Genetic and non-genetic clonal diversity in cancer evolution

Black, James R.; McGranahan, Nicholas

doi:10.1038/s41568-021-00336-2

Cited by 192 publications

(150 citation statements)

References 174 publications

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“…28,30 This multi-regional variability has been strongly correlated with intrinsic and acquired drug resistance and relapse. 27,31,32 Indeed, consistent with our work, several studies have uncovered extensive ITH of primary CRC as a prognostic factor for metastasis, as well as a predictor of drug resistance. [33][34][35] With regards to ITH of the liver metastasis, our study is among the very few published reports with a strict protocol, enabling the exact identification of metastatic genetic ITH in 56% of patients.…”

Section: Discussionsupporting

confidence: 89%

Proof-of-concept pilot study on comprehensive spatiotemporal intra-patient heterogeneity for colorectal cancer with liver metastasis

Kyrochristos

Glantzounis

Goussia

et al. 2021

Preprint

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Purpose: The mechanisms underlying high drug resistance and relapse rates after multi-modal treatment in patients with colorectal cancer (CRC) and liver metastasis (LM) remain poorly understood. We evaluate the potential translational implications of intra-patient heterogeneity (IPH) comprising primary and matched metastatic intratumor heterogeneity (ITH) coupled with circulating tumor DNA (ctDNA) variability. Patients and methods: According to our IPH-based protocol, 18 eligible patients with CRC-LM, who underwent complete tumor resection after neo-adjuvant treatment, with a total of 122 multi-regional tumor and perioperative liquid biopsies were analyzed via next-generation sequencing (NGS) of a custom 77-gene panel. The primary endpoints were the extent of IPH and the frequency of actionable mutations. Results: The proportion of patients with ITH were 53% and 56% in primary CRC and LM respectively, while 35% of patients harbored de novo mutations in LM indicating spatiotemporal tumor evolution and the necessity of multiregional analysis. Among the 56% of patients with alterations in liquid biopsies, de novo mutations in cfDNA were identified in 25% of patients, which were undetectable in both CRC and LM. All 17 patients with driver alterations harbored actionable mutations, with an average of 3.2 oncogenic events per patient, for molecularly targeted drugs either approved or under evaluation in ongoing clinical trials or in pre-clinical studies. Conclusions: Our proof-of-concept prospective study provides initial evidence and warrants the conduction of precision oncology trials to test the potential clinical utility of IPH-driven matched therapy.

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Section: Discussionsupporting

confidence: 89%

Proof-of-concept pilot study on comprehensive spatiotemporal intra-patient heterogeneity for colorectal cancer with liver metastasis

Kyrochristos

Glantzounis

Goussia

et al. 2021

Preprint

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“…For example, only very recently has the mechanism of selective advantage provided by APC mutation – the gatekeeper mutation for colorectal carcinogenesis discovered more than three decades ago (Kinzler et al, 1991) – been elucidated (Flanagan et al, 2021; Neerven et al, 2021). Moreover, potential epigenetic drivers of subclonal expansions have received comparably little attention, and there are calls for the field to move beyond the genome in the study of intra-tumour heterogeneity (Black and McGranahan, 2021).…”

Section: Introductionmentioning

confidence: 99%

Assessment of the evolutionary consequence of putative driver mutations in colorectal cancer with spatial multiomic data

Heide

Househam

Cresswell

et al. 2021

Preprint

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Cancer genomic medicine relies on targeting driver genes. However, current catalogues of cancer drivers are mostly based on indirect measurements of mutation frequencies, positions or types, rather than their effect on clonal expansions in vivo. Moreover, nongenetic drivers are largely unknown, as are the epigenetic and transcriptomic effects of genetic drivers. Here we perform spatial computational inference on multiomic data with matched whole-genome sequencing, ATAC-seq and RNA-seq. Using 436 samples, we directly quantify the contribution, or lack thereof, of putative driver genes to subclonal expansions in vivo in 30 colorectal carcinomas (4-33 samples per patient, median=15). Although subclonal neutral evolution was widespread (13/26 cases with sufficient data), there were cases with clear evidence of subclonal selection (6/26) in which we measured epigenetic and transcriptomic differences between subclones in vivo. In 7/26 cases we could not distinguish between neutral or selective evolution with the available data. We identified expanding subclones that were not driven by known genetic alterations, and propose candidate epigenetic drivers. We identified the distinguishing patterns of genomic heterogeneity produced in fast, exponentially growing tumours (7/26) versus neoplasms growing only at the periphery (19/26), as well as identifying clonally intermixed (16/28 cases with sufficient data) versus segregated malignancies (10/28). Our model-based approach measures genetic and non-genetic subclonal selection, or lack thereof, in space and time and allows in vivo comparisons of the emergent phenotypic properties of subclones within human tumours.

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“…In the past years, many new strategies for the treatment of ccRCC have emerged, including partial or radical nephrectomy ( 33 ), targeted therapies ( 34 ), or ICTs. It is worth noting that the inherent phenotypic heterogeneity of ccRCC could aggravate tumor invasion, metastasis and drug resistance, and the non-genetic heterogeneity can be transmitted through epigenetic regulation and other mechanisms ( 35 ). Therefore, is an urgent need to construct an epigenetic genomic-based stratification model to analyze the prognosis and TME of ccRCC, thus guiding individual clinical diagnosis and treatment strategies.…”

Section: Discussionmentioning

confidence: 99%

m6A Regulator-Mediated Methylation Modification Model Predicts Prognosis, Tumor Microenvironment Characterizations and Response to Immunotherapies of Clear Cell Renal Cell Carcinoma

Tian

Liu

et al. 2021

Front. Oncol.

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BackgroundThis study aims to establish an N6-methyladenosine (m6A) RNA methylation regulators-mediated methylation model and explore its role in predicting prognostic accuracy of immune contexture and characterizations of clear cell renal cell carcinoma (ccRCC).MethodsThe m6A modification subclasses (m6AMS) were identified by unsupervised cluster analysis and three clusters were determined by consensus clustering algorithm in a discovering cohort. Testing and real-world validation cohorts were used to identify predictive responses for immune checkpoint therapies (ICTs) of m6AMS.ResultsPrognostic implications landscape of m6A regulators in cancers and its differential expression levels in ccRCC patients were identified. Based on discovering cohort, ccRCC were automatically divided into three m6AMS, and cluster 3 showed significant worse survival than cluster 1/2. Importantly, it was found that the immune checkpoint molecules expression was significantly elevated in cluster 3. Besides, m6A scoreLow group (cluster 1&2) have significantly elevated TIDE score compared with m6A scoreHigh group (cluster 3). There was conspicuous tertiary lymphoid tissue, aggressive phenotype, elevated glycolysis, expression of PD-L1, abundance of CD8+ T cells, CD4+ FOXP3+ Treg cells and TCRn immune cells infiltration in the high m6A score group. Interestingly, there are significantly increased patients with clinical benefit in m6A scoreHigh group in 368 patients receiving ICTs from testing IMvigor210 (n = 292) and validation FUSCC (n = 55) cohorts.ConclusionOur discovery highlights the relationship between tumor epigenetic heterogeneity and immune contexture. Immune-rejection cluster 3 has pro-tumorigenic immune infiltration, and shows significant clinical benefits for ccRCC patients receiving ICTs, enabling patient selection for future clinical treatment.

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Genetic and non-genetic clonal diversity in cancer evolution

Cited by 192 publications

References 174 publications

Proof-of-concept pilot study on comprehensive spatiotemporal intra-patient heterogeneity for colorectal cancer with liver metastasis

Proof-of-concept pilot study on comprehensive spatiotemporal intra-patient heterogeneity for colorectal cancer with liver metastasis

Assessment of the evolutionary consequence of putative driver mutations in colorectal cancer with spatial multiomic data

m6A Regulator-Mediated Methylation Modification Model Predicts Prognosis, Tumor Microenvironment Characterizations and Response to Immunotherapies of Clear Cell Renal Cell Carcinoma

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