Mutation frequency and copy number alterations determine prognosis and metastatic tropism in 60,000 clinical cancer samples

Abstract

AbstractThe intricate interplay between somatic mutations and copy number alterations critically influences tumour evolution and patient prognosis. Traditional genomic studies often overlook this interplay by analysing these two biomarker types in isolation. Leveraging an innovative computational model capable of detecting allele-specific copy number alterations from clinical targeted panels without matched normal, we conducted a comprehensive analysis of over 500,000 mutations across 60,000 clinical samples spanning 39 cancer types. Our findings uncovered 11 genes and 6 hotspots exhibiting recurrent tumour-specific patterns of co-existing mutations and copy-number alterations across 17 tumours. By stratifying more than 24,000 patients based on these composite genotypes across multiple oncogenes and tumour suppressor genes, we identified 66 groups with distinct prognostic significance, 25% more than using a standard mutation-centric stratification. Notably, 7 groups displayed a heightened propensity for metastasis, while 16 were associated with site-specific patterns of metastatic dissemination. This augmented insight into genomic drivers enhances our understanding of cancer progression and metastasis, holding the potential to significantly foster biomarker discovery.Statement of significanceBy leveraging large datasets and new computational modelling, this study demonstrates the critical interplay between somatic mutations and copy number alterations in driving patient prognosis, tumour progression and metastatic tropism. This work implies a shift towards a more integrative and comprehensive approach in clinical sequencing, with significant implications for biomarker discovery and target identification.