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Integrated genomic characterization of endometrial carcinoma (2013)

C. Kandoth ; N. Schultz ; A. D. Cherniack ; [et al.]

Nature Publishing Group (NPG)

In: Nature. 497(7447): 67-73. doi: 10.1038/nature12113.

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Publication Date: 2013-05-03

Description: We performed an integrated genomic, transcriptomic and proteomic characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. Uterine serous tumours and approximately 25% of high-grade endometrioid tumours had extensive copy number alterations, few DNA methylation changes, low oestrogen receptor/progesterone receptor levels, and frequent TP53 mutations. Most endometrioid tumours had few copy number alterations or TP53 mutations, but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A and KRAS and novel mutations in the SWI/SNF chromatin remodelling complex gene ARID5B. A subset of endometrioid tumours that we identified had a markedly increased transversion mutation frequency and newly identified hotspot mutations in POLE. Our results classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. We demonstrated that the genomic features of endometrial carcinomas permit a reclassification that may affect post-surgical adjuvant treatment for women with aggressive tumours.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3704730/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3704730/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cancer Genome Atlas Research Network -- Kandoth, Cyriac -- Schultz, Nikolaus -- Cherniack, Andrew D -- Akbani, Rehan -- Liu, Yuexin -- Shen, Hui -- Robertson, A Gordon -- Pashtan, Itai -- Shen, Ronglai -- Benz, Christopher C -- Yau, Christina -- Laird, Peter W -- Ding, Li -- Zhang, Wei -- Mills, Gordon B -- Kucherlapati, Raju -- Mardis, Elaine R -- Levine, Douglas A -- 5U24CA143799-04/CA/NCI NIH HHS/ -- 5U24CA143835-04/CA/NCI NIH HHS/ -- 5U24CA143840-04/CA/NCI NIH HHS/ -- 5U24CA143843-04/CA/NCI NIH HHS/ -- 5U24CA143845-04/CA/NCI NIH HHS/ -- 5U24CA143848-04/CA/NCI NIH HHS/ -- 5U24CA143858-04/CA/NCI NIH HHS/ -- 5U24CA143866-04/CA/NCI NIH HHS/ -- 5U24CA143867-04/CA/NCI NIH HHS/ -- 5U24CA143882-04/CA/NCI NIH HHS/ -- 5U24CA143883-04/CA/NCI NIH HHS/ -- 5U24CA144025-04/CA/NCI NIH HHS/ -- P30 CA008748/CA/NCI NIH HHS/ -- P30 CA016086/CA/NCI NIH HHS/ -- P30 CA016672/CA/NCI NIH HHS/ -- P50 CA098258/CA/NCI NIH HHS/ -- U24 CA143799/CA/NCI NIH HHS/ -- U24 CA143835/CA/NCI NIH HHS/ -- U24 CA143840/CA/NCI NIH HHS/ -- U24 CA143843/CA/NCI NIH HHS/ -- U24 CA143845/CA/NCI NIH HHS/ -- U24 CA143848/CA/NCI NIH HHS/ -- U24 CA143858/CA/NCI NIH HHS/ -- U24 CA143866/CA/NCI NIH HHS/ -- U24 CA143867/CA/NCI NIH HHS/ -- U24 CA143882/CA/NCI NIH HHS/ -- U24 CA143883/CA/NCI NIH HHS/ -- U24 CA144025/CA/NCI NIH HHS/ -- U54 HG003067/HG/NHGRI NIH HHS/ -- U54 HG003079/HG/NHGRI NIH HHS/ -- U54 HG003273/HG/NHGRI NIH HHS/ -- U54HG003067-11/HG/NHGRI NIH HHS/ -- U54HG003079-10/HG/NHGRI NIH HHS/ -- U54HG003273-10/HG/NHGRI NIH HHS/ -- England -- Nature. 2013 May 2;497(7447):67-73. doi: 10.1038/nature12113.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23636398" target="_blank"〉PubMed〈/a〉

Keywords: Breast Neoplasms/genetics ; Chromosome Aberrations ; DNA Copy Number Variations/genetics ; DNA Mutational Analysis ; DNA Polymerase II/genetics ; DNA-Binding Proteins/genetics ; Endometrial Neoplasms/*classification/*genetics ; Exome/genetics ; Female ; Gene Expression Regulation, Neoplastic ; Genome, Human/*genetics ; Genomics ; Humans ; Ovarian Neoplasms/genetics ; Signal Transduction ; Transcription Factors/genetics

Print ISSN: 0028-0836

Electronic ISSN: 1476-4687

Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics

Published by Nature Publishing Group (NPG)

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Developing gossypol derivatives with enhanced antitumor activity (1995)

Liang, X. S. ; Rogers, A. J. ; Webber, C. L. ; [et al.]

Springer

Investigational new drugs 13 (1995), S. 181-186

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ISSN: 1573-0646

Keywords: gossypol ; gossypolone ; Schiffs base derivatives ; breast cancer

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology , Medicine

Notes: Summary Preclinical and clinical studies have pointed to the antitumor potential of the naturally occurring polyphenolic binaphthyl dialdehyde, gossypol, as well as its purified (−,+) enantiomers. To explore further the antitumor properties of this multifunctional agent, we synthesized several reactive derivatives including the (−,+) enantiomers of gossypolone and four different gossypol Schiffs bases (AR1, AR2, AR3, AR4). The biological activities of these new agents were screened by measuring theirin vitro antiproliferative activity against malignant (MCF-7, MCF-7/adr) or immortalized (HBL-100) human breast epithelial cell lines. Racemic gossypolone showed relatively uniform antiproliferative activity against all of the breast epithelial cell lines with 3- to 5-fold less activity than (-)-gossypol against MCF-7 and MCF-7/adr cells. Of interest, the relative antitumor potency of purified gossypolone enantiomers was reverse that of gossypol enantiomers, since (+)-gossypolone showed up to 3-fold greater inhibition of MCF-7 culture growth than (-)-gossypolone. Of the Schiff's base derivatives only AR3 with its isopropyl amine substituent demonstrated cytotoxic activity comparable to that of (-)-gossypol; derivatives with ethyl, propyl, or butyl amine substituents (AR1, AR2, AR4) had little growth inhibitory activity at culture concentrations up to 25 μM. AR3 activity was greatest against HBL-100 and MCF-7 cells [MCF-7 IC50 values: AR3=0.9 μM, (-)-gossypol=2.3 μM]; unlike (-)-gossypol, however, AR3 showed substantially reduced activity against the multidrug-resistant subline, MCF-7/adr. These structure-activity comparisons suggest that isolation of (−,+)-enantiomers of AR3 and additional chemical modifications including the synthesis of an isopropyl amine Schiff's base of gossypolone will likely yield a newer generation of gossypol analogues with enhanced anticancer potential.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/BF00873798

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