All Publications

  • Pervasive chromosomal instability and karyotype order in tumour evolution. Nature Watkins, T. B., Lim, E. L., Petkovic, M., Elizalde, S., Birkbak, N. J., Wilson, G. A., Moore, D. A., Gronroos, E., Rowan, A., Dewhurst, S. M., Demeulemeester, J., Dentro, S. C., Horswell, S., Au, L., Haase, K., Escudero, M., Rosenthal, R., Bakir, M. A., Xu, H., Litchfield, K., Lu, W. T., Mourikis, T. P., Dietzen, M., Spain, L., Cresswell, G. D., Biswas, D., Lamy, P., Nordentoft, I., Harbst, K., Castro-Giner, F., Yates, L. R., Caramia, F., Jaulin, F., Vicier, C., Tomlinson, I. P., Brastianos, P. K., Cho, R. J., Bastian, B. C., Dyrskjot, L., Jonsson, G. B., Savas, P., Loi, S., Campbell, P. J., Andre, F., Luscombe, N. M., Steeghs, N., Tjan-Heijnen, V. C., Szallasi, Z., Turajlic, S., Jamal-Hanjani, M., Van Loo, P., Bakhoum, S. F., Schwarz, R. F., McGranahan, N., Swanton, C. 2020


    Chromosomal instability in cancer consists of dynamic changes to the number and structure of chromosomes1,2. The resulting diversity in somatic copy number alterations (SCNAs) may provide the variation necessary for tumour evolution1,3,4. Here we use multi-sample phasing and SCNA analysis of 1,421 samples from 394 tumours across 22tumour types to show that continuous chromosomal instability results in pervasive SCNA heterogeneity. Parallel evolutionary events, which cause disruption in the same genes (such as BCL9,MCL1, ARNT (also known as HIF1B), TERT and MYC) within separate subclones, were present in 37% of tumours. Most recurrent lossesprobably occurred before whole-genome doubling, that was foundas a clonal event in 49% of tumours. However, loss of heterozygosity at the human leukocyte antigen (HLA) locus and loss of chromosome 8p to a single haploid copy recurred at substantial subclonal frequencies, even in tumours with whole-genome doubling, indicating ongoing karyotype remodelling. Focal amplifications that affected chromosomes 1q21 (which encompasses BCL9,MCL1 and ARNT), 5p15.33 (TERT), 11q13.3 (CCND1), 19q12 (CCNE1) and 8q24.1 (MYC) were frequently subclonal yet appeared to be clonal within single samples. Analysis of an independent series of 1,024 metastatic samples revealed that 13 focal SCNAs were enriched in metastatic samples, including gains in chromosome 8q24.1 (encompassing MYC) in clear cell renal cellcarcinoma and chromosome 11q13.3 (encompassing CCND1) in HER2+ breast cancer. Chromosomal instability may enable the continuous selection of SCNAs, which are established as ordered events that often occur in parallel, throughout tumour evolution.

    View details for DOI 10.1038/s41586-020-2698-6

    View details for PubMedID 32879494

  • Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers. Nature genetics Blakely, C. M., Watkins, T. B., Wu, W. n., Gini, B. n., Chabon, J. J., McCoach, C. E., McGranahan, N. n., Wilson, G. A., Birkbak, N. J., Olivas, V. R., Rotow, J. n., Maynard, A. n., Wang, V. n., Gubens, M. A., Banks, K. C., Lanman, R. B., Caulin, A. F., St John, J. n., Cordero, A. R., Giannikopoulos, P. n., Simmons, A. D., Mack, P. C., Gandara, D. R., Husain, H. n., Doebele, R. C., Riess, J. W., Diehn, M. n., Swanton, C. n., Bivona, T. G. 2017; 49 (12): 1693–1704


    A widespread approach to modern cancer therapy is to identify a single oncogenic driver gene and target its mutant-protein product (for example, EGFR-inhibitor treatment in EGFR-mutant lung cancers). However, genetically driven resistance to targeted therapy limits patient survival. Through genomic analysis of 1,122 EGFR-mutant lung cancer cell-free DNA samples and whole-exome analysis of seven longitudinally collected tumor samples from a patient with EGFR-mutant lung cancer, we identified critical co-occurring oncogenic events present in most advanced-stage EGFR-mutant lung cancers. We defined new pathways limiting EGFR-inhibitor response, including WNT/β-catenin alterations and cell-cycle-gene (CDK4 and CDK6) mutations. Tumor genomic complexity increases with EGFR-inhibitor treatment, and co-occurring alterations in CTNNB1 and PIK3CA exhibit nonredundant functions that cooperatively promote tumor metastasis or limit EGFR-inhibitor response. This study calls for revisiting the prevailing single-gene driver-oncogene view and links clinical outcomes to co-occurring genetic alterations in patients with advanced-stage EGFR-mutant lung cancer.

    View details for PubMedID 29106415

    View details for PubMedCentralID PMC5709185