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Updated: May 24, 2026

Comparative Lesions Analysis Through a Targeted Sequencing Approach
Published on: November 5, 2019
Intratumor heterogeneity and branched evolution revealed by multiregion sequencing
Marco Gerlinger1, Andrew J Rowan1, Stuart Horswell1
1Cancer Research UK London Research Institute (M. Gerlinger, A.J.R., S.H., D.E., E.G., P.M., N.M., A.S., B.P., S.B., N.Q.M., C.R.S., B.S.-D., G.C., G.S., J.D., C.S.), Royal Marsden Hospital Department of Medicine (J.L., M.N., L.P., G.S., M. Gore), Wellcome Trust Sanger Institute (P.T., I.V., A.B., D.J., K.R., C.L., P.A.F.), Barts Cancer Institute at the Barts and the London School of Medicine and Dentistry (M. Gerlinger), and the University College London Cancer Institute (C.S.) - all in London; the Technical University of Denmark, Lyngby (A.C.E., Z.S.); and Harvard Medical School, Boston (Z.S.). Address reprint requests to Dr. Swanton at the Cancer Research UK London Research Institute, Translational Cancer Therapeutics Laboratory, 44 Lincoln's Inn Fields, London WC2A 3LY, United Kingdom, or at charles.swanton@cancer.org.uk.
Intratumor heterogeneity, or variations within a tumor, complicates cancer treatment. Understanding this diversity is crucial for developing effective personalized medicine and biomarkers.
Area of Science:
- Oncology
- Genomics
- Cancer Biology
Background:
- Intratumor heterogeneity (ITH) drives tumor evolution and adaptation.
- ITH challenges personalized medicine approaches relying on single biopsies.
Purpose of the Study:
- To investigate the extent and consequences of ITH in renal carcinomas.
- To analyze genomic and transcriptomic diversity within primary and metastatic tumors.
Main Methods:
- Exome sequencing, chromosome aberration analysis, and ploidy profiling of multiple tumor samples.
- Immunohistochemistry, mutation functional analysis, and mRNA expression profiling to assess ITH consequences.
Main Results:
- Phylogenetic analysis revealed branched tumor evolution with significant subclonal mutations.
- ITH observed in mammalian target of rapamycin (mTOR) pathway mutations and tumor suppressor genes (SETD2, PTEN, KDM5C).
- Distinct gene expression signatures and divergent allelic imbalance/ploidy profiles found across tumor regions.
Conclusions:
- ITH can lead to underestimation of the tumor genomic landscape from single biopsies.
- ITH poses significant challenges for personalized medicine and biomarker development.
- Heterogeneous protein function and Darwinian selection due to ITH may drive therapeutic failure.
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