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From astrocytoma to glioblastoma: a clonal evolution study.

ABSTRACT: Astrocytomas often recur after surgical resection, but the underlying mechanism remains enigmatic. Elucidation of clonal evolution in primary and relapse tumors may provide important information on tumor progression. Here, we examined genetic factors underlying recurrence in a patient with astrocytoma initially diagnosed with World Health Organization (WHO) grade II astrocytoma, who then relapsed with glioblastoma (WHO grade IV) complicated with local anaplastic astrocytoma (WHO grade III). We performed genomic DNA sequencing and data analysis of paired tumor tissue specimens and a peripheral blood sample (control), and used expands software for subclone analysis. A germline NOTCH1 missense mutation was identified in the peripheral blood sample, the primary tumor and the relapse tumor; in addition, we identified a tumor protein p53 (TP53) heterozygous nonsense mutation in the primary tumor and a TP53 homozygous nonsense mutation and an IDH1 heterozygous missense mutation in the relapse tumor. Clonal evolution trees indicated higher heterogeneity in the relapse tumor. Although germline mutations might contribute to the driving force of the primary tumor, aggressive chemotherapy and radiation may apply selective pressure for tumor clonal evolution; furthermore, a total loss of function of gatekeeping genes (TP53) may result in impaired DNA repair and catastrophic chromosomal aberrations.

SUBMITTER: Yang F

PROVIDER: S-EPMC7193157 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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From astrocytoma to glioblastoma: a clonal evolution study.

Yang Fuhua F Zou Yunding Y Gong Qiang Q Chen Jieping J Li Wei-Dong WD Huang Qilin Q

FEBS open bio 20200322 5

Astrocytomas often recur after surgical resection, but the underlying mechanism remains enigmatic. Elucidation of clonal evolution in primary and relapse tumors may provide important information on tumor progression. Here, we examined genetic factors underlying recurrence in a patient with astrocytoma initially diagnosed with World Health Organization (WHO) grade II astrocytoma, who then relapsed with glioblastoma (WHO grade IV) complicated with local anaplastic astrocytoma (WHO grade III). We p ...[more]

PMID: 32069381

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Project description:Anaplastic astrocytoma (AA) and its more aggressive counterpart, glioblastoma multiforme (GBM), are the most common intrinsic brain tumors in adults and are almost universally fatal. A deeper understanding of the molecular relationship of these tumor types is necessary to derive insights into the diagnosis, prognosis, and treatment of gliomas. Although genomewide profiling of expression levels with microarrays can be used to identify differentially expressed genes between these tumor types, comparative studies so far have resulted in gene lists that show little overlap.To achieve a more accurate and stable list of the differentially expressed genes and pathways between primary GBM and AA, we performed a meta-analysis using publicly available genome-scale mRNA data sets. There were four data sets with sufficiently large sample sizes of both GBMs and AAs, all of which coincidentally used human U133 platforms from Affymetrix, allowing for easier and more precise integration of data. After scoring genes and pathways within each data set, we combined the statistics across studies using the nonparametric rank sum method to identify the features that differentiate GBMs and AAs. We found >900 statistically significant probe sets after correction for multiple testing from the >22,000 tested. We also used the rank sum approach to select >20 significant Biocarta pathways after correction for multiple testing out of >175 pathways examined. The most significant pathway was the hypoxia-inducible factor (HIF) pathway. Our analysis suggests that many of the most statistically significant genes work together in a HIF1A/VEGF-regulated network to increase angiogenesis and invasion in GBM when compared to AA.We have performed a meta-analysis of genome-scale mRNA expression data for 289 human malignant gliomas and have identified a list of >900 probe sets and >20 pathways that are significantly different between GBM and AA. These feature lists could be utilized to aid in diagnosis, prognosis, and grade reduction of high-grade gliomas and to identify genes that were not previously suspected of playing an important role in glioma biology. More generally, this approach suggests that combined analysis of existing data sets can reveal new insights and that the large amount of publicly available cancer data sets should be further utilized in a similar manner.

Project description:BACKGROUND:Glioblastoma (GBM) is the most common malignant brain cancer occurring in adults, and is associated with dismal outcome and few therapeutic options. GBM has been shown to predominantly disrupt three core pathways through somatic aberrations, rendering it ideal for precision medicine approaches. METHODS:We describe a 35-year-old female patient with recurrent GBM following surgical removal of the primary tumour, adjuvant treatment with temozolomide and a 3-year disease-free period. Rapid whole-genome sequencing (WGS) of three separate tumour regions at recurrence was carried out and interpreted relative to WGS of two regions of the primary tumour. RESULTS:We found extensive mutational and copy-number heterogeneity within the primary tumour. We identified a TP53 mutation and two focal amplifications involving PDGFRA, KIT and CDK4, on chromosomes 4 and 12. A clonal IDH1 R132H mutation in the primary, a known GBM driver event, was detectable at only very low frequency in the recurrent tumour. After sub-clonal diversification, evidence was found for a whole-genome doubling event and a translocation between the amplified regions of PDGFRA, KIT and CDK4, encoded within a double-minute chromosome also incorporating miR26a-2. The WGS analysis uncovered progressive evolution of the double-minute chromosome converging on the KIT/PDGFRA/PI3K/mTOR axis, superseding the IDH1 mutation in dominance in a mutually exclusive manner at recurrence, consequently the patient was treated with imatinib. Despite rapid sequencing and cancer genome-guided therapy against amplified oncogenes, the disease progressed, and the patient died shortly after. CONCLUSION:This case sheds light on the dynamic evolution of a GBM tumour, defining the origins of the lethal sub-clone, the macro-evolutionary genomic events dominating the disease at recurrence and the loss of a clonal driver. Even in the era of rapid WGS analysis, cases such as this illustrate the significant hurdles for precision medicine success.

Project description:BackgroundFollicular lymphoma (FL) is an indolent, yet incurable B cell malignancy. A subset of patients experience an increased mortality rate driven by two distinct clinical end points: histological transformation and early progression after immunochemotherapy. The nature of tumor clonal dynamics leading to these clinical end points is poorly understood, and previously determined genetic alterations do not explain the majority of transformed cases or accurately predict early progressive disease. We contend that detailed knowledge of the expansion patterns of specific cell populations plus their associated mutations would provide insight into therapeutic strategies and disease biology over the time course of FL clinical histories.Methods and findingsUsing a combination of whole genome sequencing, targeted deep sequencing, and digital droplet PCR on matched diagnostic and relapse specimens, we deciphered the constituent clonal populations in 15 transformation cases and 6 progression cases, and measured the change in clonal population abundance over time. We observed widely divergent patterns of clonal dynamics in transformed cases relative to progressed cases. Transformation specimens were generally composed of clones that were rare or absent in diagnostic specimens, consistent with dramatic clonal expansions that came to dominate the transformation specimens. This pattern was independent of time to transformation and treatment modality. By contrast, early progression specimens were composed of clones that were already present in the diagnostic specimens and exhibited only moderate clonal dynamics, even in the presence of immunochemotherapy. Analysis of somatic mutations impacting 94 genes was undertaken in an extension cohort consisting of 395 samples from 277 patients in order to decipher disrupted biology in the two clinical end points. We found 12 genes that were more commonly mutated in transformed samples than in the preceding FL tumors, including TP53, B2M, CCND3, GNA13, S1PR2, and P2RY8. Moreover, ten genes were more commonly mutated in diagnostic specimens of patients with early progression, including TP53, BTG1, MKI67, and XBP1.ConclusionsOur results illuminate contrasting modes of evolution shaping the clinical histories of transformation and progression. They have implications for interpretation of evolutionary dynamics in the context of treatment-induced selective pressures, and indicate that transformation and progression will require different clinical management strategies.

Dataset Information

From astrocytoma to glioblastoma: a clonal evolution study.

Publications

From astrocytoma to glioblastoma: a clonal evolution study.

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