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Brooks, Angela

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Brooks

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Angela

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Brooks, Angela
Author's Publications: search.filters.isAuthorOfPublication.1125863b-854e-42cf-8900-5f222edbfc78

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    A Pan-Cancer Analysis of Transcriptome Changes Associated with Somatic Mutations in U2AF1 Reveals Commonly Altered Splicing Events
    (Public Library of Science, 2014) Brooks, Angela; Choi, Peter; de Waal, Luc; Sharifnia, Tanaz; Imielinski, Marcin; Saksena, Gordon; Pedamallu, Chandra Sekhar; Sivachenko, Andrey; Rosenberg, Mara; Chmielecki, Juliann; Lawrence, Michael S.; DeLuca, David S.; Getz, Gad; Meyerson, Matthew
    Although recurrent somatic mutations in the splicing factor U2AF1 (also known as U2AF35) have been identified in multiple cancer types, the effects of these mutations on the cancer transcriptome have yet to be fully elucidated. Here, we identified splicing alterations associated with U2AF1 mutations across distinct cancers using DNA and RNA sequencing data from The Cancer Genome Atlas (TCGA). Using RNA-Seq data from 182 lung adenocarcinomas and 167 acute myeloid leukemias (AML), in which U2AF1 is somatically mutated in 3–4% of cases, we identified 131 and 369 splicing alterations, respectively, that were significantly associated with U2AF1 mutation. Of these, 30 splicing alterations were statistically significant in both lung adenocarcinoma and AML, including three genes in the Cancer Gene Census, CTNNB1, CHCHD7, and PICALM. Cell line experiments expressing U2AF1 S34F in HeLa cells and in 293T cells provide further support that these altered splicing events are caused by U2AF1 mutation. Consistent with the function of U2AF1 in 3′ splice site recognition, we found that S34F/Y mutations cause preferences for CAG over UAG 3′ splice site sequences. This report demonstrates consistent effects of U2AF1 mutation on splicing in distinct cancer cell types.
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    Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas
    (2016) Campbell, Joshua David; Alexandrov, Anton; Kim, Jaegil; Wala, Jeremiah; Hawley, Alice; Pedamallu, Chandra Sekhar; Shukla, Sachet A.; Guo, Guangwu; Brooks, Angela; Murray, Bradley A.; Imielinski, Marcin; Hu, Xin; Ling, Shiyun; Akbani, Rehan; Rosenberg, Mara; Cibulskis, Carrie; Ramachandran, Aruna; Collisson, Eric A.; Kwiatkowski, David; Lawrence, Michael; Weinstein, John N.; Verhaak, Roel G. W.; Wu, Catherine; Hammerman, Peter S.; Cherniack, Andrew D.; Getz, Gad; Artyomov, Maxim N.; Schreiber, Robert; Govindan, Ramaswamy; Meyerson, Matthew
    To compare lung adenocarcinoma (ADC) and lung squamous cell carcinoma (SqCC) and to identify new drivers of lung carcinogenesis, we examined exome sequences and copy number profiles of 660 lung ADC and 484 lung SqCC tumor/normal pairs. Recurrent alterations in lung SqCCs were more similar to other squamous carcinomas than to lung ADCs. Novel significantly mutated genes included PPP3CA, DOT1L, and FTSJD1 in lung ADC, RASA1 in lung SqCC, and KLF5, EP300, and CREBBP in both tumor types. Novel amplification peaks encompassed MIR21 in lung ADC, MIR205 in lung SqCC, and MAPK1 in both. Lung ADCs lacking receptor tyrosine kinase/Ras/Raf alterations revealed mutations in SOS1, VAV1, RASA1, and ARHGAP35. Regarding neoantigens, 47% of the lung ADC and 53% of the lung SqCC tumors had at least 5 predicted neoepitopes. While targeted therapies for lung ADC and lung SqCC are largely distinct, immunotherapies may aid in treatment for both subtypes.
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    A Retrospective Review of FDA v. Brown Williamson Tobacco Corporation and the Issue of Congressional Intent
    (2004) Brooks, Angela; Hutt, Peter Barton
    Contrary to a tradition of the FDA (Federal Food and Drug Administration) consistently maintaining that it could not assert jurisdiction over tobacco products, the agency issued a determination of jurisdiction over cigarettes and smokeless tobacco and proposed a set of regulations in 1996 in an effort to combat the public health problems caused by tobacco products. Rather than a complete ban, the FDA proposed regulations aimed solely at younger Americans due to its conclusion that such an approach was safer for the public health. Despite a variety of arguments by the FDA, the Supreme Court held that the FDA could not assert jurisdiction over tobacco products because Congress had directly addressed that precise question and had precluded the FDA from regulating cigarettes and smokeless tobacco. Examining the FDA regulatory scheme as well as the several pieces of tobacco-specific legislation enacted by Congress, the Court found that the FDA’s regulation of tobacco products would be contradictory to the FDCA (Food, Drug, and Cosmetic Act) as a whole and to Congress’ intent to adopt a separate regulatory regime for tobacco products. Through a narrow interpretation of the FDCA and a broad reading of the tobacco-related legislation broadly, the Court concluded that Congress could not have intended the FDA to regulate cigarettes and smokeless tobacco.