Charting genomic heterogeneity in tumours : from bulk to single cell
Tumours do not consist of a single homogeneous population but are complex heterogeneous systems that contain billions of ever-evolving cells with no two tumours being the same. Tumour heterogeneity is present at three levels, 1) inter-patient heterogeneity; 2) intra-patient heterogeneity; and 3) intra-tumour heterogeneity (ITH). Understanding all levels of heterogeneity is crucial for patient prognosis and treatment choice. To this end, we aimed to improve our understanding of all three levels of tumour heterogeneity.
In paper I we investigated the prevalence, type, length, and genomic distribution of 853.218 somatic copy number alterations (SCNAs) across 20.249 tumours belonging to 32 cancer types. Based on the 1) number of SCNAs; 2) percentage of the genome altered; and 3) average SCNA size, we found high levels of inter-patient heterogeneity, both between and within cancer types. We found that specific chromosomes were preferentially lost or gained depending on cancer type. Lastly, we detected co-alterations of key oncogenes and TSGs. Taken together, we provided a comprehensive analysis on SCNAs across many cancer types as a valuable resource for the community.
In paper II we sought to elucidate intra-patient heterogeneity in non-small cell lung cancer (NSCLC) and their matched brain metastasis (BM). We performed shallow wholegenome sequencing (WGS) on 51 primary NSCLC and matched BM, whole exome sequencing on 40 of the pairs, multi-region sequencing of 15 BMs, and shallow WGS on an additional cohort of 115 BMs. We showed that there is significant intra-patient heterogeneity at the SCNA level, with BM samples showing, on average, more SCNAs compared to their matched NSCLC. In contrast, multi-region sequencing of 15 BMs did not show significant ITH at the level of SCNAs. Finally, we identified putative metastatic driver SCNAs and singlenucleotide variants in key tumour suppressor genes (TSGs) and oncogenes.
In paper III we aimed to assess the level of ITH in early localized prostate cancer. We performed organ-wide, multi-region, single-cell DNA sequencing on two prostate midsections. We found transient chromosomal instability (CIN) both in tumour and normal prostate tissue, evidenced by a large number of cells with unique chromosomal (arm) losses and or gains. Furthermore, we found three distinct groups of cells within the prostate: 1) diploid cells; 2) pseudo-diploid cells; and 3) monster cells. We observed an enrichment of diploid cells in normal regions and pseudo-diploid cells in tumour-rich regions, while monster cells were equally distributed over the entire prostate, again suggesting that there were elevated CIN levels across the prostate. Lastly, we detected highly localized subclones that were exclusive to tumour-rich regions and harboured deletions in TSGs that are known to be frequently deleted in prostate cancer.
Taken together, with this thesis, I have contributed to advance the understanding of inter-patient, intra-patient, and intra-tumour heterogeneity.
List of scientific papers
I. Harbers, L. et al. Somatic Copy Number Alterations in Human Cancers: An Analysis of Publicly Available Data From The Cancer Genome Atlas. Frontiers in Oncology. 11, (2021).
https://doi.org/10.3389/fonc.2021.700568
II. Nicoś, M.*, Harbers, L.*, et al. Genomic Profiling Identifies Putative Pathogenic Alterations in NSCLC Brain Metastases. JTO Clinical and Research Reports. 3, (2022). *Equally contributing authors.
https://doi.org/10.1016/j.jtocrr.2022.100435
III. Zhang, N.*, Harbers, L.*, Simonetti, M.*, et al. High clonal diversity and spatial genetic admixture in early prostate cancer and surrounding normal tissue. *Equally contributing auhtors. [Submitted]
History
Defence date
2024-01-12Department
- Department of Microbiology, Tumor and Cell Biology
Publisher/Institution
Karolinska InstitutetMain supervisor
Crosetto, NicolaCo-supervisors
Linnarsson, Sten; Friedländer, MarcPublication year
2023Thesis type
- Doctoral thesis
ISBN
978-91-8017-153-3Number of supporting papers
3Language
- eng