A novel independence test for somatic alterations in cancer shows that biology drives mutual exclusivity but chance explains co-occurrence

Canisius, Sander; Martens, John W.M.; Wessels, Lodewyk F.A.

doi:10.1101/052803

Cited by 4 publications

(7 citation statements)

References 49 publications

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“…Mutual exclusivity of various alterations was statistically assessed using the DISCOVER R package (v0.9.3) 41 . All p-values derived from multiple testing were corrected using built-in false discovery rate (FDR).…”

Section: Mutual Exclusivity Analysismentioning

confidence: 99%

“…c, Mutual exclusivity of copy number losses of chromosome arms 17p, 16q, and 8q. Significance was assessed using the impurity test for mutual exclusivity, implemented in the R package DISCOVER 41 .…”

Section: Code Availabilitymentioning

confidence: 99%

“…e, Protein-protein interaction (PPI) network of CBFA2T2 TurboID proteins and G3/G4 MB driver genes (Fig. 1a) using STRING 41 . Edges between CBFA2T2 and diamond-shaped nodes are not drawn for simplicity.…”

Section: Code Availabilitymentioning

confidence: 99%

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Failure of human rhombic lip differentiation underlies medulloblastoma formation

Hendrikse

Haldipur

Saulnier

et al. 2022

Nature

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Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain [1][2][3][4] . Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage [5][6][7][8] . By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL 9,10 . However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage 3,4 . Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental

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Section: Mutual Exclusivity Analysismentioning

confidence: 99%

Section: Code Availabilitymentioning

confidence: 99%

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Failure of human rhombic lip differentiation underlies medulloblastoma formation

Hendrikse

Haldipur

Saulnier

et al. 2022

Nature

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“…We focused on the proportion of genes with mutations in different senescence subtypes, and we compared the differences in the top 10 mutated genes in the three senescence subtypes using the chi-square test. Since existing studies have reported that exclusive or co-occurring somatic changes in cancer can indicate functional interactions, 57,58 we also explored the mutual exclusion or coexistence of genes in three senescence subtypes. According to a previous study, 32 10 canonical signaling pathways consisting of 335 genes were evaluated as oncogenic pathways (Table S4).…”

Section: Mutation Landscape Of Crc Senescence Subtypesmentioning

confidence: 99%

Senescence‐based colorectal cancer subtyping reveals distinct molecular characteristics and therapeutic strategies

Lv,

Cai,

et al. 2023

MedComm

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Cellular senescence has been listed as a hallmark of cancer, but its role in colorectal cancer (CRC) remains unclear. We comprehensively evaluated the transcriptome, genome, digital pathology, and clinical data from multiple datasets of CRC patients and proposed a novel senescence subtype for CRC. Multi‐omics data was used to analyze the biological features, tumor microenvironment, and mutation landscape of senescence subtypes, as well as drug sensitivity and immunotherapy response. The senescence score was constructed to better quantify senescence in each patient for clinical use. Unsupervised learning revealed three transcriptome‐based senescence subtypes. Cluster 1, characterized by low senescence and activated proliferative pathways, was sensitive to chemotherapeutic drugs. Cluster 2, characterized by intermediate senescence and high immune infiltration, exhibited significant immunotherapeutic advantages. Cluster 3, characterized by high senescence, high immune, and stroma infiltration, had a worse prognosis and maybe benefit from targeted therapy. We further constructed a senescence scoring system based on seven senescent genes through machine learning. Lower senescence scores were highly predictive of longer disease‐free survival, and patients with low senescence scores may benefit from immunotherapy. We proposed the senescence subtypes of CRC and our findings provide potential treatment interventions for each CRC senescence subtype to promote precision treatment.

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“…31 Genetic lesion co-occurrences and mutual exclusions were computed using the R package DISCOVER available on Bioconductor with the default parameters. 32…”

Section: Next-generation Sequencing Copy Number and Molecular Analysesmentioning

confidence: 99%

PRC2 loss of function confers a targetable vulnerability to BET proteins in T-ALL

Andrieu

Kohn

Simonin

et al. 2021

Blood

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T-cell acute lymphoblastic leukemia (T-ALL) are aggressive hematological cancers with dismal outcomes, and are in need of new therapeutic options. Polycomb Repressor Complex 2 (PRC2) loss-of-function alterations were reported in pediatric T-ALL; yet their clinical relevance and functional consequences remain elusive. Here, we extensively analyzed PRC2 alterations in a large series of 218 adult T-ALL patients. We found that PRC2 genetic lesions are frequent events in T-ALL and are not restricted to ETP-ALL. PRC2 loss of function associates with activating mutations of the IL7R/JAK/STAT pathway. PRC2-altered T-ALL patients poorly respond to prednisone, have low bone marrow blast clearance, and persistent minimal residual disease. Furthermore, we identified that PRC2 loss of function profoundly reshapes the genetic and epigenetic landscapes, leading to the reactivation of stem cell programs that cooperate with Bromodomain and Extraterminal (BET) proteins to sustain T-ALL. This study identifies BET proteins as key mediators of the PRC2 loss of function-induced remodeling. Our data has uncovered a targetable vulnerability to BET inhibition that can be exploited to treat PRC2-altered T-ALL patients.

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A novel independence test for somatic alterations in cancer shows that biology drives mutual exclusivity but chance explains co-occurrence

Cited by 4 publications

References 49 publications

Failure of human rhombic lip differentiation underlies medulloblastoma formation

Failure of human rhombic lip differentiation underlies medulloblastoma formation

Senescence‐based colorectal cancer subtyping reveals distinct molecular characteristics and therapeutic strategies

PRC2 loss of function confers a targetable vulnerability to BET proteins in T-ALL

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