ABSTRACT
Survival rates of cancer patients vary widely within and between malignancies. While genetic aberrations are at the root of all cancers, individual genomic features cannot explain these distinct disease outcomes. In contrast, intra-tumour heterogeneity (ITH) has the potential to elucidate pan-cancer survival rates and the biology that drives cancer prognosis. Unfortunately, a comprehensive and effective framework to measure ITH across cancers is missing. Here, we introduce a scalable measure of chromosomal copy number heterogeneity (CNH) that predicts patient survival across cancers. We show that the level of ITH can be derived from a single-sample copy number profile. Using gene-expression data and live cell imaging we demonstrate that ongoing chromosomal instability underlies the observed heterogeneity. Analysing 11,534 primary cancer samples from 37 different malignancies, we find that copy number heterogeneity can be accurately deduced and predicts cancer survival across tissues of origin and stages of disease. Our results provide a unifying molecular explanation for the different survival rates observed between cancer types.
Subject(s)
DNA Copy Number Variations , Genetic Heterogeneity , Models, Genetic , Neoplasms/mortality , Tumor Microenvironment/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Child , Computer Simulation , Datasets as Topic , Female , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Genomics , Humans , Male , Middle Aged , Mutation , Neoplasms/genetics , Neoplasms/pathology , Prognosis , Progression-Free Survival , Risk Assessment/methods , Survival Rate , Young AdultABSTRACT
The metastatic process is complex and remains a major obstacle in the management of colorectal cancer. To gain a better insight into the pathology of metastasis, we investigated genomic aberrations in a large cohort of matched colorectal cancer primaries and distant metastases from various sites by high resolution array comparative genomic hybridization. In total, 62 primary colorectal cancers, and 68 matched metastases (22 liver, 11 lung, 12 ovary, 12 omentum, and 11 distant lymph nodes) were analyzed. Public datasets were used for validation purposes. Metastases resemble their matched primary tumors in the majority of the patients. This validates the significant overlap in chromosomal aberrations between primary tumors and corresponding metastases observed previously. We observed 15 statistically significant different regions between the primary tumors and their matched metastases, of which only one recurrent event in metastases was observed. We conclude, based on detailed analysis and large independent datasets, that chromosomal copy number aberrations in colorectal metastases resemble their primary counterparts, and differences are typically non-recurrent.
