Mutation analysis of 24 known cancer genes in the NCI-60 cell line set

Ikediobi, Ogechi; Davies, Helen; Bignell, Graham R.; Edkins, Sarah; Stevens, C; O’Meara, Sarah; Santarius, Thomas; Avis, Tim; Barthorpe, Syd; Brackenbury, Lisa; Buck, Gemma; Butler, Adam; Clements, Jody; Cole, Jennifer; Dicks, Ed; Forbes, Simon; Gray, Kristian; Halliday, Kelly; Harrison, Rachel; Hills, Katy; Hinton, Jonathan; Hunter, Chris; Jenkinson, Andy; Jones, David R.; Kosmidou, Vivienne; Lugg, Richard; Menzies, Andrew; Mironenko, Tatiana; Parker, Adrian; Perry, Janet; Raine, Keiran; Richardson, David; Shepherd, Rebecca; Small, Alex; Smith, Raffaella; Solomon, Helen; Stephens, Philip J.; Teague, Jon W.; Tofts, Calli; Varian, Jennifer; Webb, Tony; West, Sofie; Widaa, Sara; Yates, Andy; Reinhold, William C.; Weinstein, John N.; Stratton, Michael R.; Futreal, P. Andrew; Wooster, Richard

doi:10.1158/1535-7163.mct-06-0433

Cited by 371 publications

(385 citation statements)

References 29 publications

(38 reference statements)

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“…Despite its original classification as MCF7 breast cancer -derived, OVCAR-8/ADR will be considered here as ovarian in origin because of compelling evidence from our karyotypic analyses (35,55) that it is a (drug-resistant) derivative of OVCAR-8. That conclusion has been corroborated by our gene expression studies and by our analyses of single nucleotide polymorphisms (43). Figure 1A and B show two visualizations of CpG methylation of the E-cad promoter region.…”

Section: Dna Methylation Profilessupporting

confidence: 78%

Detailed DNA methylation profiles of the E-cadherin promoter in the NCI-60 cancer cells

Reinhold

Reimers

Maunakea

et al. 2007

Molecular Cancer Therapeutics

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E-cadherin (E-cad) is a transmembrane adhesion glycoprotein, the expression of which is often reduced in invasive or metastatic tumors. To assess E-cad's distribution among different types of cancer cells, we used bisulfitesequencing for detailed, base-by-base measurement of CpG methylation in E-cad's promoter region in the NCI-60 cell lines. The mean methylation levels of the cell lines were distributed bimodally, with values pushed toward either the high or low end of the methylation scale. The 38 epithelial cell lines showed substantially lower (28%) mean methylation levels compared with the nonepithelial cell lines (58%). The CpG site at -143 with respect to the transcriptional start was commonly methylated at intermediate levels, even in cell lines with low overall DNA methylation. We also profiled the NCI-60 cell lines using Affymetrix U133 microarrays and found E-cad expression to be correlated with E-cad methylation at highly statistically significant levels. Above a threshold of f20% to 30% mean methylation, the expression of E-cad was effectively silenced. Overall, this study provides a type of detailed analysis of methylation that can also be applied to other cancer-related genes. As has been shown

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Section: Dna Methylation Profilessupporting

confidence: 78%

Detailed DNA methylation profiles of the E-cadherin promoter in the NCI-60 cancer cells

Reinhold

Reimers

Maunakea

et al. 2007

Molecular Cancer Therapeutics

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“…The MDA-MB-231 cell line has activating K-Ras and B-Raf mutations (Ikediobi et al, 2006) and like the activated MCF10A.ErbB2 cell line is responsive to the pro-migratory and pro-invasive effects of TGF-b ( Figure 5). In both the MCF10A.ErbB2 and MDA-MB-231 cells, expression of endoglin attenuates the promigratory/invasive activities of TGF-b but has no effect on TGF-b-mediated Smad2/3 or Smad1/5/8 signaling.…”

Section: Discussionmentioning

confidence: 99%

Endoglin expression in breast tumor cells suppresses invasion and metastasis and correlates with improved clinical outcome

et al. 2010

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Tumor growth factor-b (TGF-b) signaling in cancer has been implicated in growth suppression of early lesions and enhancing tumor cell invasion and metastasis. However, the cellular mechanisms that determine this signaling output in individual tumors are still largely unknown. In endothelial cells, TGF-b signaling is modulated by the TGF-b coreceptor endoglin (CD105). Here we demonstrate that endoglin is expressed in a subset of invasive breast cancers and cell lines and is subject to epigenetic silencing by gene methylation. Endoglin downregulation in non-tumorigenic MCF10A breast cells leads to the formation of abnormal acini in 3D culture, but does not promote cell migration or transformation. In contrast, in the presence of activated ErbB2, endoglin downregulation in MCF10A cells leads to enhanced invasion into a 3D matrix. Consistent with these data, ectopic expression of endoglin in MDA-MB-231 cells blocks TGF-b-enhanced cell motility and invasion and reduces lung colonization in an in vivo metastasis model. Unlike endothelial cells, endoglin does not modulate Smadmediated TGF-b signaling in breast cells but attenuates the cytoskeletal remodeling to impair cell migration and invasion. Importantly, in a large cohort of invasive breast cancers, lack of endoglin expression in the tumor cell compartment correlates with ENG gene methylation and poor clinical outcome.

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“…Mutational analysis across a range of sporadic tumors has identified loss of function LKB1 mutations most frequently in non-small cell lung carcinomas; between 5 and 17% of cases depending on the population studied (Sanchez-Cespedes et al, 2002;Ji et al, 2007;Koivunen et al, 2008). Somatic inactivating mutations in LKB1 have also been reported in approximately 5% of pancreatic cancers and melanomas, and in single specimens of prostate cancer and cervical cancer (Avizienyte et al, , 1999Bignell et al, 1998;Wang et al, 1998;Guldberg et al, 1999;Rowan et al, 1999;Su et al, 1999;Forster et al, 2000;Ikediobi et al, 2006). Overall, the incidence of LKB1 mutation in sporadic cancers, other than lung cancer, appears low despite the high penetrance of carcinomas associated with PJS.…”

Section: Peutz-jeghers Syndrome and Human Cancer Geneticsmentioning

confidence: 99%

“…This phenotype is recapitulated in mice with specific Lkb1 deletion in the pancreatic epithelium. Finally, based on the analysis of a limited number of cell lines, it appears that Lkb1 mutations are associated with human prostate cancer (Ikediobi et al, 2006). In the mouse, deletion of Lkb1 in the prostatic epithelium leads to hyperplasia and prostatic intra-epithelial neoplasia (Pearson et al, 2008).…”

Section: Malignant Tumors and Cystic Neoplasmsmentioning

confidence: 99%

LKB1; linking cell structure and tumor suppression

2008

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Germ line mutations in the LKB1 tumor suppressor gene are associated with the Peutz-Jeghers polyposis and cancer syndrome. Somatic mutations in Lkb1 are observed in sporadic pulmonary, pancreatic and biliary cancers and melanomas. The LKB1 serine-threonine kinase functionally and biochemically links control of cellular structure and energy utilization through activation of the AMPK family of kinases. Lkb1 regulates cell polarity through downstream kinases including AMPKs, MARKs and BRSKs, and nutrient utilization and cellular metabolism through the AMPK-mTOR pathway. LKB1 has been shown to affect normal chromosomal segregation, TGF-b signaling in the mesenchyme and WNT and p53 activity. Although each of the LKB1-dependent processes and downstream pathways have been individually delineated through work across a range of experimental systems, how they relate to Lkb1's role as a tumor suppressor remains to be fully explored and elucidated. The recent development of mouse cancer models harboring engineered mutations in Lkb1 have offered insights into how LKB1 may be functioning to restrain tumorigenesis and how its role as a master regulator of polarity and metabolism could contribute to its tumor suppressor function.

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Mutation analysis of 24 known cancer genes in the NCI-60 cell line set

Abstract: The panel of 60 human cancer cell lines (the NCI-

Cited by 371 publications

References 29 publications

Detailed DNA methylation profiles of the E-cadherin promoter in the NCI-60 cancer cells

Detailed DNA methylation profiles of the E-cadherin promoter in the NCI-60 cancer cells

Endoglin expression in breast tumor cells suppresses invasion and metastasis and correlates with improved clinical outcome

LKB1; linking cell structure and tumor suppression

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