Journal
CELL REPORTS
Volume 31, Issue 5, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2020.107550
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Funding
- Renal and Skin Unit Research Team
- Roche Tissue Diagnostics - Medical Research Council [MR/P014712/1]
- Rosetrees Trust [A2204]
- Cancer Research UK
- CRUK Lung Cancer Centre of Excellence - Fondation de France
- Royal Society Napier Research Professor
- Francis Crick Institute
- Medical Research Council [FC001169]
- Wellcome Trust [FC001169]
- (CRUK Cancer Immunotherapy Catalyst Network)
- CRUK Lung Cancer Centre of Excellence
- NovoNordisk Foundation [ID16584]
- Breast Cancer Research Foundation (BCRF)
- Stand Up To Cancer (SU2C)-LUNGevity-American Lung Association Lung Cancer Interception Dream Team Translational Research Grant [SU2C-AACR-DT23-17]
- scientific partner of SU2C
- European Research Council (ERC) under the European Union [FP7-THESEUS-617844]
- European Commission ITN [607722]
- ERC Advanced Grant (PROTEUS) from the ERC under the European Union [835297]
- European Union [665233]
- National Institute for Health Research (NIHR) RM/ICR Biomedical Research Centre for Cancer - Cancer Research UK [C50947/A18176]
- NIHR Biomedical Research Centre at the Royal Marsden Hospital [A109]
- Kidney and Melanoma Cancer Fund of The Royal Marsden Cancer Charity
- Ventana Medical Systems Inc. [10467, 10530]
- MRC [MR/P014712/1] Funding Source: UKRI
- European Research Council (ERC) [835297] Funding Source: European Research Council (ERC)
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Although thousands of solid tumors have been sequenced to date, a fundamental under-sampling bias is inherent in current methodologies. This is caused by a tissue sample input of fixed dimensions (e.g., 6 mm biopsy), which becomes grossly under-powered as tumor volume scales. Here, we demonstrate representative sequencing (Rep-Seq) as a new method to achieve unbiased tumor tissue sampling. Rep-Seq uses fixed residual tumor material, which is homogenized and subjected to next-generation sequencing. Analysis of intratumor tumor mutation burden (TMB) variability shows a high level of misclassification using current single-biopsy methods, with 20% of lung and 52% of bladder tumors having at least one biopsy with high TMB but low clonal TMB overall. Misclassification rates by contrast are reduced to 2% (lung) and 4% (bladder) when a more representative sampling methodology is used. Rep-Seq offers an improved sampling protocol for tumor profiling, with significant potential for improved clinical utility and more accurate deconvolution of clonal structure.
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