# The long tail of oncogenic drivers in prostate cancer

Source: https://onco.cc/key-papers/paper-armenia-long-tail-oncogenic-drivers-prostate-nat-genet-2018/  
OnCo record `paper-armenia-long-tail-oncogenic-drivers-prostate-nat-genet-2018` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Reanalysing 1,013 prostate cancers the same way found 97 genes driving the disease, 70 of them new, and almost all of them mutated in fewer than three tumours in a hundred.

## Summary

Exome sequencing data from 1,013 prostate cancers were aggregated and uniformly analysed. A new class of ETS fusion-negative tumours was identified and validated, defined by mutations in epigenetic regulators, alongside alterations in pathways not previously implicated in prostate cancer such as the spliceosome pathway. The incidence of significantly mutated genes followed a long-tail distribution, with many genes mutated in less than 3% of cases. Ninety-seven significantly mutated genes were identified in total, including 70 not previously implicated in prostate cancer, among them the ubiquitin ligase CUL3 and the transcription factor SPEN. Comparing primary and metastatic prostate cancer identified genomic markers that may inform risk stratification.

## Fields

- Kind: Key paper
- Last checked: 2026-09-25
- Journal: Nature Genetics
- Year: 2018
- DOI: 10.1038/s41588-018-0078-z
- Authors: Armenia J, Wankowicz SAM, Liu D, et al.
- Findings: Ninety-seven significantly mutated genes, 70 of them new to prostate cancer.; A new ETS fusion-negative class defined by mutations in epigenetic regulators.; Alterations in the spliceosome pathway, not previously implicated.; A long-tail distribution with many drivers below 3% prevalence.
- What it means: It is the quantitative answer to why prostate cancer has so few targeted therapies. The common events are not druggable, the druggable ones are individually rare, and no trial can be powered on a driver present in 2% of men without an international basket.
- Caveats: Aggregating exomes from different studies means different capture kits and different pipelines even after uniform reanalysis.; A mixture of primary and metastatic samples.; Statistical significance of a mutated gene is not the same as a demonstrated driver function.

## Sources

- Armenia et al., Nat Genet 2018: the long tail of oncogenic drivers across 1,013 uniformly analysed prostate cancer exomes: https://doi.org/10.1038/s41588-018-0078-z
- PubMed: https://pubmed.ncbi.nlm.nih.gov/29610475/
- cBioPortal study prad_p1000 (MSK and Dana-Farber, Nat Genet 2018; 1,013 uniformly reanalysed prostate cancer exomes, primary and metastatic): https://www.cbioportal.org/study/summary?id=prad_p1000

## Connected records

- cancers: [Metastatic castration-resistant prostate cancer](https://onco.cc/cancers/prostate-mcrpc/), [Prostate cancer](https://onco.cc/cancers/prostate/)
- technologies: [Whole-exome & whole-genome sequencing](https://onco.cc/technologies/wes-wgs/)
- targets: [ERG](https://onco.cc/targets/erg/), [FOXA1](https://onco.cc/targets/foxa1/), [KMT2C](https://onco.cc/targets/kmt2c/), [KMT2D](https://onco.cc/targets/kmt2d/), [SPOP](https://onco.cc/targets/spop/)
- pathways: [Epigenetic reprogramming](https://onco.cc/pathways/epigenetic-reprogramming/), [Prostate cancer (KEGG map)](https://onco.cc/pathways/prostate-cancer-signalling/), [RNA splicing](https://onco.cc/pathways/rna-splicing/), [Ubiquitin-proteasome system & protein homeostasis](https://onco.cc/pathways/ubiquitin-proteasome-system/)
- terms: [Driver mutation](https://onco.cc/terms/driver-mutation/), [Gene fusion](https://onco.cc/terms/gene-fusion/), [Somatic mutations from exome and genome sequencing (WXS, WGS)](https://onco.cc/terms/somatic-mutations-wxs-wgs/), [Variant of uncertain significance (VUS)](https://onco.cc/terms/vus/)
- journals: [Nature Genetics](https://onco.cc/journals/nature-genetics/)

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