Copy number alterations assessed at the single-cell level revealed mono- and polyclonal seeding patterns of distant metastasis in a small-cell lung cancer patient

Ferronika, Paranita; Bos, van den H.; Taudt, Aaron; Spierings, Diana C.J.; Saber, Aly; Hiltermann, T Jeroen N; Kok, Klaas; Porubský, David; Wekken, Anthonie J. van der; Timens, Wim; Foijer, Floris; Colomé-Tatché, Maria; Groen, Harry J.M.; Lansdorp, Peter M; Berg, van den Anke

doi:10.1093/annonc/mdx182

Cited by 20 publications

(12 citation statements)

References 5 publications

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“…Thus, M4 seemed derived from the same tumour subclone as the previously developed metastases. The existence of such clones, including very small ones, in different types of cancer matching the distant metastasis profile, was demonstrated by single-cell sequencing experiments including some by our group [19].…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Profiling of Primary and Metastatic ccRCC Reveals a High Homology of the Metastases to a Subregion of the Primary Tumour

Ferronika

Hof

Kats-Ugurlu

et al. 2019

Cancers

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While intratumour genetic heterogeneity of primary clear cell renal cell carcinoma (ccRCC) is well characterized, the genomic profiles of metastatic ccRCCs are seldom studied. We profiled the genomes and transcriptomes of a primary tumour and matched metastases to better understand the evolutionary processes that lead to metastasis. In one ccRCC patient, four regions of the primary tumour, one region of the thrombus in the inferior vena cava, and four lung metastases (including one taken after pegylated (PEG)-interferon therapy) were analysed separately. Each sample was analysed for copy number alterations and somatic mutations by whole exome sequencing. We also evaluated gene expression profiles for this patient and 15 primary tumour and 15 metastasis samples from four additional patients. Copy number profiles of the index patient showed two distinct subgroups: one consisted of three primary tumours with relatively minor copy number changes, the other of a primary tumour, the thrombus, and the lung metastases, all with a similar copy number pattern and tetraploid-like characteristics. Somatic mutation profiles indicated parallel clonal evolution with similar numbers of private mutations in each primary tumour and metastatic sample. Expression profiling of the five patients revealed significantly changed expression levels of 57 genes between primary tumours and metastases, with enrichment in the extracellular matrix cluster. The copy number profiles suggest a punctuated evolution from a subregion of the primary tumour. This process, which differentiated the metastases from the primary tumours, most likely occurred rapidly, possibly even before metastasis formation. The evolutionary patterns we deduced from the genomic alterations were also reflected in the gene expression profiles.

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Section: Discussionmentioning

confidence: 99%

Comprehensive Profiling of Primary and Metastatic ccRCC Reveals a High Homology of the Metastases to a Subregion of the Primary Tumour

Ferronika

Hof

Kats-Ugurlu

et al. 2019

Cancers

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“…Moreover, mutation profiling detected in 14 paired primary and metastatic tumors of TKI‐naive samples showed that 13 of 14 (92.9%) pairs had identical mutational status. However, higher HS values of KRAS , HER2 , and PIK3CA were observed in metastatic tumors than in unpaired primary tumors, and heterogeneity between primary and metastatic tumors in copy‐number alterations may partly contribute to the differences (Ferronika et al ., ; Sveen et al ., ). Together, these data indicate that although some genes may be involved in clonal divergence, the use of archived primary tumor in molecular diagnosis is feasible to identify the driver mutations of lung adenocarcinoma.…”

Section: Discussionmentioning

confidence: 97%

Subjecting appropriate lung adenocarcinoma samples to next‐generation sequencing‐based molecular testing: challenges and possible solutions

Qiu

Ling

et al. 2018

Molecular Oncology

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Next‐generation sequencing (NGS) has recently been rapidly adopted in the molecular diagnosis of cancer, but it still faces some obstacles. In this study, 665 lung adenocarcinoma samples (558 TKI‐naive and 107 TKI‐relapsed samples) were interrogated using NGS, and the challenges and possible solutions of subjecting appropriate tissue samples to NGS testing were explored. The results showed that lower frequencies of HER2/BRAF/PIK3CA and acquired EGFR T790M mutations were observed in biopsy samples with <20% tumor cellularity than in those with ≥20%, but there were no significant differences in the frequencies of EGFR or KRAS mutations. Moreover, tumor heterogeneity was assessed by heterogeneity score (HS), which was calculated through multiplying by 2 the mutant allele frequency (MAF) of tumor cells. In TKI‐naive samples, intratumor heterogeneity could occur in EGFR,KRAS,HER2,BRAF, and PIK3CA mutant tumors, but the degree was variable. Higher EGFR, but lower BRAF and PIK3CA HS values were observed compared with KRAS HS. In TKI‐relapsed samples, analysis of concomitant sensitizing EGFR and T790M MAFs showed that intratumor heterogeneity was common in acquired EGFR T790M mutant tumors. The mutational status between primary and metastatic tumors was usually concordant, but KRAS,HER2, and PIK3CA HS were significantly higher in metastatic tumors than in primary tumors. Additionally, the discordance rate of mutational status in multifocal lung adenocarcinomas diagnosed as equivocal or multiple primary tumors was high. Together, our findings demonstrate that a comprehensive quality assessment is necessary during tissue process to mitigate the challenges of poor tumor cellularity, tumor heterogeneity, and multifocal clonally independent tumors.

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“…Tumor heterogeneity is another challenge in using CRISPR/Cas9 technology as a therapeutic tool in cancer patients. Tumors usually contain one or more dominant clones and several minor subclones [7,74,75]. When patients are treated with a specific drug, tumor cell populations go through selection pressure.…”

Section: Discussionmentioning

confidence: 99%

CRISPR/Cas9 for overcoming drug resistance in solid tumors

et al. 2019

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Objectives In this review, we focus on the application of clustered regularly interspaced short palindromic repeats (CRISPR)/ CRISPR associated nuclease 9 (Cas9), as a powerful genome editing system, in the identification of resistance mechanisms and in overcoming drug resistance in the most frequent solid tumors. Data acquisition Data were collected by conducting systematic searching of scientific English literature using specific keywords such as Bcancer^, BCRISPR^and related combinations. Results The review findings revealed the importance of CRISPR/Cas9 system in understanding drug resistance mechanisms and identification of resistance-related genes such as PBRM1, SLFN11 and ATPE1 in different cancers. We also provided an overview of genes, including RSF1, CDK5, and SGOL1, whose disruption can synergize with the currently available drugs such as paclitaxel and sorafenib. Conclusion The data suggest CRISPR/Cas9 system as a useful tool in elucidating the molecular basis of drug resistance and improving clinical outcomes.

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Copy number alterations assessed at the single-cell level revealed mono- and polyclonal seeding patterns of distant metastasis in a small-cell lung cancer patient

Abstract: Differential protein stability and clinical responses of EML4-ALKfusion variants to various ALK inhibitors in advanced ALK-rearranged non-small cell lung cancer.

Cited by 20 publications

References 5 publications

Comprehensive Profiling of Primary and Metastatic ccRCC Reveals a High Homology of the Metastases to a Subregion of the Primary Tumour

Comprehensive Profiling of Primary and Metastatic ccRCC Reveals a High Homology of the Metastases to a Subregion of the Primary Tumour

Subjecting appropriate lung adenocarcinoma samples to next‐generation sequencing‐based molecular testing: challenges and possible solutions

CRISPR/Cas9 for overcoming drug resistance in solid tumors

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