BRCA1/MAD2L1 Deficiency Disrupts the Spindle Assembly Checkpoint to Confer Vinorelbine Resistance in Mesothelioma

Busacca, Sara; O’Regan, Laura; Singh, Ajit; Sharkey, Annabel J.; Dawson, Alan G.; Dzialo, Joanna; Parsons, Aimee; Kumar, Neelam; Schunselaar, Laurel M.; Guppy, Naomi; Nakas, Apostolos; Sheaff, Michael; Mansfield, Aaron S.; Janes, Sam M.; Baas, Paul; Fry, Andrew M.; Fennell, Dean A.

doi:10.1158/1535-7163.mct-20-0363

Cited by 17 publications

(14 citation statements)

References 29 publications

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“…To investigate whether RAE1 could be a therapeutic target, we performed a comprehensive analysis of 276 genes encoding microtubule‐regulating proteins 19 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 using TCGA data and evaluated their potential efficacy as a therapeutic target. We calculated the fold change in mRNA expression of each gene in tumor tissues compared to normal tissues, the correlation between mRNA expression and DNA copy number, and whether the high expression group was associated with poor prognosis.…”

Section: Resultsmentioning

confidence: 99%

Mitotic checkpoint regulator RAE1 promotes tumor growth in colorectal cancer

et al. 2021

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Microtubules are among the most successful targets for anticancer therapy because they play important roles in cell proliferation as they constitute the mitotic spindle, which is critical for chromosome segregation during mitosis. Hence, identifying new therapeutic targets encoding proteins that regulate microtubule assembly and function specifically in cancer cells is critical. In the present study, we identified a candidate gene that promotes tumor progression, ribonucleic acid export 1 (RAE1), a mitotic checkpoint regulator, on chromosome 20q through a bioinformatics approach using datasets of colorectal cancer (CRC), including The Cancer Genome Atlas (TCGA). RAE1 was ubiquitously amplified and overexpressed in tumor cells. High expression of RAE1 in tumor tissues was positively associated with distant metastasis and was an independent poor prognostic factor in CRC. In vitro and in vivo analysis showed that RAE1 promoted tumor growth, inhibited apoptosis, and promoted cell cycle progression, possibly with a decreased proportion of multipolar spindle cells in CRC. Furthermore, RAE1 induced chemoresistance through its anti–apoptotic effect. In addition, overexpression of RAE1 and significant effects on survival were observed in various types of cancer, including CRC. In conclusion, we identified RAE1 as a novel gene that facilitates tumor growth in part by inhibiting apoptosis and promoting cell cycle progression through stabilizing spindle bipolarity and facilitating tumor growth. We suggest that it is a potential therapeutic target to overcome therapeutic resistance of CRC.

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Section: Resultsmentioning

confidence: 99%

Mitotic checkpoint regulator RAE1 promotes tumor growth in colorectal cancer

et al. 2021

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“…Vinorelbine requires BRCA1 to initiate apoptosis in preclinical models and the deletion of BRCA1/MAD2L1 is a putative predictive marker of Vinorelbine resistance in mesothelioma 47 . It can be seen that the upregulation or down-regulation of gene expression has a guiding role in the treatment of cancer patients.…”

Section: Discussionmentioning

confidence: 99%

The Diagnostic and Prognostic Value of BEN-Domain (BEND) Family Genes in Gastric Cancer

Fan

Yang

Liang

et al. 2022

Preprint

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BEND(BEN domain-containing protein)is a domain protein-coding gene, whose abnormal expression is related to the occurrence of malignant tumors. But studies on gastric cancer are rare. We attempted to investigate the role of BEND family genes in evaluating the prognosis of gastric cancer and guiding clinical treatment. We analyzed the BEND family genes expression, prognostic value, and drug sensitivity in pan-cancer, and the correlation between their expression and tumor microenvironment of gastric cancer, stemness index, immune subtypes, and clinicopathological characteristics were analyzed. We constructed a model using BEND3P1 and BEND6 to evaluate the prognosis of gastric cancer patients. Multivariate Cox proportional risk model analysis showed that risk score is an independent risk factor for gastric cancer patients. To assess the value of risk score for prognosis, patients were divided into high-risk and low-risk groups based on median risk scores, and survival analyses were performed. The results showed that the OS of patients with high-risk scores is significantly lower. We also constructed a nomogram to predict individual survival probability using the BEND risk score and clinical case characteristics. In conclusion, the BEND family genes can predict the prognosis and guide the treatment of gastric cancer patients.

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“…37 SAC can lead to mitotic arrest while maintaining genome stability and preventing chromosome mis-segregation and aneuploidy arising during cellular division. MAD2L1 has been described as BRCA1 associated in breast cancer and mesothelioma, 53,54 while cancers related to BRCA1/2 mutations are known to present more chromosomal instability. Furthermore, downregulation of BRCA1 seems to inactivate SAC.…”

Section: Discussionmentioning

confidence: 99%

Genetic variant in SPDL1 reveals novel mechanism linking pulmonary fibrosis risk and cancer protection

Koskela

Häppölä

et al. 2021

Preprint

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Idiopathic Pulmonary Fibrosis (IPF) is a rare disease with poor prognosis. By contrast, cancer is common in any elderly population and a leading killer, but is now often curable. Of note, whereas IPF is driven by cellular senescence, cancer is characterized by uncontrolled cell division. Using data available from two large biobank-based studies (Finnish FinnGen study and UK biobank), we conducted a comprehensive analysis of the shared genetic background of IPF and cancer. In a population sample of 218,792 Finns with complete longitudinal health histories, we estimated the effect of individual genetic variants to the lifetime risk of IPF and cancer. We extend the analysis from IPF-GWAS to pan-cancer meta-analysis over FinnGen and UK Biobank and finally to the identification of genetic drivers of somatic chromosomal alterations. We detected six loci (SPDL1, MAD1L1, MAP2K1, RTEL1-STMN3, TERC-ACTRT3, OBFC1) associated with both IPF and cancer, all closely related to cellular division. However, each individual signal is found with opposite effects over the two diseases, termed as antagonistic pleiotropy. Several of these loci (TERC-ACTRT3, RTEL1-STMN3, OBFC1) are among the strongest inherited factors for constitutive telomere length variation and consistently indicate that shorter telomere length would increase the risk for IPF but protect from malignancy. However, a Finnish enriched SPDL1 missense variant and a common MAD1L1 intronic variant had no effect on telomere length but were shown to protect individuals from accumulation of somatic mutations. The decreased risk of cancer in SPDL1 and MAD1L1 variant carriers might result from a lower number of chromosomal alterations accumulated over time, conversely leading to fibrosis in the lung due to cellular senescence-induced inflammation. We hypothesize that the SPDL1 missense variant functions as gain-of-function mutation, leading to cellular senescence, a barrier to cancer and a driver of fibrosis in IPF. If translated to therapy, these findings might not only be able to offer relief to individuals with IPF, but also to protect from onset of cancer.

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BRCA1/MAD2L1 Deficiency Disrupts the Spindle Assembly Checkpoint to Confer Vinorelbine Resistance in Mesothelioma

Cited by 17 publications

References 29 publications

Mitotic checkpoint regulator RAE1 promotes tumor growth in colorectal cancer

Mitotic checkpoint regulator RAE1 promotes tumor growth in colorectal cancer

The Diagnostic and Prognostic Value of BEN-Domain (BEND) Family Genes in Gastric Cancer

Genetic variant in SPDL1 reveals novel mechanism linking pulmonary fibrosis risk and cancer protection

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