2023
DOI: 10.1038/s41586-023-05706-4
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Genomic–transcriptomic evolution in lung cancer and metastasis

Abstract: Intratumour heterogeneity (ITH) fuels lung cancer evolution, which leads to immune evasion and resistance to therapy1. Here, using paired whole-exome and RNA sequencing data, we investigate intratumour transcriptomic diversity in 354 non-small cell lung cancer tumours from 347 out of the first 421 patients prospectively recruited into the TRACERx study2,3. Analyses of 947 tumour regions, representing both primary and metastatic disease, alongside 96 tumour-adjacent normal tissue samples implicate the transcrip… Show more

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Cited by 51 publications
(25 citation statements)
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“…10g and Methods). This result was consistent with findings in our companion papers 9,26 , in which metastatic seeding was associated with a higher propensity for subclonal expansion 9 and proliferative transcriptional signatures 26 . Overall, these data highlight the need to consider not only the number or proportion of subclonal mutations but also the clonal architecture specific to each tumour region when exploring the association between genomic ITH and prognosis.…”
Section: Genomic Ith and Prognosissupporting
confidence: 93%
“…10g and Methods). This result was consistent with findings in our companion papers 9,26 , in which metastatic seeding was associated with a higher propensity for subclonal expansion 9 and proliferative transcriptional signatures 26 . Overall, these data highlight the need to consider not only the number or proportion of subclonal mutations but also the clonal architecture specific to each tumour region when exploring the association between genomic ITH and prognosis.…”
Section: Genomic Ith and Prognosissupporting
confidence: 93%
“…The data from this study are part of the first 421 patients prospectively analysed from the TRACERx cohort (NCT01888601 approved by the National Research Ethics Service Committee London, with sponsor's approval of the study by University College London with the following details: REC reference 13/LO/1546, protocol number UCL/12/0279, IRAS project ID 138871). Data obtention followed similar steps to those described in the study of the first 100 patients 52,53 and is described in full in the accompanying studies [54][55][56] . Informed consent for entry into the TRACERx study was mandatory and was obtained from every patient.…”
Section: Tracerx Cohortmentioning
confidence: 99%
“…Transcriptomic data (50 million paired reads per sample with a length of 75 bp or 100 bp per read) analysed in this study were derived from the TRACERx cohort that is described in full in the accompanying studies [54][55][56] . Data obtention followed similar steps to those previously described 57 .…”
Section: Tracerx Rna-seq Cohortmentioning
confidence: 99%
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“…Second, there are processes in human cells not found in the mouse that may be critical for HT, including the role for APOBEC-mediated hypermutation. Studies of EGFR-mutated LUAD have found APOBEC mutagenesis signatures after treatment with EGFR-targeted therapies ( 11 , 73 , 74 ), and this mutational signature is enriched after HT ( 1 , 61 ). It is unclear whether APOBEC mutations are directly responsible for activating the PI3K signaling pathway, (hypothetically) relieving intolerance of the AT2 cell to Myc ( 1 , 59 , 61 ); however, other studies would suggest that this is possible ( 75 , 76 ).…”
Section: Limitations Of the Studymentioning
confidence: 99%