Abstract
Chromosome arm aneuploidies (CAAs) are pervasive in cancers. However, how they affect cancer development, prognosis and treatment remains largely unknown. Here, we analyse CAA profiles of 23,427 tumours, identifying aspects of tumour evolution including probable orders in which CAAs occur and CAAs predicting tissue-specific metastasis. Both haematological and solid cancers initially gain chromosome arms, while only solid cancers subsequently preferentially lose multiple arms. 72 CAAs and 88 synergistically co-occurring CAA pairs multivariately predict good or poor survival for 58% of 6977 patients, with negligible impact of whole-genome doubling. Additionally, machine learning identifies 31 CAAs that robustly alter response to 56 chemotherapeutic drugs across cell lines representing 17 cancer types. We also uncover 1024 potential synthetic lethal pharmacogenomic interactions. Notably, in predicting drug response, CAAs substantially outperform mutations and focal deletions/amplifications combined. Thus, CAAs predict cancer prognosis, shape tumour evolution, metastasis and drug response, and may advance precision oncology.
Highlights
Chromosome arm aneuploidies (CAAs) are pervasive in cancers
We found that chromosome arm-level aneuploidies (CAAs) burden is higher in whole-genome doubling (WGD)-positive (WGD+) samples than in WGD-negative (WGD−) samples, increased CAA burden in solid cancers compared to haematological malignancies is independent of WGD status (Supplementary Fig. 2a, b)
Several studies have previously studied CAAs across multiple cancer types[15,16,17]. These revealed that CAAs are common in cancers, yet they are tumour type-specific, and CAA burden is associated with TP53 mutations, cell proliferation, cell cycle gene expression and low levels of tumour-infiltrating immune cells
Summary
Chromosome arm aneuploidies (CAAs) are pervasive in cancers. how they affect cancer development, prognosis and treatment remains largely unknown. A recent landmark study identified a large number of mutations and focal SCNA-drug interactions across many cancer types[21]. Such associations between focal SCNAs and drug response may be understood, if the drug target is encoded by a gene located on the focal SCNA. It is possible that more complex pharmacogenomic interactions exist Compared to those of focal SCNAs, the frequencies of chromosome arm-level aneuploidies (CAAs) are about 30 times higher than expected based on the inverse-length distribution of focal SCNAs and this phenomenon is widespread among cancer types[14].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
