Genomic characterization of pediatric T-cell acute lymphoblastic leukemia reveals novel recurrent driver mutations

Spinella, Jean-François; Cassart, Pauline; Richer, Chantal; Saillour, Virginie; Ouimet, Manon; Langlois, Sylvie; St-Onge, Pascal; Sontag, Thomas; Healy, Jasmine; Minden, Mark D.; Sinnett, Daniel

doi:10.18632/oncotarget.11796

Cited by 50 publications

(48 citation statements)

References 114 publications

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“…Interestingly, nearly 60% of MED12 mutations were identified from immature T‐ALL cases, suggesting that pediatric T‐ALLs harbor genomic complexity. Identifying early disease‐driven mutations will help to stratify patients for personalized treatments . In chronic lymphocytic leukemia (CLL), N‐terminal MED12 mutations were identified with a frequency of 5.2% (37 of 709 patients), 6.9% (12 of 188 patients), and 8.8% (10 110 patients) in 3 independent studies .…”

Section: Med12 Mutations In Human Cancersmentioning

confidence: 99%

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The emerging role of mediator complex subunit 12 in tumorigenesis and response to chemotherapeutics

Zhang

O’Regan

2019

Cancer

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Transcriptional dysregulation induced by disease‐defining genetic alterations of proteins in transcriptional machinery is a key feature of cancers. Mediator complex subunit 12 (MED12) is the central architectural subunit in the kinase module of Mediator, a large transcriptional regulatory complex that controls essential steps of transcription. Emerging evidence links deregulated MED12 to human cancers. MED12 is frequently mutated in benign tumors and cancers. Although the missense mutations of MED12 in benign tumors disrupt the kinase activity of Mediator, MED12 mutations in cancers could eliminate the interaction between Mediator complex and RNA polymerase II, leading to severe transcriptional misregulation. Aberrant expression of MED12 is associated with the prognosis of various types of human cancers. Loss of MED12 function has been associated with the development of resistance to chemotherapeutics. Moreover, MED12 is modified by posttranscriptional regulations. Arginine methylation of MED12 has been shown to regulate MED12‐mediated transcriptional regulation and response to chemotherapeutics in human cancer cell lines. In this mini‐review, the authors provide an overview of the roles of MED12 in the development of benign and malignant tumors as well as its roles in chemoresistance. The studies of MED12 exemplify that aberrant transcriptional programming is a therapeutic vulnerability for certain types of cancer.

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Section: Med12 Mutations In Human Cancersmentioning

confidence: 99%

“…MED12 expression is also strongly associated with the sensitivity of leukemia to chemotherapeutics. In Jurkat leukemia cells, loss of MED12 prevented cells from entering apoptosis after chemotherapy …”

Section: Deregulation Of Med12 Expression In Human Cancersmentioning

confidence: 99%

The emerging role of mediator complex subunit 12 in tumorigenesis and response to chemotherapeutics

Zhang

O’Regan

2019

Cancer

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“…Variants were prioritized as previously described. 23 See supplemental Data ("Variant annotation and prioritization of cancer driver gene mutations") for details.…”

Section: Genome Sequencing and Variant Identificationmentioning

confidence: 99%

Mutational dynamics of early and late relapsed childhood ALL: rapid clonal expansion and long-term dormancy

et al. 2018

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Key Points• Two distinct evolutionary patterns govern early and late relapse.• Evolutionary patterns suggest a mutationdriven resistance for early relapses and a reexpansion of dormant cells for late ones.Childhood acute lymphoblastic leukemia (cALL) is the most frequent pediatric cancer.Refractory/relapsed cALL presents a survival rate of ;45% and is still one of the leading causes of death by disease among children. Mechanisms, such as clonal competition and evolutionary adaptation, govern treatment resistance. However, the underlying clonal dynamics leading to multiple relapses and differentiating early (,36 months postdiagnosis) from late relapse events remain elusive. Here, we use an integrative genome-based analysis combined with serial sampling of relapsed tumors (from primary tumor to #4 relapse events) from 19 pre-B-cell cALL patients (8 early and 11 late relapses) to assess the fitness of somatic mutations and infer their ancestral relationships. By quantifying both general clonal dynamics and newly acquired subclonal diversity, we show that 2 distinct evolutionary patterns govern early and late relapse: on one hand, a highly dynamic pattern, sustained by a putative defect of DNA repair processes, illustrating the quick emergence of fitter clones, and on the other hand, a quasi-inert evolution pattern, suggesting the escape from dormancy of leukemia stem cells likely spared from initial cytoreductive therapy.These results offer new insights into cALL relapse mechanisms and highlight the pressing need for adapted treatment strategies to circumvent resistance mechanisms.

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“…Sensitive calling algorithms such as SNooPer that is tailored around the data, will thus be indispensable to weed out true somatic variants and identify potential driver mutations or actionable targets. SNooPer was developed in response to this need and has already proven its utility in identifying novel mutations in childhood leukemia [45–47]. …”

Section: Resultsmentioning

confidence: 99%

SNooPer: a machine learning-based method for somatic variant identification from low-pass next-generation sequencing

et al. 2016

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BackgroundNext-generation sequencing (NGS) allows unbiased, in-depth interrogation of cancer genomes. Many somatic variant callers have been developed yet accurate ascertainment of somatic variants remains a considerable challenge as evidenced by the varying mutation call rates and low concordance among callers. Statistical model-based algorithms that are currently available perform well under ideal scenarios, such as high sequencing depth, homogeneous tumor samples, high somatic variant allele frequency (VAF), but show limited performance with sub-optimal data such as low-pass whole-exome/genome sequencing data. While the goal of any cancer sequencing project is to identify a relevant, and limited, set of somatic variants for further sequence/functional validation, the inherently complex nature of cancer genomes combined with technical issues directly related to sequencing and alignment can affect either the specificity and/or sensitivity of most callers.ResultsFor these reasons, we developed SNooPer, a versatile machine learning approach that uses Random Forest classification models to accurately call somatic variants in low-depth sequencing data. SNooPer uses a subset of variant positions from the sequencing output for which the class, true variation or sequencing error, is known to train the data-specific model. Here, using a real dataset of 40 childhood acute lymphoblastic leukemia patients, we show how the SNooPer algorithm is not affected by low coverage or low VAFs, and can be used to reduce overall sequencing costs while maintaining high specificity and sensitivity to somatic variant calling. When compared to three benchmarked somatic callers, SNooPer demonstrated the best overall performance.ConclusionsWhile the goal of any cancer sequencing project is to identify a relevant, and limited, set of somatic variants for further sequence/functional validation, the inherently complex nature of cancer genomes combined with technical issues directly related to sequencing and alignment can affect either the specificity and/or sensitivity of most callers. The flexibility of SNooPer’s random forest protects against technical bias and systematic errors, and is appealing in that it does not rely on user-defined parameters. The code and user guide can be downloaded at https://sourceforge.net/projects/snooper/.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3281-2) contains supplementary material, which is available to authorized users.

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Genomic characterization of pediatric T-cell acute lymphoblastic leukemia reveals novel recurrent driver mutations

Cited by 50 publications

References 114 publications

The emerging role of mediator complex subunit 12 in tumorigenesis and response to chemotherapeutics

The emerging role of mediator complex subunit 12 in tumorigenesis and response to chemotherapeutics

Mutational dynamics of early and late relapsed childhood ALL: rapid clonal expansion and long-term dormancy

SNooPer: a machine learning-based method for somatic variant identification from low-pass next-generation sequencing

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