Bioconductor package for the association analysis of genomic regions based on permutation tests. Bioinformatics. 2015; 32(2):289-91. PMC: 4708104. DOI: 10.1093/bioinformatics/btv562. View

13.

Farmery J, Smith M, Lynch A . Telomerecat: A ploidy-agnostic method for estimating telomere length from whole genome sequencing data. Sci Rep. 2018; 8(1):1300. PMC: 5778012. DOI: 10.1038/s41598-017-14403-y. View

14.

Faisal F, Sundi D, Tosoian J, Choeurng V, Alshalalfa M, Ross A . Racial Variations in Prostate Cancer Molecular Subtypes and Androgen Receptor Signaling Reflect Anatomic Tumor Location. Eur Urol. 2015; 70(1):14-17. PMC: 4826623. DOI: 10.1016/j.eururo.2015.09.031. View

15.

Boyd L, Mao X, Lu Y . The complexity of prostate cancer: genomic alterations and heterogeneity. Nat Rev Urol. 2012; 9(11):652-64. DOI: 10.1038/nrurol.2012.185. View

16.

Fraser M, Sabelnykova V, Yamaguchi T, Heisler L, Livingstone J, Huang V . Genomic hallmarks of localized, non-indolent prostate cancer. Nature. 2017; 541(7637):359-364. DOI: 10.1038/nature20788. View

17.

Weischenfeldt J, Simon R, Feuerbach L, Schlangen K, Weichenhan D, Minner S . Integrative genomic analyses reveal an androgen-driven somatic alteration landscape in early-onset prostate cancer. Cancer Cell. 2013; 23(2):159-70. DOI: 10.1016/j.ccr.2013.01.002. View

18.

Fearon E, Vogelstein B . A genetic model for colorectal tumorigenesis. Cell. 1990; 61(5):759-67. DOI: 10.1016/0092-8674(90)90186-i. View

19.

Pomerantz M, Li F, Takeda D, Lenci R, Chonkar A, Chabot M . The androgen receptor cistrome is extensively reprogrammed in human prostate tumorigenesis. Nat Genet. 2015; 47(11):1346-51. PMC: 4707683. DOI: 10.1038/ng.3419. View

20.

Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik V, Paschka P, Roberts N . Genomic Classification and Prognosis in Acute Myeloid Leukemia. N Engl J Med. 2016; 374(23):2209-2221. PMC: 4979995. DOI: 10.1056/NEJMoa1516192. View