Meghan L. Rudd
National Institutes of Health
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Featured researches published by Meghan L. Rudd.
Nature Genetics | 2012
Matthieu Le Gallo; Andrea J O'Hara; Meghan L. Rudd; Mary Ellen Urick; Nancy F. Hansen; Nigel J. O'Neil; Jessica C. Price; Suiyuan Zhang; Bryant M England; Andrew K. Godwin; Dennis C. Sgroi; Philip Hieter; James C. Mullikin; Maria J. Merino; Daphne W. Bell
Endometrial cancer is the sixth most commonly diagnosed cancer in women worldwide, causing ∼74,000 deaths annually. Serous endometrial cancers are a clinically aggressive subtype with a poorly defined genetic etiology. We used whole-exome sequencing to comprehensively search for somatic mutations within ∼22,000 protein-encoding genes in 13 primary serous endometrial tumors. We subsequently resequenced 18 genes, which were mutated in more than 1 tumor and/or were components of an enriched functional grouping, from 40 additional serous tumors. We identified high frequencies of somatic mutations in CHD4 (17%), EP300 (8%), ARID1A (6%), TSPYL2 (6%), FBXW7 (29%), SPOP (8%), MAP3K4 (6%) and ABCC9 (6%). Overall, 36.5% of serous tumors had a mutated chromatin-remodeling gene, and 35% had a mutated ubiquitin ligase complex gene, implicating frequent mutational disruption of these processes in the molecular pathogenesis of one of the deadliest forms of endometrial cancer.
Clinical Cancer Research | 2011
Meghan L. Rudd; Jessica C. Price; Sarah Fogoros; Andrew K. Godwin; Dennis C. Sgroi; Maria J. Merino; Daphne W. Bell
Purpose: The goal of this study was to comprehensively define the incidence of mutations in all exons of PIK3CA in both endometrioid endometrial cancer (EEC) and nonendometrioid endometrial cancer (NEEC). Experimental Design: We resequenced all coding exons of PIK3CA and PTEN, and exons 1 and 2 of KRAS, from 108 primary endometrial tumors. Somatic mutations were confirmed by sequencing matched normal DNAs. The biochemical properties of a subset of novel PIK3CA mutations were determined by exogenously expressing wild type and mutant constructs in U2OS cells and measuring levels of AKTSer473 phosphorylation. Results: Somatic PIK3CA mutations were detected in 52.4% of 42 EECs and 33.3% of 66 NEECs. Half (29 of 58) of all nonsynonymous PIK3CA mutations were in exons 1–7 and half were in exons 9 and 20. The exons 1–7 mutations localized to the ABD, ABD-RBD linker and C2 domains of p110α. Within these regions, Arg88, Arg93, Gly106, Lys111, Glu365, and Glu453, were recurrently mutated; Arg88, Arg93, and Lys111 formed mutation hotspots. The p110α-R93W, -G106R, -G106V, -K111E, -delP449-L455, and -E453K mutants led to increased levels of phospho-AKTSer473 compared to wild-type p110α. Overall, 62% of exons 1–7 PIK3CA mutants and 64% of exons 9–20 PIK3CA mutants were activating; 72% of exon 1–7 mutations have not previously been reported in endometrial cancer. Conclusions: Our study identified a new subgroup of endometrial cancer patients with activating mutations in the amino-terminal domains of p110α; these patients might be appropriate for consideration in clinical trials of targeted therapies directed against the PI3K pathway. Clin Cancer Res; 17(6); 1331–40. ©2011 AACR.
Cancer Research | 2011
Mary Ellen Urick; Meghan L. Rudd; Andrew K. Godwin; Dennis C. Sgroi; Maria J. Merino; Daphne W. Bell
Phosphoinositide 3-kinase (PI3K) is an important therapeutic target. Mutations in PIK3CA, which encodes p110α, the catalytic subunit of PI3K, occur in endometrioid endometrial cancers (EEC) and nonendometrioid endometrial cancers (NEEC). The goal of this study was to determine whether PIK3R1, which encodes p85α, the inhibitory subunit of PI3K, is mutated in endometrial carcinoma. We carried out exonic sequencing of PIK3R1 from 42 EECs and 66 NEECs. The pattern of PIK3R1 mutations was compared with the patterns of PIK3CA, PTEN, and KRAS mutations. The biochemical effect of seven PIK3R1 mutations was examined by stable expression in U2OS cells, followed by coimmunoprecipitation analysis of p110α, and Western blotting of phospho-AKT(Ser473) (p-AKT(Ser473)). We found that PIK3R1 was somatically mutated in 43% of EECs and 12% of NEECs. The majority of mutations (93.3%) were localized to the p85α-nSH2 and -iSH2 domains. Several mutations were recurrent. PIK3R1 mutations were significantly (P = 0.0015) more frequent in PIK3CA-wild type EECs (70%) than in PIK3CA mutant EECs (18%). Introduction of wild-type p85α into U2OS cells reduced the level of p-AKT(Ser473) compared with the vector control. Five p85α mutants, p85αdelH450-E451, p85αdelK459, p85αdelY463-L466, p85αdelR574-T576, and the p85αN564D positive control, were shown to bind p110α and led to increased levels of p-AKT(Ser473). The p85αR348X and p85αK511VfsX2 mutants did not bind p110α and showed no appreciable change in p-AKT(Ser473) levels. In conclusion, our study has revealed a new mode of PI3K alteration in primary endometrial tumors and warrants future studies to determine whether PIK3R1 mutations correlate with clinical outcome to targeted therapies directed against the PI3K pathway in EEC and NEEC.
PLOS Genetics | 2011
Daphne W. Bell; Nilabja Sikdar; Kyoo-young Lee; Jessica C. Price; Raghunath Chatterjee; Hee-Dong Park; Jennifer T. Fox; Masamichi Ishiai; Meghan L. Rudd; Lana M. Pollock; Sarah Fogoros; Hassan Mohamed; Christin L. Hanigan; Nisc Comparative Sequencing Program; Suiyuan Zhang; Pedro Cruz; Gabriel Renaud; Nancy F. Hansen; Praveen F. Cherukuri; Bhavesh Borate; Kirk J. McManus; Jan Stoepel; Payal Sipahimalani; Andrew K. Godwin; Dennis C. Sgroi; Maria J. Merino; Gene Elliot; Abdel G. Elkahloun; Charles Vinson; Minoru Takata
ATAD5, the human ortholog of yeast Elg1, plays a role in PCNA deubiquitination. Since PCNA modification is important to regulate DNA damage bypass, ATAD5 may be important for suppression of genomic instability in mammals in vivo. To test this hypothesis, we generated heterozygous (Atad5+/m) mice that were haploinsuffficient for Atad5. Atad5+/m mice displayed high levels of genomic instability in vivo, and Atad5+/m mouse embryonic fibroblasts (MEFs) exhibited molecular defects in PCNA deubiquitination in response to DNA damage, as well as DNA damage hypersensitivity and high levels of genomic instability, apoptosis, and aneuploidy. Importantly, 90% of haploinsufficient Atad5+/m mice developed tumors, including sarcomas, carcinomas, and adenocarcinomas, between 11 and 20 months of age. High levels of genomic alterations were evident in tumors that arose in the Atad5+/m mice. Consistent with a role for Atad5 in suppressing tumorigenesis, we also identified somatic mutations of ATAD5 in 4.6% of sporadic human endometrial tumors, including two nonsense mutations that resulted in loss of proper ATAD5 function. Taken together, our findings indicate that loss-of-function mutations in mammalian Atad5 are sufficient to cause genomic instability and tumorigenesis.
PLOS ONE | 2013
Jessica C. Price; Lana M. Pollock; Meghan L. Rudd; Sarah Fogoros; Hassan Mohamed; Christin L. Hanigan; Matthieu Le Gallo; Suiyuan Zhang; Pedro Cruz; Praveen F. Cherukuri; Nancy F. Hansen; Kirk J. McManus; Andrew K. Godwin; Dennis C. Sgroi; James C. Mullikin; Maria J. Merino; Philip Hieter; Daphne W. Bell
Most endometrial cancers can be classified histologically as endometrioid, serous, or clear cell. Non-endometrioid endometrial cancers (NEECs; serous and clear cell) are the most clinically aggressive of the three major histotypes and are characterized by aneuploidy, a feature of chromosome instability. The genetic alterations that underlie chromosome instability in endometrial cancer are poorly understood. In the present study, we used Sanger sequencing to search for nucleotide variants in the coding exons and splice junctions of 21 candidate chromosome instability genes, including 19 genes implicated in sister chromatid cohesion, from 24 primary, microsatellite-stable NEECs. Somatic mutations were verified by sequencing matched normal DNAs. We subsequently resequenced mutated genes from 41 additional NEECs as well as 42 endometrioid ECs (EECs). We uncovered nonsynonymous somatic mutations in ESCO1, CHTF18, and MRE11A in, respectively, 3.7% (4 of 107), 1.9% (2 of 107), and 1.9% (2 of 107) of endometrial tumors. Overall, 7.7% (5 of 65) of NEECs and 2.4% (1 of 42) of EECs had somatically mutated one or more of the three genes. A subset of mutations are predicted to impact protein function. The co-occurrence of somatic mutations in ESCO1 and CHTF18 was statistically significant (P = 0.0011, two-tailed Fishers exact test). This is the first report of somatic mutations within ESCO1 and CHTF18 in endometrial tumors and of MRE11A mutations in microsatellite-stable endometrial tumors. Our findings warrant future studies to determine whether these mutations are driver events that contribute to the pathogenesis of endometrial cancer.
Cancer | 2017
Matthieu Le Gallo; Meghan L. Rudd; Mary Ellen Urick; Nancy F. Hansen; Suiyuan Zhang; Fred Lozy; Dennis C. Sgroi; August Vidal Bel; Xavier Matias-Guiu; Russell Broaddus; Karen H. Lu; Douglas A. Levine; David G. Mutch; Paul J. Goodfellow; Helga B. Salvesen; James C. Mullikin; Daphne W. Bell; Nisc Comparative Sequencing Program
The molecular pathogenesis of clear cell endometrial cancer (CCEC), a tumor type with a relatively unfavorable prognosis, is not well defined. We searched exome‐wide for novel somatically mutated genes in CCEC and assessed the mutational spectrum of known and candidate driver genes in a large cohort of cases.
BMC Cancer | 2014
Meghan L. Rudd; Hassan Mohamed; Jessica C. Price; Andrea J O’Hara; Matthieu Le Gallo; Mary Ellen Urick; Pedro Cruz; Suiyuan Zhang; Nancy F. Hansen; Andrew K. Godwin; Dennis C. Sgroi; Tyra G. Wolfsberg; James C. Mullikin; Maria J. Merino; Daphne W. Bell
BackgroundEndometrial cancer (EC) is the 8th leading cause of cancer death amongst American women. Most ECs are endometrioid, serous, or clear cell carcinomas, or an admixture of histologies. Serous and clear ECs are clinically aggressive tumors for which alternative therapeutic approaches are needed. The purpose of this study was to search for somatic mutations in the tyrosine kinome of serous and clear cell ECs, because mutated kinases can point to potential therapeutic targets.MethodsIn a mutation discovery screen, we PCR amplified and Sanger sequenced the exons encoding the catalytic domains of 86 tyrosine kinases from 24 serous, 11 clear cell, and 5 mixed histology ECs. For somatically mutated genes, we next sequenced the remaining coding exons from the 40 discovery screen tumors and sequenced all coding exons from another 72 ECs (10 clear cell, 21 serous, 41 endometrioid). We assessed the copy number of mutated kinases in this cohort of 112 tumors using quantitative real time PCR, and we used immunoblotting to measure expression of these kinases in endometrial cancer cell lines.ResultsOverall, we identified somatic mutations in TNK2 (tyrosine kinase non-receptor, 2) and DDR1 (discoidin domain receptor tyrosine kinase 1) in 5.3% (6 of 112) and 2.7% (3 of 112) of ECs. Copy number gains of TNK2 and DDR1 were identified in another 4.5% and 0.9% of 112 cases respectively. Immunoblotting confirmed TNK2 and DDR1 expression in endometrial cancer cell lines. Three of five missense mutations in TNK2 and one of two missense mutations in DDR1 are predicted to impact protein function by two or more in silico algorithms. The TNK2P761Rfs*72 frameshift mutation was recurrent in EC, and the DDR1R570Q missense mutation was recurrent across tumor types.ConclusionsThis is the first study to systematically search for mutations in the tyrosine kinome in clear cell endometrial tumors. Our findings indicate that high-frequency somatic mutations in the catalytic domains of the tyrosine kinome are rare in clear cell ECs. We uncovered ten new mutations in TNK2 and DDR1 within serous and endometrioid ECs, thus providing novel insights into the mutation spectrum of each gene in EC.
Cancer | 2018
Matthieu Le Gallo; Meghan L. Rudd; Mary Ellen Urick; Nancy F. Hansen; Maria J. Merino; David G. Mutch; Paul J. Goodfellow; James C. Mullikin; Daphne W. Bell
Uterine carcinosarcomas (UCSs) are a rare but clinically aggressive form of cancer. They are biphasic tumors consisting of both epithelial and sarcomatous components. The majority of uterine carcinosarcomas are clonal, with the carcinomatous cells undergoing metaplasia to give rise to the sarcomatous component. The objective of the current study was to identify novel somatically mutated genes in UCSs.
Archive | 2017
Mary Ellen Urick; Meghan L. Rudd; Daphne W. Bell
Serous endometrial cancer is a particularly aggressive form of uterine cancer that is associated with a poor prognosis. In the era of precision medicine, defining the molecular alterations that drive tumor development can uncover druggable targets for which molecularly based therapies already exist as well as provide a starting point to develop novel targeted therapies and companion diagnostics. In this chapter, we review the current state of knowledge regarding the molecular pathology of serous endometrial cancer, and discuss how this knowledge is being utilized in the clinical setting.
Cancer Research | 2017
Mary Ellen Urick; Bo Hong; Meghan L. Rudd; Daphne W. Bell
The goal of this study is to elucidate the functional consequences of FBXW7 mutations in the context of endometrial carcinoma (EC). EC is a heterogeneous disease, consisting of multiple histological subtypes associated with distinct clinical outcomes. Endometrioid endometrial cancer is the most commonly diagnosed subtype and is associated with an overall favorable prognosis. Less common but more clinically aggressive subtypes that contribute disproportionately to patient deaths include clear cell and serous ECs. We previously reported that FBXW7 is somatically mutated in 10% of endometrioid, 13% of clear cell and 29% of serous ECs. FBXW7 functions as a substrate-recognition protein within a SKP/CUL1/F-Box ubiquitin ligase complex, which targets numerous proteins for ubiquitin-mediated proteosomal degradation. Although FBXW7 is a known tumor suppressor, the functional consequences of these mutations have not yet been fully elucidated in the context of EC. As a means to this end, we utilized shRNA and Western blotting to identify proteins that are upregulated following FBXW7 depletion in ARK1 serous EC cells. Among proteins that were consistently upregulated were cyclin E1 and cMYC. We treated EC cells harboring endogenous FBXW7 mutations and those with wildtype FBXW7 with a proteasome inhibitor to confirm that EC cells regulate cyclin E1 and cMYC through proteasome degradation. Furthermore, we identified three EC cell lines that harbor endogenous mutations in FBXW7 and show that these cell lines exhibit delayed degradation of these substrates compared to EC cells expressing wildtype FBXW7. Finally, we generated expression constructs for wildtype FBXW7α and six recurrent mutants found in EC. We show that transient exogenous overexpression of five out of six recurrent FBXW7 mutant constructs in two different serous EC cell lines resulted in increased levels of phosphorylated cMYC and cyclin E1 compared to wildtype FBXW7α. These results suggest that not all recurrent FBXW7 mutations are functionally equivalent. Our findings begin to reveal the molecular consequences of FBXW7 mutations in EC and ongoing studies are aimed at elucidating additional functional consequences of these aberrations in the context of EC. Citation Format: Mary Ellen Urick, Bo Hong, Meghan L. Rudd, Daphne W. Bell. Uncovering the functional relevance of FBXW7 mutations in endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3419. doi:10.1158/1538-7445.AM2017-3419