Deletions of chromosomes 3p and 14q molecularly subclassify clear cell renal cell carcinoma

Kroeger, Nils; Klatte, Tobias; Chamie, Karim; Rao, Priya; Birkhäuser, Frédéric D.; Sonn, Geoffrey A.; Riss, Joseph; Kabbinavar, Fairooz; Belldegrun, Arie S.; Pantuck, Allan J.

doi:10.1002/cncr.27947

Cited by 54 publications

(32 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…2), we first investigated classical 3p loss313233. To quantify 3p loss, we computed the fraction of chromosome 3p where the CNA data supported at least low-level copy number loss (using a log2 ratio).…”

Section: Resultsmentioning

confidence: 99%

Analysis of renal cancer cell lines from two major resources enables genomics-guided cell line selection

et al. 2017

View full text Add to dashboard Cite

The utility of cancer cell lines is affected by the similarity to endogenous tumour cells. Here we compare genomic data from 65 kidney-derived cell lines from the Cancer Cell Line Encyclopedia and the COSMIC Cell Lines Project to three renal cancer subtypes from The Cancer Genome Atlas: clear cell renal cell carcinoma (ccRCC, also known as kidney renal clear cell carcinoma), papillary (pRCC, also known as kidney papillary) and chromophobe (chRCC, also known as kidney chromophobe) renal cell carcinoma. Clustering copy number alterations shows that most cell lines resemble ccRCC, a few (including some often used as models of ccRCC) resemble pRCC, and none resemble chRCC. Human ccRCC tumours clustering with cell lines display clinical and genomic features of more aggressive disease, suggesting that cell lines best represent aggressive tumours. We stratify mutations and copy number alterations for important kidney cancer genes by the consistency between databases, and classify cell lines into established gene expression-based indolent and aggressive subtypes. Our results could aid investigators in analysing appropriate renal cancer cell lines.

show abstract

Section: Resultsmentioning

confidence: 99%

Analysis of renal cancer cell lines from two major resources enables genomics-guided cell line selection

et al. 2017

View full text Add to dashboard Cite

show abstract

“…In the case of renal cancer, recent genetic and functional studies also implicated HIF-1a as a tumour suppressor gene 44 . Loss of HIF-1a expression was found to be associated with worse survival rate in patients with ccRCC 45 . Changes in expression levels of HIF-a proteins present in a wide spectrum of cancers occur through a multitude of mechanisms, including hypoxia, loss-of-function of tumour suppressor genes, activating mutations in oncogenes, and activation of kinase signalling pathways 15 .…”

Section: Mapping Cancer Mutations and Phosphorylation Sitesmentioning

confidence: 94%

Structural integration in hypoxia-inducible factors

Potluri

et al. 2015

Nature

267

345

View full text Add to dashboard Cite

The hypoxia-inducible factors (HIFs) coordinate cellular adaptations to low oxygen stress by regulating transcriptional programs in erythropoiesis, angiogenesis and metabolism. These programs promote the growth and progression of many tumours, making HIFs attractive anticancer targets. Transcriptionally active HIFs consist of HIF-α and ARNT (also called HIF-1β) subunits. Here we describe crystal structures for each of mouse HIF-2α-ARNT and HIF-1α-ARNT heterodimers in states that include bound small molecules and their hypoxia response element. A highly integrated quaternary architecture is shared by HIF-2α-ARNT and HIF-1α-ARNT, wherein ARNT spirals around the outside of each HIF-α subunit. Five distinct pockets are observed that permit small-molecule binding, including PAS domain encapsulated sites and an interfacial cavity formed through subunit heterodimerization. The DNA-reading head rotates, extends and cooperates with a distal PAS domain to bind hypoxia response elements. HIF-α mutations linked to human cancers map to sensitive sites that establish DNA binding and the stability of PAS domains and pockets.

show abstract

“…In some cancers, such as renal clear cell carcinoma, clinical data indicate that HIF-2α overexpression is associated with disease progression and mortality, whereas HIF-1α expression is silenced, often by gene deletion (16). In contrast, in colon carcinoma, clinical data indicate that HIF-1α overexpression is associated with disease progression and HIF-2α expression is silenced (17).…”

Section: Hif-1 Mediates Adaptive Responses To Reduced O 2 Availabilitymentioning

confidence: 99%

HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations

Semenza¹

2013

J. Clin. Invest.

1,106

999

View full text Add to dashboard Cite

Hypoxia occurs frequently in human cancers and induces adaptive changes in cell metabolism that include a switch from oxidative phosphorylation to glycolysis, increased glycogen synthesis, and a switch from glucose to glutamine as the major substrate for fatty acid synthesis. This broad metabolic reprogramming is coordinated at the transcriptional level by HIF-1, which functions as a master regulator to balance oxygen supply and demand. HIF-1 is also activated in cancer cells by tumor suppressor (e.g., VHL) loss of function and oncogene gain of function (leading to PI3K/AKT/mTOR activity) and mediates metabolic alterations that drive cancer progression and resistance to therapy. Inhibitors of HIF-1 or metabolic enzymes may impair the metabolic flexibility of cancer cells and make them more sensitive to anticancer drugs. IntroductionAll human cells require a constant supply of O 2 to carry out oxidative phosphorylation in the mitochondria for ATP generation. Under hypoxic conditions when O 2 availability is reduced, cells generally respond in three ways: (a) cell proliferation is inhibited to prevent any further increase in the number of O 2 -consuming cells; (b) the rate of oxidative phosphorylation is decreased and the rate of glycolysis is increased in order to decrease O 2 consumption per cell; and (c) the production of angiogenic factors is increased in order to increase O 2 delivery. Mutations in cancer cells dysregulate cell growth and metabolism, but the mechanisms and consequences of this dysregulation vary widely from one cancer to another and even one from cancer cell to another. In some cancer cells, O 2 still regulates the rate of cell proliferation, whereas others continue to divide even under severely hypoxic conditions; some cancers are well vascularized and perfused, whereas most cancers contain steep O 2 gradients that reflect the distance to the nearest blood vessel, the number of intervening cells and their metabolic activity, and the rate at which blood is flowing through the vessel. The metabolism of individual cancer cells reflects the presence of particular genetic alterations, which may alter metabolism in an O 2 -independent manner, as well as the spatial and temporal heterogeneity of O 2 availability within the tumor microenvironment. This Review summarizes the role of HIF-1 in the regulation of cancer cell metabolism, focusing primarily on the use of glucose as a metabolic substrate.

show abstract

Deletions of chromosomes 3p and 14q molecularly subclassify clear cell renal cell carcinoma

Cited by 54 publications

References 26 publications

Analysis of renal cancer cell lines from two major resources enables genomics-guided cell line selection

Analysis of renal cancer cell lines from two major resources enables genomics-guided cell line selection

Structural integration in hypoxia-inducible factors

HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations

Contact Info

Product

Resources

About