Whole-genome sequencing of bladder cancers reveals somatic CDKN1A mutations and clinicopathological associations with mutation burden

Rao, S. Madhusudana; McLean, Chelsea; Walker, Alexandra K.; Jaeger, Emma; Kartsonaki, Christiana; Marsden, Luke; Camps, Carme; Kaisaki, Pamela J.; Allan, Christopher M.; Attar, Moustafa; Bell, John; Bentley, David L.; Broxholme, John; Buck, David; Cazier, Jean‐Baptiste; Copley, Richard R.; Cornall, Richard J.; Donnelly, Peter; Fiddy, Simon; Green, Angie; Gregory, Lorna; Grocock, Russell; Hatton, Edouard; Holmes, Chris; Hughes, Linda; Humburg, Peter; Humphray, Sean; Kanapin, Alexander; Kingsbury, Zoya; Knight, Julian C.; Lamble, Sarah; Lise, Stefano; Lonie, Lorne; Lunter, Gerton; Martin, Hilary C.; Murray, Lisa; McCarthy, Davis J.; McVean, Gil; Pagnamenta, Alistair T.; Piazza, Paolo; Polanco, Guadelupe; Ratcliffe, Peter J.; Rimmer, Andy; Sahgal, Natasha; Trebes, Amy; Wilkie, Andrew; Wright, Barlow C.; Yau, Christopher; Taylor, Jenny C; Catto, James W.F.; Tomlinson, Ian; Kiltie, Anne E.; Hamdy, Freddie C.

doi:10.1038/ncomms4756

Cited by 88 publications

(83 citation statements)

References 22 publications

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“…High expression of p21 is associated with poor prognosis of cancer [11][12][13] . Although mutation of the p21 gene has been reported in bladder cancer [14] , most reported studies failed to show the loss-of-function mutations of p21 [15][16][17] . These results suggest that p21 may not be a classical tumor suppressor.…”

Section: P21 As An Oncogenementioning

confidence: 99%

Oncogenic role of p21 in hepatocarcinogenesis suggests a new treatment strategy

Ohkoshi

Yano

Matsuda

2015

WJG

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A well-known tumor suppressor, p21, acts paradoxically by promoting tumor growth in some cellular conditions. These conflicting functions have been demonstrated in association with the HBx gene and in hepatocarcinogenesis. The molecular behavior of p21 depends on its subcellular localization. Nuclear p21 may inhibit cell proliferation and be proapoptotic, while cytoplasmic p21 may have oncogenic and anti-apoptotic functions. Because most typical tumor suppressive proteins also have different effects according to subcellular localization, elucidating the regulatory mechanisms underlying nucleo-cytoplasmic transport of these proteins would be significant and may lead to a new strategy for anti-hepatocellular carcinoma (HCC) therapy. Chromosome region maintenance 1 (CRM1) is a major nuclear export receptor involved in transport of tumor suppressors from nucleus to cytoplasm. Expression of CRM1 is enhanced in a variety of malignancies and in vitro studies have shown the efficacy of specific inhibition of CRM1 against cancer cell lines. Interestingly, interferon may keep p21 in the nucleus; this is one of the mechanisms of its anti-hepatocarcinogenic function. Here we review the oncogenic property of p21, which depends on its subcellular localization, and discuss the rationale underlying a new strategy for HCC treatment and prevention. Core tip: A well-known tumor suppressor, p21, can act paradoxically by promoting tumor growth, depending on its subcellular localization. Nuclear p21 may inhibit cell proliferation while cytoplasmic p21 may be associated with anti-apoptotic and oncogenic functions. REVIEW

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Section: P21 As An Oncogenementioning

confidence: 99%

Oncogenic role of p21 in hepatocarcinogenesis suggests a new treatment strategy

Ohkoshi

Yano

Matsuda

2015

WJG

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“…In contrast, high-grade BCs are aggressive tumors that may present before or after the onset of muscle invasion (5). These poorly differentiated urothelial cancers have widespread chromosomal instability, multiple mutations, and are best characterized by deficiency of p53-mediated pathways (3). High-grade tumors share many molecular alterations regardless of stage and respond poorly to chemotherapy (6).…”

Section: Introductionmentioning

confidence: 99%

Identification of Differentially Expressed Long Noncoding RNAs in Bladder Cancer

Schmitz

Borkowska

Drayton

et al. 2014

Clinical Cancer Research

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Purpose: Loss of epigenetic gene regulation through altered long noncoding RNA (lncRNA) expression seems important in human cancer. LncRNAs have diagnostic and therapeutic potential, and offer insights into the biology disease, but little is known of their expression in urothelial cancer. Here, we identify differentially expressed lncRNAs with potential regulatory functions in urothelial cancer.Experimental Design: The expression of 17,112 lncRNAs and 22,074 mRNAs was determined using microarrays in 83 normal and malignant urothelial (discovery) samples and selected RNAs with qPCR in 138 samples for validation. Significantly differentially expressed RNAs were identified and stratified according to tumor phenotype. siRNA knockdown, functional assays, and whole-genome transcriptomic profiling were used to identify potential roles of selected lncRNAs.Results: We observed upregulation of many lncRNAs in urothelial cancer that was distinct to corresponding, more balanced changes for mRNAs. In general, lncRNA expression reflected disease phenotype. We identified 32 lncRNAs with potential roles in disease progression. Focusing upon a promising candidate, we implicate upregulation of AB074278 in apoptosis avoidance and the maintenance of a proproliferative state in cancer through a potential interaction with EMP1, a tumor suppressor and a negative regulator of cell proliferation.Conclusions: We report differential expression profiles for numerous lncRNA in urothelial cancer. We identify phenotype-specific expression and a potential mechanistic target to explain this observation.

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“…Recently, the use of genome-wide deep sequencing allowed us to perform extensive work on structural variations, including copynumber changes and translocations. Using whole-genome sequencing to identify somatic mutations and chromosomal changes in 14 bladder cancers of different grades and stages, the result shows that CDKN1A dysfunction is not simply an alternative mechanism for p53 pathway inactivation, and strong positive associations exist between higher tumor stage/grade and greater clonal diversity, the number of somatic mutations, and the burden of copy number changes [39]. DNA methylation is a significant epigenetic mechanism of gene regulation that can interpret the tumor genetic heterogeneity.…”

Section: Basis Of Tumor Heterogeneity: Genetic Heterogeneitymentioning

confidence: 99%

Bladder Tumor Heterogeneity: The Impact on Clinical Treatment

Chen¹,

Qi²,

Cao³

et al. 2015

Urol Int

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Bladder cancer relapse and treatment failure in most patients have often been attributed to chemoresistance in tumor cells and metastasis. Emerging evidence indicates that tumor heterogeneity may play an equally important role and extends to virtually all measurable properties of cancer cells. Although the idea of tumor heterogeneity is not new, little attention has been paid to applying it to understand and control bladder cancer progression. With the development of biotechnology, such as Gene sequencing, recent advances in understanding its generation model, original basis, consequent problems, and derived therapies provide great potential for tumor heterogeneity to be considered a new insight in the treatment of bladder cancers.

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Whole-genome sequencing of bladder cancers reveals somatic CDKN1A mutations and clinicopathological associations with mutation burden

Cited by 88 publications

References 22 publications

Oncogenic role of p21 in hepatocarcinogenesis suggests a new treatment strategy

Oncogenic role of p21 in hepatocarcinogenesis suggests a new treatment strategy

Identification of Differentially Expressed Long Noncoding RNAs in Bladder Cancer

Bladder Tumor Heterogeneity: The Impact on Clinical Treatment

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