Clone copy number diversity is linked to survival in lung cancer

Piotr Pawlik, Kristiana Grigoriadis, Abigail Bunkum, Helena Coggan, Alexander M. Frankell, Carlos Martinez-Ruiz, Takahiro Karasaki, Ariana Huebner, Andrew Rowan, Jasmin Fisher, Allan Hackshaw, Charles Swanton, Simone Zaccaria () and Nicholas McGranahan ()
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Piotr Pawlik: University College London Cancer Institute
Kristiana Grigoriadis: University College London Cancer Institute
Abigail Bunkum: University College London Cancer Institute
Helena Coggan: University College London Cancer Institute
Alexander M. Frankell: University College London Cancer Institute
Carlos Martinez-Ruiz: University College London Cancer Institute
Takahiro Karasaki: University College London Cancer Institute
Ariana Huebner: University College London Cancer Institute
Andrew Rowan: University College London Cancer Institute
Jasmin Fisher: University College London Cancer Institute
Allan Hackshaw: Cancer Research UK & UCL Cancer Trials Centre
Charles Swanton: University College London Cancer Institute
Simone Zaccaria: University College London Cancer Institute
Nicholas McGranahan: University College London Cancer Institute

Nature, 2025, vol. 646, issue 8083, 190-197

Abstract: Abstract Both single nucleotide variants (SNVs) and somatic copy number alterations (SCNAs) accumulate in cancer cells during tumour development, fuelling clonal evolution. However, accurate estimation of clone-specific copy numbers from bulk DNA-sequencing data is challenging. Here we present allele-specific phylogenetic analysis of copy number alterations (ALPACA), a method to infer SNV and SCNA coevolution by leveraging phylogenetic trees reconstructed from multi-sample bulk tumour sequencing data using SNV frequencies. ALPACA estimates the SCNA evolution of simulated tumours with a higher accuracy than current state-of-the-art methods1–4. ALPACA uncovers loss-of-heterozygosity and amplification events in minor clones that may be missed using standard approaches and reveals the temporal order of somatic alterations. Analysing clone-specific copy numbers in TRACERx421 lung tumours5,6, we find evidence of increased chromosomal instability in metastasis-seeding clones and enrichment for losses affecting tumour suppressor genes and amplification affecting CCND1. Furthermore, we identify increased SCNA rates in both tumours with polyclonal metastatic dissemination and tumours with extrathoracic metastases, and an association between higher clone copy number diversity and reduced disease-free survival in patients with lung cancer.

Date: 2025
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DOI: 10.1038/s41586-025-09398-w

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