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Evolutionary trajectories of small cell lung cancer under therapy.
- Source :
-
Nature [Nature] 2024 Mar; Vol. 627 (8005), pp. 880-889. Date of Electronic Publication: 2024 Mar 13. - Publication Year :
- 2024
-
Abstract
- The evolutionary processes that underlie the marked sensitivity of small cell lung cancer (SCLC) to chemotherapy and rapid relapse are unknown <superscript>1-3</superscript> . 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.<br /> (© 2024. The Author(s).)
- Subjects :
- Animals
Female
Humans
Male
Mice
Middle Aged
Clone Cells drug effects
Clone Cells metabolism
Clone Cells pathology
Drug Resistance, Neoplasm drug effects
Drug Resistance, Neoplasm genetics
Genes, myc genetics
Mutation
Neoplasm Recurrence, Local genetics
Neoplasm Recurrence, Local pathology
Recurrence
Evolution, Molecular
Immunotherapy
Lung Neoplasms genetics
Lung Neoplasms immunology
Lung Neoplasms pathology
Lung Neoplasms therapy
Platinum pharmacology
Platinum therapeutic use
Small Cell Lung Carcinoma genetics
Small Cell Lung Carcinoma immunology
Small Cell Lung Carcinoma pathology
Small Cell Lung Carcinoma therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4687
- Volume :
- 627
- Issue :
- 8005
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 38480884
- Full Text :
- https://doi.org/10.1038/s41586-024-07177-7