# The clonal and mutational evolution spectrum of primary triple-negative breast cancers

Source: https://onco.cc/key-papers/paper-shah-tnbc-clonal-evolution-nature-2012/  
OnCo record `paper-shah-tnbc-clonal-evolution-nature-2012` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Sequencing 104 triple-negative breast cancers at diagnosis showed they range from tumours with a handful of mutations to tumours with hundreds, that only about a third of mutations are even expressed, and that TP53, PIK3CA and PTEN are the changes present in most of the tumour's cells.

## Summary

104 primary TNBCs were profiled by exome and RNA sequencing with deep re-sequencing of 2,414 somatic mutations to measure clonal frequency. The cancers showed a wide, continuous spectrum of genomic evolution; about 36% of mutations were expressed. Basal TNBC showed more variation in clonal frequencies than non-basal TNBC. TP53, PIK3CA and PTEN mutations were clonally dominant compared with other genes, though in some tumours their frequencies were incompatible with founder status; mutations in cytoskeletal, cell-shape and motility genes occurred at lower clonal frequency, suggesting later acquisition.

The cohort is deposited as brca_bccrc (British Columbia, Nature 2012) on cBioPortal.

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Journal: Nature
- Year: 2012
- DOI: 10.1038/nature10933
- Authors: Shah SP, Roth A, Goya R, et al.
- Findings: Coding mutation counts ranged from a handful to hundreds per tumour; about 36% of mutations were expressed.; TP53, PIK3CA and PTEN were clonally dominant; basal TNBC showed wider clonal variation than non-basal.; Cytoskeletal and motility gene mutations were subclonal, consistent with later acquisition.
- What it means: The first TNBC-specific genome paper established that the disease has no shared driver beyond TP53 and that each tumour is a clonal mixture, the reason single-target drugs have struggled and ctDNA tracking needs patient-specific variants.
- Caveats: 104 tumours from one Canadian centre; exome depth of the era.; Clonal frequencies were estimated from bulk tissue without single-cell confirmation.

## Sources

- Shah et al., Nature 2012: clonal and mutational evolution spectrum of 104 primary TNBCs: https://doi.org/10.1038/nature10933
- PubMed: https://pubmed.ncbi.nlm.nih.gov/22495314/

## Connected records

- cancers: [Triple-negative breast cancer (TNBC)](https://onco.cc/cancers/tnbc/)
- targets: [PIK3CA / PI3K-alpha](https://onco.cc/targets/pik3ca/), [PTEN](https://onco.cc/targets/pten/), [TP53](https://onco.cc/targets/tp53/)
- pathways: [Clonal evolution & minimal residual disease](https://onco.cc/pathways/clonal-evolution/)
- terms: [Next-generation sequencing (NGS)](https://onco.cc/terms/ngs/)
- journals: [Nature](https://onco.cc/journals/nature/)

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