# Gerlinger: a single biopsy misses most of the mutations in a kidney tumour

Source: https://onco.cc/key-papers/paper-gerlinger-intratumour-heterogeneity-nejm-2012/  
OnCo record `paper-gerlinger-intratumour-heterogeneity-nejm-2012` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Sequencing multiple regions of four kidney cancers and their metastases showed that around two-thirds of mutations were not shared across the whole tumour, that good- and poor-prognosis gene signatures coexisted in the same tumour, and that different regions had independently hit the same genes.

## Summary

Swanton's group performed exome sequencing, chromosome aberration analysis and ploidy profiling on multiple spatially separated samples from primary clear-cell renal carcinomas and associated metastases in four patients, reconstructing phylogenetic trees for each tumour.

Branched rather than linear evolution was the rule: 63-69% of all somatic mutations in the index case were not detectable in every region. Prognostic gene expression signatures classified different regions of the same tumour as favourable or unfavourable. Convergent evolution was seen, with distinct inactivating mutations in SETD2, KDM5C and PTEN arising in different regions, indicating strong selection on those pathways.

The paper made intratumour heterogeneity a central problem for biomarkers, drug resistance and trial design, and led directly to the TRACERx programme.

## Fields

- Kind: Key paper
- Last checked: 2026-09-08
- Journal: New England Journal of Medicine
- Year: 2012
- DOI: 10.1056/NEJMoa1113205
- Authors: Gerlinger M, Rowan AJ, Horswell S, et al.
- Findings: 63-69% of somatic mutations in the index tumour were not present in every region sampled; A single biopsy captured only a minority of the tumour's mutational landscape; Good- and poor-prognosis expression signatures were found in different regions of the same tumour; Convergent evolution: distinct loss-of-function mutations in SETD2, KDM5C and PTEN in separate regions of the same tumour
- What it means: A single biopsy is an incomplete picture of a patient's cancer. Truncal mutations shared by all cells (in kidney cancer, VHL) are the most reliable drug targets, whereas mutations in only some branches predict resistance. This is why liquid biopsy and multi-region sampling matter.
- Caveats: Four patients; the extent of heterogeneity varies across cancer types; Clear-cell renal carcinoma may be unusually heterogeneous; Exome sequencing depth of the time limited detection of low-frequency subclones; Clinical consequences (whether targeting truncal alterations improves outcomes) were not tested

## Sources

- DOI: https://doi.org/10.1056/NEJMoa1113205

## Connected records

- key papers: [TRACERx first 100: tracking how lung cancers evolve, and how chromosomal chaos predicts relapse](https://onco.cc/key-papers/paper-tracerx-100-nejm-2017/)
- ideas: [A clone report from blood at every treatment cycle](https://onco.cc/ideas/idea-bio1-ctdna-clone-report/)
- cancers: [Renal cell carcinoma](https://onco.cc/cancers/rcc/)
- fronts: [Diagnostics & Biomarkers](https://onco.cc/fronts/diagnostics/)
- technologies: [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/), [Whole-exome & whole-genome sequencing](https://onco.cc/technologies/wes-wgs/)
- institutions: [Cancer Research UK](https://onco.cc/institutions/cruk/), [The Francis Crick Institute](https://onco.cc/institutions/francis-crick/)
- pathways: [Clonal evolution & minimal residual disease](https://onco.cc/pathways/clonal-evolution/)
- terms: [Clonal evolution and the ecological view of cancer](https://onco.cc/terms/clonal-evolution-theory/), [Drug resistance (primary and acquired)](https://onco.cc/terms/resistance/), [Variant allele frequency (VAF)](https://onco.cc/terms/vaf/)
- people: [Charles Swanton](https://onco.cc/people/charles-swanton/), [Christina Curtis](https://onco.cc/people/christina-curtis/)
- bottlenecks: [Acquired resistance to every therapy](https://onco.cc/bottlenecks/b-resistance/), [Biomarkers are not validated or standardised](https://onco.cc/bottlenecks/b-biomarker-validation/), [Tumour heterogeneity and clonal evolution](https://onco.cc/bottlenecks/b-tumor-heterogeneity/)
- journals: [New England Journal of Medicine](https://onco.cc/journals/nejm/)

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