Clone copy number diversity is linked to survival in lung cancer
- Piotr Pawlik
- Kristiana Grigoriadis
- Abigail Bunkum
- Helena Coggan
- Alexander M. Frankell
- Carlos Martínez-Ruiz
- Takahiro Karasaki
- Ariana Huebner
- Andrew Rowan
- Jasmin Fisher
- Allan Hackshaw
- Charles Swanton
- Simone Zaccaria
- Nicholas McGranahan
2025-08-13
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 methods 1–4 . 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 tumours 5,6 , 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.