DNA repair proteins affect the response of cells to genotoxic stresses, and are often mutated or silenced in cancers. The RecQ helicases are a family of DNA repair proteins whose inactivation can predispose individuals to cancer (e.g. Werner syndrome, etc.) and can enhance the anti-tumor effects of chemotherapy. The biological significance of inactivation of the RecQ helicases in cancer is largely unknown, although predicted to be of importance based on studies of WRN and BlM in colorectal and breast cancer. Thus, we will assess the expression of the RecQ helicases, BlM, WRN, RECQL, RECQL4, and RECQL5 as well as candidate RECQ helicase interacting proteins in colorectal and breast cancer, and will determine how these proteins affect the responsiveness of these cancers to chemotherapeutic agents, especially TOPO1 inhibitors. Furthermore, WRN and likely the other RecQ helicases can be inactivated in cancer by an epigenetic mechanism-aberrant DNA methylation. Thus, the role of DNA methylation in silencing the RecQ helicases will be assessed and correlated with the clinical behavior of these cancers.
The Specific Aims of these studies are:
Aim 1 : To determine the frequency of loss of expression and epigenetic inactivation of RecQ helicases in common epithelial cancers: colorectal cancer and breast cancer.
Aim 2 : To determine the role of WRN, BlM, and RECQL4 inactivation and RECQ helicase interacting proteins in modifying the effect of chemotherapy on colorectal cancers (CRC).
Aim3 : To determine the role of WRN, BlM, and RECQL4 inactivation and RECQ helicase interacting proteins in modulating the effect of chemotherapy on breast cancers (BrCA).
In Aims 2 and 3, The RECQ helicase interacting proteins to be studied will be selected from candidates that are genetically or epigenetically altered in CRC or BrCA (e.g. MRE11 and MlH1) and aberrantly expressed. We will determine if methylation or loss of expression of the RECQ helicases and/or intereacting proteins affects sensitivity to chemotherapy by correlating the methylation and expression status of these genes in to response to treatment using two well annotated cohorts from clinical trials (CALBGB 89803 and SWOG S9313). These studies will be done with the support of Core A and Core C as well as Projects 2 and 3.

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Schmitt, Michael W; Pritchard, Justin R; Leighow, Scott M et al. (2018) Single-Molecule Sequencing Reveals Patterns of Preexisting Drug Resistance That Suggest Treatment Strategies in Philadelphia-Positive Leukemias. Clin Cancer Res 24:5321-5334
Mikheev, Andrei M; Mikheeva, Svetlana A; Severs, Liza J et al. (2018) Targeting TWIST1 through loss of function inhibits tumorigenicity of human glioblastoma. Mol Oncol 12:1188-1202
Lee, Su-In; Celik, Safiye; Logsdon, Benjamin A et al. (2018) A machine learning approach to integrate big data for precision medicine in acute myeloid leukemia. Nat Commun 9:42
Salk, Jesse J; Schmitt, Michael W; Loeb, Lawrence A (2018) Enhancing the accuracy of next-generation sequencing for detecting rare and subclonal mutations. Nat Rev Genet 19:269-285
Davis, Luther; Zhang, Yinbo; Maizels, Nancy (2018) Assaying Repair at DNA Nicks. Methods Enzymol 601:71-89
Yu, Ming; Heinzerling, Tai J; Grady, William M (2018) DNA Methylation Analysis Using Droplet Digital PCR. Methods Mol Biol 1768:363-383
Knijnenburg, Theo A; Wang, Linghua; Zimmermann, Michael T et al. (2018) Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas. Cell Rep 23:239-254.e6
Orozco, Javier I J; Knijnenburg, Theo A; Manughian-Peter, Ayla O et al. (2018) Epigenetic profiling for the molecular classification of metastatic brain tumors. Nat Commun 9:4627
Kamath-Loeb, Ashwini S; Zavala-van Rankin, Diego G; Flores-Morales, Jeny et al. (2017) Homozygosity for the WRN Helicase-Inactivating Variant, R834C, does not confer a Werner syndrome clinical phenotype. Sci Rep 7:44081
Oshima, Junko; Sidorova, Julia M; Monnat Jr, Raymond J (2017) Werner syndrome: Clinical features, pathogenesis and potential therapeutic interventions. Ageing Res Rev 33:105-114

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