Pan-cancer association of a centrosome amplification gene expression signature with genomic alterations and clinical outcome

Almeida, Bernardo Pinto de; Vieira, André Filipe; Paredes, Joana; Bettencourt-Dias, Mónica; Barbosa‐Morais, Nuno L.

doi:10.1371/journal.pcbi.1006832

Cited by 44 publications

(57 citation statements)

References 88 publications

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“…We only used cohorts with at least 10 death events, and the performance of the C1/C2 classification was compared to the performance of classifications based on random sets of genes. The C1/C2 classification was prognostic in 7 of the 17 analyzed cohorts (univariate Cox regressions, p < 0.05): LGG, LIHC, LUAD, PAAD, MESO, KIRC, and BRCA, with the C2 class having a decreased survival ( Figure 9 ), which is consistent with the reports of the proliferation, CA20, TP53, and RB signatures [ 49 , 52 , 53 , 54 , 55 ]. The cohorts where the C1/C2 classification seemed to be more associated with survival were also the ones with lower scores for proliferation [ 59 ], CA20 ( Figure 6 and Figure 7 ), TP53 [ 55 ], and RB [ 54 ] signatures.…”

Section: Resultssupporting

confidence: 82%

“…This feature can be found in pre-neoplasias and tumors from multiple cancer types, and multiple compounds targeting centrosomal proteins have shown promising results [ 51 ]. Therefore, we studied centrosome amplification using a 20 genes signature (CA20) [ 52 ] that is associated with unfavorable prognosis in multiple TCGA cohorts [ 53 ]. The last major difference between C1 and C2 is associated with response to DNA damage and apoptosis pathways.…”

Section: Resultsmentioning

confidence: 99%

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Pan-Cancer Molecular Patterns and Biological Implications Associated with a Tumor-Specific Molecular Signature

Rocha

García

Montoro

et al. 2020

Cells

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Studying tissue-independent components of cancer and defining pan-cancer subtypes could be addressed using tissue-specific molecular signatures if classification errors are controlled. Since PAM50 is a well-known, United States Food and Drug Administration (FDA)-approved and commercially available breast cancer signature, we applied it with uncertainty assessment to classify tumor samples from over 33 cancer types, discarded unassigned samples, and studied the emerging tumor-agnostic molecular patterns. The percentage of unassigned samples ranged between 55.5% and 86.9% in non-breast tissues, and gene set analysis suggested that the remaining samples could be grouped into two classes (named C1 and C2) regardless of the tissue. The C2 class was more dedifferentiated, more proliferative, with higher centrosome amplification, and potentially more TP53 and RB1 mutations. We identified 28 gene sets and 95 genes mainly associated with cell-cycle progression, cell-cycle checkpoints, and DNA damage that were consistently exacerbated in the C2 class. In some cancer types, the C1/C2 classification was associated with survival and drug sensitivity, and modulated the prognostic meaning of the immune infiltrate. Our results suggest that PAM50 could be repurposed for a pan-cancer context when paired with uncertainty assessment, resulting in two classes with molecular, biological, and clinical implications.

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Section: Resultssupporting

confidence: 82%

Section: Resultsmentioning

confidence: 99%

Pan-Cancer Molecular Patterns and Biological Implications Associated with a Tumor-Specific Molecular Signature

Rocha

García

Montoro

et al. 2020

Cells

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“…, 2005 ; Tang et al. , 2011 ) and together are transcript signatures of CA in cancer cells ( De Almeida et al. , 2019 ).…”

Section: Resultsmentioning

confidence: 99%

Growth disadvantage associated with centrosome amplification drives population-level centriole number homeostasis

Sala

Farrell

Stearns

2020

MBoC

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The centriole duplication cycle normally ensures that centriole number is maintained at two centrioles per G1 cell. However, some circumstances can result in an aberrant increase in centriole number—a phenotype that is particularly prevalent in several types of cancer. Following an artificial increase in centriole number without tetraploidization due to transient overexpression of the kinase PLK4, human cells return to a normal centriole number during the proliferation of the population. We examine the mechanisms responsible for this return to normal centriole number at the population level in human retinal pigment epithelial cells. We find that the return to normal centriole number in the population of induced cells cannot be explained by limited duplication of centrioles, instability of extra centrioles, or by grossly asymmetric segregation of extra centrioles in mitosis. However, cells with extra centrioles display heterogenous phenotypes including extended cell cycle arrest, longer interphase durations, and death, which overall result in a proliferative disadvantage relative to normal cells in the population. Although about half of cells with extra centrioles in a population were able to divide, the extent of the disadvantages conferred by other fates is sufficient to account for the observed rate of return to normal centriole number. These results suggest that only under conditions of either positive selection for cells with extra centrioles, continuous generation of such centrioles, or alleviation of the disadvantageous growth phenotypes, would they be maintained in a population.

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“…Structural and numerical aberrations of centrosomes were reported in various malignancies 39 . Regulators of centrosome duplication, including Aurora A and PLK1, are frequently dysregulated or mutated in cancers including breast cancer 40 . In breast tissues, centrosome aberrations are present in pre‐malignant lesions 41‐43 .…”

Section: The Centrosomementioning

confidence: 99%

Dysregulation of the centrosome induced by BRCA1 deficiency contributes to tissue‐specific carcinogenesis

Yoshino

Fang

et al. 2021

Cancer Science

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Alterations in breast cancer gene 1 (BRCA1), a tumor suppressor gene, increase the risk of breast and ovarian cancers. BRCA1 forms a heterodimer with BRCA1‐associated RING domain protein 1 (BARD1) and functions in multiple cellular processes, including DNA repair and centrosome regulation. BRCA1 acts as a tumor suppressor by promoting homologous recombination (HR) repair, and alterations in BRCA1 cause HR deficiency, not only in breast and ovarian tissues but also in other tissues. The molecular mechanisms underlying BRCA1 alteration‐induced carcinogenesis remain unclear. Centrosomes are the major microtubule‐organizing centers and function in bipolar spindle formation. The regulation of centrosome number is critical for chromosome segregation in mitosis, which maintains genomic stability. BRCA1/BARD1 function in centrosome regulation together with Obg‐like ATPase (OLA1) and receptor for activating protein C kinase 1 (RACK1). Cancer‐derived variants of BRCA1, BARD1, OLA1, and RACK1 do not interact, and aberrant expression of these proteins results in abnormal centrosome duplication in mammary‐derived cells, and rarely in other cell types. RACK1 is involved in centriole duplication in the S phase by promoting polo‐like kinase 1 activation by Aurora A, which is critical for centrosome duplication. Centriole number is higher in cells derived from mammary tissues compared with in those derived from other tissues, suggesting that tissue‐specific centrosome characterization may shed light on the tissue specificity of BRCA1‐associated carcinogenesis. Here, we explored the role of the BRCA1‐containing complex in centrosome regulation and the effect of its deficiency on tissue‐specific carcinogenesis.

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Pan-cancer association of a centrosome amplification gene expression signature with genomic alterations and clinical outcome

Cited by 44 publications

References 88 publications

Pan-Cancer Molecular Patterns and Biological Implications Associated with a Tumor-Specific Molecular Signature

Pan-Cancer Molecular Patterns and Biological Implications Associated with a Tumor-Specific Molecular Signature

Growth disadvantage associated with centrosome amplification drives population-level centriole number homeostasis

Dysregulation of the centrosome induced by BRCA1 deficiency contributes to tissue‐specific carcinogenesis

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