Glioblastoma adaptation traced through decline of an IDH1 clonal driver and macro-evolution of a double-minute chromosome

Favero, Francesco; McGranahan, Nicholas; Salm, Maximilian P; Sanborn, J. Zachary; Benz, Stephen C.; Becq, Jennifer; Peden, John F.; Kingsbury, Zoya; Grocok, R. J.; Humphray, Sean; Spencer‐Dene, Bradley; Gutteridge, Alice; Brada, Michael; Roger, Sébastien; Dietrich, Pierre‐Yves; Forshew, Tim; Gerlinger, Marco; Rowan, Andrew; Stamp, Gordon; Eklund, Aron C.; Szállási, Zoltán; Swanton, Charles

doi:10.1093/annonc/mdv127

Cited by 49 publications

(35 citation statements)

References 24 publications

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“…Viral integration analysis was performed by BamBam [21,22] by two co-authors (CV and ZS). Sequence was aligned using bwa [23], marked for duplicates using superDeDuper [24], and GATK [25] was used for indel realignment and quality recalibration (see supplemental data for details).…”

Section: Viral Integrationmentioning

confidence: 99%

Polyoma virus-associated carcinomas of the urologic tract: a clinicopathologic and molecular study

Sirohi

Vaske²,

Sanborn³

et al. 2018

Modern Pathology

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In recent years, there has been increased interest in carcinomas of the urologic tract, that demonstrate association with the polyoma virus BK arising in immunosuppressed individuals, though the nature of this association is uncertain. To begin to understand this phenomenon, we reviewed the clinical, morphological, and immunohistochemical features of 11 carcinomas of the urologic tract, mainly urothelial (N = 9) and collecting duct carcinomas (N = 2), occurring during immunosuppression, and expressing polyoma virus T-antigen by immunohistochemistry. These were compared to a control group of carcinomas (N = 8), also arising during immunosuppression, but without T-antigen expression. A subset of both groups were also studied by hybrid capture-based DNA sequencing, probing not only for 479 cancer-related human genes, but also for polyoma and other viral sequences. Polyoma T-antigen-expressing tumors arose in 7 males and 4 females, at a median age of 66, and were aggressive, high-grade tumors with more than 1 variant morphologic pattern identified in 81% of cases, and a majority (73%) presenting at high stage category (>pT3). Diffuse polyoma T-antigen staining was seen in 91% of cases, with co-localization of aberrant p53 staining in 89%. Sequencing detected a lower number of deleterious mutations among T-antigen-expressing cases (average 1.62; 1/8 with TP53 mutation) compared to control cases (average 3.5, 2/4 with TP53 mutation). Only BK virus was detected with clonal integration and breakpoints randomly distributed across the human and viral genomes in 5/5 of the polyoma T-antigen-expressing carcinomas, and in none of the controls (0/4). In summary, these findings identify aggressive clinicopathologic features of polyoma T-antigen-expressing carcinomas, document BK as the strain involved, and associate BK viral integration with T-antigen expression and p53 aberrancy. While the apparent randomness of viral insertion sites is functionally unclear, the differing rates of mutations between T-antigen-expressing and control cases is intriguing.

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Section: Viral Integrationmentioning

confidence: 99%

Polyoma virus-associated carcinomas of the urologic tract: a clinicopathologic and molecular study

Sirohi

Vaske²,

Sanborn³

et al. 2018

Modern Pathology

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“…16 Similarly, a positive correlation between intratumoral heterogeneity and tumor grade and a negative correlation between intratumoral heterogeneity and patient survival have been shown in gliomas. 14 Furthermore, newly developed sequencing technologies have demonstrated some of the clonal changes seen between initial and recurrent tumors in low-grade glioma, 17,[18][19][20][21] and other tumor types. 22 The biological and therapeutic implications of intratumoral heterogeneity have recently been reviewed.…”

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confidence: 99%

Detailed longitudinal sampling of glioma stem cells in situ reveals Chr7 gain and Chr10 loss as repeated events in primary tumor formation and recurrence

Baysan

Woolard

Cam

et al. 2017

Intl Journal of Cancer

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Intratumoral heterogeneity at the genetic, epigenetic, transcriptomic, and morphologic levels is a commonly observed phenomenon in many aggressive cancer types. Clonal evolution during tumor formation and in response to therapeutic intervention can be predicted utilizing reverse engineering approaches on detailed genomic snapshots of heterogeneous patient tumor samples. In this study, we developed an extensive dataset for a GBM case via the generation of polyclonal and monoclonal glioma stem cell lines from initial diagnosis, and from multiple sections of distant tumor locations of the deceased patient's brain following tumor recurrence. Our analyses revealed the tissue-wide expansion of a new clone in the recurrent tumor and chromosome 7 gain and chromosome 10 loss as repeated genomic events in primary and recurrent disease. Moreover, chromosome 7 gain and chromosome 10 loss produced similar alterations in mRNA expression profiles in primary and recurrent tumors despite possessing other highly heterogeneous and divergent genomic alterations between the tumors. We identified ETV1 and CDK6 as putative candidate genes, and NFKB (complex), IL1B, IL6, Akt and VEGF as potential signaling regulators, as potentially central downstream effectors of chr7 gain and chr10 loss. Finally, the differences caused by the transcriptomic shift following gain of chromosome 7 and loss of chromosome 10 were consistent with those generally seen in GBM samples compared to normal brain in large-scale patient-tumor data sets.

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“…1; TABLE 1) could more gen erally remove redundant or unnecessary functions, such as activities of the cancer progenitor cell that no longer serve any 'use ful' purpose for the cancer, or even passenger mutations 34 that were once selectively neutral but became deleterious. There is a case report in the literature of apparent loss of a driver mutation as a cancer progresses, as exempli fied by a pathogenic mutation in isocitrate dehydrogenase 1 (IDH1) in a posttreatment glioblastoma 35 . Furthermore, the high fre quency of inactivating somatic mutations in some genes with a role in differentiated cells and no plausible role in carcinogenesis 2 may not always reflect factors like the large size of some of these genes and their tolerance of mutations, but instead may reflect a non trivial benefit to the cell, as it no longer has to make the proteins encoded by these genes.…”

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confidence: 99%

The mini-driver model of polygenic cancer evolution

2015

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Much of cancer genetics research has focused on the identification of the most-important somatic mutations ('major drivers') that cause tumour growth. However, many mutations found in cancer might not be major drivers or 'passenger' mutations, but instead might have relatively weak tumour-promoting effects. Our aim is to highlight the existence of these mutations (termed 'mini drivers' herein), as multiple mini-driver mutations might substitute for a major-driver change, especially in the presence of genomic instability or high mutagen exposure. The mini-driver model has clinical implications: for example, the effects of therapeutically targeting such genes may be limited. However, the main importance of the model lies in helping to provide a complete understanding of tumorigenesis, especially as we anticipate that an increasing number of mini-driver mutations will be found by cancer genome sequencing.

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Glioblastoma adaptation traced through decline of an IDH1 clonal driver and macro-evolution of a double-minute chromosome

Cited by 49 publications

References 24 publications

Polyoma virus-associated carcinomas of the urologic tract: a clinicopathologic and molecular study

Polyoma virus-associated carcinomas of the urologic tract: a clinicopathologic and molecular study

Detailed longitudinal sampling of glioma stem cells in situ reveals Chr7 gain and Chr10 loss as repeated events in primary tumor formation and recurrence

The mini-driver model of polygenic cancer evolution

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