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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 study^2,3. Analyses of 947 tumour regions, representing both primary and metastatic disease, alongside 96 tumour-adjacent normal tissue samples implicate the transcriptome as a major source of phenotypic variation. Gene expression levels and ITH relate to patterns of positive and negative selection during tumour evolution. We observe frequent copy number-independent allele-specific expression that is linked to epigenomic dysfunction. Allele-specific expression can also result in genomic-transcriptomic parallel evolution, which converges on cancer gene disruption. We extract signatures of RNA single-base substitutions and link their aetiology to the activity of the RNA-editing enzymes ADAR and APOBEC3A, thereby revealing otherwise undetected ongoing APOBEC activity in tumours. Characterizing the transcriptomes of primary-metastatic tumour pairs, we combine multiple machine-learning approaches that leverage genomic and transcriptomic variables to link metastasis-seeding potential to the evolutionary context of mutations and increased proliferation within primary tumour regions. These results highlight the interplay between the genome and transcriptome in influencing ITH, lung cancer evolution and metastasis.

SUBMITTER: Martinez-Ruiz C

PROVIDER: S-EPMC10115639 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Genomic-transcriptomic evolution in lung cancer and metastasis.

Martínez-Ruiz Carlos C Black James R M JRM Puttick Clare C Hill Mark S MS Demeulemeester Jonas J Larose Cadieux Elizabeth E Thol Kerstin K Jones Thomas P TP Veeriah Selvaraju S Naceur-Lombardelli Cristina C Toncheva Antonia A Prymas Paulina P Rowan Andrew A Ward Sophia S Cubitt Laura L Athanasopoulou Foteini F Pich Oriol O Karasaki Takahiro T Moore David A DA Salgado Roberto R Colliver Emma E Castignani Carla C Dietzen Michelle M Huebner Ariana A Al Bakir Maise M Tanić Miljana M Watkins Thomas B K TBK Lim Emilia L EL Al-Rashed Ali M AM Lang Danny D Clements James J Cook Daniel E DE Rosenthal Rachel R Wilson Gareth A GA Frankell Alexander M AM de Carné Trécesson Sophie S East Philip P Kanu Nnennaya N Litchfield Kevin K Birkbak Nicolai J NJ Hackshaw Allan A Beck Stephan S Van Loo Peter P Jamal-Hanjani Mariam M Swanton Charles C McGranahan Nicholas N

Nature 20230412 7957

Intratumour heterogeneity (ITH) fuels lung cancer evolution, which leads to immune evasion and resistance to therapy<sup>1</sup>. 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 study<sup>2,3</sup>. Analyses of 947 tumour regions, representing both primary and metastatic disease, alongside 96 tumour-adjacent normal t ...[more]

PMID: 37046093

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Project description:BackgroundWe investigated the biological predisposition to site of metastasis in patients with NSCLC based on their molecular profiling and program death ligand PD-L1 status. We sought to identify any association between metastatic site and molecular profile in NSCLC patients.MethodsThis was a retrospective analysis of patients with stage IV NSCLC who were newly diagnosed from January 2014 to June 2022. Clinical characteristics, pathology, molecular reports, and imaging were retrieved and analyzed.ResultsA total of 143 patients were included in the study. Median age was 65 years, with an equal number of men (n=71) and women (n=72). The most common histology was adenocarcinoma (81.8%). At least one genetic mutation was discovered in 100 patients. Mutations with a targetable drug were found in 86 patients. The most common mutations were TP53 (25.2%), EGFR (24.5%), KRAS/NRAS (20.3%), and CDKN2A/2B (7.7%). Patients with any mutation were significantly more likely to have metastatic disease to the brain (57% vs. 37%, p=0.03), but there was no difference in metastatic disease to bone (34% vs. 26%, p=0.32). Patients without a discoverable mutation were significantly more likely to have metastatic disease to other sites (e.g., adrenal gland 91% vs. liver 66%, p=0.002). There was no difference in progression-free survival (PFS) or overall survival (OS) between those with versus without mutations. Median PFS and OS were significantly longer in patients with an EGFR mutation than those with KRAS/NRAS or TP53 mutations. Patients with PD-L1 >1% or TP53 were significantly more likely to have metastatic disease to organs other than bone or brain (p=0.047 and p=0.023, respectively). We identified four prognostic groups in metastatic NSCLC. Patients with PD-L1 <1% and no actionable mutations have the poorest prognosis, with median survival of around 20 months.ConclusionPatients with mutations discoverable on NGS are more likely to have metastatic disease to the brain. KRAS/NRAS in particular has a predilection to metastasize to the brain and bone. PD-L1 expression and a TP53 mutation, on the other hand, tend to lead to metastasis of NSCLC to organs other than brain or bone. These results need to be corroborated in larger prospective studies.

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Genomic-transcriptomic evolution in lung cancer and metastasis.

Publications

Genomic-transcriptomic evolution in lung cancer and metastasis.

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