Citations 2
A Rare TP53 Mutation Predominant in Ashkenazi Jews Confers Risk of Multiple Cancers
Powers, Jacquelyn , Pinto, Emília M. , Barnoud, Thibaut , Leung, Jessica C. , Martynyuk, Tetyana , Kossenkov, Andrew V. , Philips, Aaron H., Desai, Heena , Hausler, Ryan , Le, Anh N. , Pyle, Louise C. , Zelley, Kristin , Nathanson, Katherine L. , Slavin, Thomas P. , Weitzel, Jeffrey N. , Stopfer, Jill E. , Offit, Kenneth , Dolinsky, Jill S. , Gutierrez, Stephanie, McGoldrick, Kelly , Levin, Brooke , Edelman, Morris, Levy, Carolyn Fein , Spunt, Sheri L. , Zambetti, Gerard P. , Li, Marilyn M , MacFarland, Suzanne P , Pyle, Louise C , Zelley, Kristin , Domchek, Susan M , Weitzel, Jeffrey N , Garber, J. E. , Joseph, Vijai , Levin, Brooke , Levy, Carolyn Fein , Spunt, Sheri L , Nathanson, Katherine L , Kelly, Gregory, Domchek, Susan M. , Garber, Judy E. , Vijai, Joseph , Couch, Fergus J. , Kriwacki, Richard W. , Ribeiro, Raul C , Murphy, Maureen E. , Maxwell, Kara N.
Cancer Research | July 16, 2020 | Volume: 80 | Issue: 17 | Pages: 3732-3744
Abstract Germline mutations in TP53 cause a rare high penetrance cancer syndrome, Li–Fraumeni syndrome (LFS). Here, we identified a rare TP53 tetramerization domain missense mutation, c.1000G>C;p.G334R, in a family with multiple late-onset LFS-spectrum cancers. Twenty additional c.1000G>C probands and one c.1000G>A proband were identified, and available tumors showed biallelic somatic inactivation of TP53. The majority of families were of Ashkenazi Jewish descent, and the TP53 c.1000G>C allele was found on a commonly inherited chromosome 17p13.1 haplotype. Transient transfection of the p.G334R allele conferred a mild defect in colony suppression assays. Lymphoblastoid cell lines from the index family in comparison with TP53 normal lines showed that although classical p53 target gene activation was maintained, a subset of p53 target genes (including PCLO, PLTP, PLXNB3, and LCN15) showed defective transactivation when treated with Nutlin-3a. Structural analysis demonstrated thermal instability of the G334R-mutant tetramer, and the G334R-mutant protein showed increased preponderance of mutant conformation. Clinical case review in comparison with classic LFS cohorts demonstrated similar rates of pediatric adrenocortical tumors and other LFS component cancers, but the latter at significantly later ages of onset. Our data show that TP53 c.1000G>C;p.G334R is found predominantly in Ashkenazi Jewish individuals, causes a mild defect in p53 function, and leads to low penetrance LFS. Significance: TP53 c.1000C>G;p.G334R is a pathogenic, Ashkenazi Jewish–predominant mutation associated with a familial multiple cancer syndrome in which carriers should undergo screening and preventive measures to reduce cancer risk.
BET Inhibitors Suppress ALDH Activity by Targeting ALDH1A1 Super-Enhancer in Ovarian Cancer
Yokoyama, Yuhki , Zhu, Hengrui , Lee, Jeong Heon, Kossenkov, Andrew V. , Wu, Sherry Y. , Wickramasinghe, Jayamanna, Yin, Xiangfan, Palozola, Katherine C. , Showe, Louise C. , Zaret, Kenneth S. , Liu, Qin , Speicher, David W. , Conejo-García, José R. , Bradner, James E. , Zhang, Zhiguo , Ördög, Tamás , Bitler, Benjamin G. , Lee, Jeong‐Heon , Gardini, Alessandro , Sood, Anil K. , Zhang, Rugang , Zhang, Zhiguo , Lee, Jeong-Heon
Cancer Research | November 1, 2016 | Volume: 76 | Issue: 21 | Pages: 6320-6330
Abstract The emergence of tumor cells with certain stem-like characteristics, such as high aldehyde dehydrogenase (ALDH) activity due to ALDH1A1 expression, contributes to chemotherapy resistance and tumor relapse. However, clinically applicable inhibitors of ALDH activity have not been reported. There is evidence to suggest that epigenetic regulation of stem-related genes contributes to chemotherapy efficacy. Here, we show that bromodomain and extraterminal (BET) inhibitors suppress ALDH activity by abrogating BRD4-mediated ALDH1A1 expression through a super-enhancer element and its associated enhancer RNA. The clinically applicable small-molecule BET inhibitor JQ1 suppressed the outgrowth of cisplatin-treated ovarian cancer cells both in vitro and in vivo. Combination of JQ1 and cisplatin improved the survival of ovarian cancer–bearing mice in an orthotopic model. These phenotypes correlate with inhibition of ALDH1A1 expression through a super-enhancer element and other stem-related genes in promoter regions bound by BRD4. Thus, targeting the BET protein BRD4 using clinically applicable small-molecule inhibitors, such as JQ1, is a promising strategy for targeting ALDH activity in epithelial ovarian cancer. Cancer Res; 76(21); 6320–30. ©2016 AACR.