Evolutionary trajectories of small cell lung cancer under therapy
Research output: Contribution to journal › Research article › Contributed › peer-review
Contributors
Abstract
The evolutionary processes that underlie the marked sensitivity of small cell lung cancer (SCLC) to chemotherapy and rapid relapse are unknown1–3. Here we determined tumour phylogenies at diagnosis and throughout chemotherapy and immunotherapy by multiregion sequencing of 160 tumours from 65 patients. Treatment-naive SCLC exhibited clonal homogeneity at distinct tumour sites, whereas first-line platinum-based chemotherapy led to a burst in genomic intratumour heterogeneity and spatial clonal diversity. We observed branched evolution and a shift to ancestral clones underlying tumour relapse. Effective radio- or immunotherapy induced a re-expansion of founder clones with acquired genomic damage from first-line chemotherapy. Whereas TP53 and RB1 alterations were exclusively part of the common ancestor, MYC family amplifications were frequently not constituents of the founder clone. At relapse, emerging subclonal mutations affected key genes associated with SCLC biology, and tumours harbouring clonal CREBBP/EP300 alterations underwent genome duplications. Gene-damaging TP53 alterations and co-alterations of TP53 missense mutations with TP73, CREBBP/EP300 or FMN2 were significantly associated with shorter disease relapse following chemotherapy. In summary, we uncover key processes of the genomic evolution of SCLC under therapy, identify the common ancestor as the source of clonal diversity at relapse and show central genomic patterns associated with sensitivity and resistance to chemotherapy.
Details
Original language | English |
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Pages (from-to) | 880-889 |
Number of pages | 10 |
Journal | Nature |
Volume | 627 |
Issue number | 8005 |
Publication status | Published - 28 Mar 2024 |
Peer-reviewed | Yes |
External IDs
PubMed | 38480884 |
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Keywords
Sustainable Development Goals
ASJC Scopus subject areas
Keywords
- Genes, myc/genetics, Recurrence, Platinum/pharmacology, Humans, Middle Aged, Male, Drug Resistance, Neoplasm/drug effects, Neoplasm Recurrence, Local/genetics, Small Cell Lung Carcinoma/genetics, Lung Neoplasms/genetics, Animals, Immunotherapy, Female, Mice, Clone Cells/drug effects, Mutation, Evolution, Molecular