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LamisEngLabDissertation171206F.pdf (43.09 MB)

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Novel Role of SEC23B as a Cancer Susceptibility Gene in Cowden Syndrome and Apparently Sporadic Thyroid Cancer

Yehia, Lamis
http://rave.ohiolink.edu/etdc/view?acc_num=case1512647647672648

Abstract Details

2018, Doctor of Philosophy, Case Western Reserve University, Pathology.
Hereditary cancer syndromes serve as powerful models for uncovering cancer-relevant genes. Identification of cancer-predisposing genes not only facilitates gene-enabled molecular diagnosis, cancer risk assessment and gene-specific clinical management, but also offers valuable insights into therapeutically targetable pathways contributing to sporadic tumorigenesis. We study Cowden syndrome (CS) as a model for germline predisposition to cancer. CS is an autosomal dominant disorder characterized by high lifetime risks of epithelial cancers, with ~50% of patients wildtype for known predisposition genes. Using whole-exome and Sanger sequencing of a multi-generation CS family with thyroid and other cancers, we identified a pathogenic missense heterozygous variant in SEC23B (c.1781T>G, p.Val594Gly) that segregated with phenotype. SEC23B encodes Sec23 Homolog B, a component of coat protein complex II (COPII), transporting proteins from endoplasmic reticulum (ER) to Golgi apparatus. Interestingly, germline homozygous or compound heterozygous SEC23B mutations cause an unrelated disorder, Congenital Dyserythropoietic Anemia Type II, and SEC23B-deficient mice show secretory organ degeneration due to ER stress-associated apoptosis. Extending our genetic studies, we also found germline heterozygous SEC23B variants in 3/96 (3%) unrelated mutation negative CS probands with thyroid cancer, and in The Cancer Genome Atlas (TCGA), representing apparently sporadic cancers. We note that TCGA thyroid cancer dataset is enriched for unique germline deleterious SEC23B variants that were associated with a significantly younger age at onset. At the functional level, by characterizing the p.Val594Gly variant in a non-malignant thyroid cell line, we provide evidence that it is a functional mutation that results in ER stress-mediated cell colony formation and survival, growth, and invasion, reflecting aspects of a cancer phenotype. Importantly, these phenotypes occurred with absence of CDA II-like decreased SEC23B protein, suggesting possible change-of-function effects. We hence hypothesized the existence of a novel role for SEC23B, whereby germline heterozygous variants associate with cancer-predisposition potentially mediated by adaptation to ER stress. To test our hypothesis, we further show mutant SEC23B exists within nucleoli, besides classical distribution at the ER/Golgi. This occurs in the absence of nucleolar localization of other COPII proteins and does not compromise canonical secretory function. Global transcriptomic and polysome profiling analyses reveal increased expression of ribosomal protein and translation-related genes, accompanied by enhanced translational capacity in mutant cells in response to ER stress. We also show mutant SEC23B directly binds to Upstream Binding Transcription Factor (UBF), concomitantly with increased UBF binding at the ribosomal DNA (rDNA) promoter region with ER stress. Unexpectedly, we then show wildtype SEC23B can also localize to nucleoli under proteasome inhibition conditions, with different distribution compared to mutant cells. Unbiased proteomic analyses further show SEC23B interacts with proteins in the ER stress, protein ubiquitination, and EIF2 signaling pathways. We validate the genotype-specific differential SEC23B-UBA52 (ribosomal protein RPL40) interaction and provide evidence that both proteins are co-regulated upon knockdown. Overall, our data indicate SEC23B has potential non-canonical COPII-independent function, particularly within the ribosome biogenesis pathway, and that may contribute to the pathogenesis of cancer-predisposition.
Charis Eng, MD, PhD (Advisor)
Shigemi Matsuyama, PhD (Committee Chair)
Clive Hamlin, PhD (Committee Member)
George Stark, PhD (Committee Member)
Ruth Keri, PhD (Committee Member)
Thomas LaFramboise, PhD (Committee Member)
152 p.
Bioinformatics; Biomedical Research; Cellular Biology; Genetics
Cowden syndrome, hereditary cancer syndromes, PTEN wildtype, SEC23B, ribosome biogenesis

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Citations

  • Yehia, L. (2018). Novel Role of SEC23B as a Cancer Susceptibility Gene in Cowden Syndrome and Apparently Sporadic Thyroid Cancer [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1512647647672648

    APA Style (7th edition)

  • Yehia, Lamis. Novel Role of SEC23B as a Cancer Susceptibility Gene in Cowden Syndrome and Apparently Sporadic Thyroid Cancer . 2018. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1512647647672648.

    MLA Style (8th edition)

  • Yehia, Lamis. "Novel Role of SEC23B as a Cancer Susceptibility Gene in Cowden Syndrome and Apparently Sporadic Thyroid Cancer ." Doctoral dissertation, Case Western Reserve University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=case1512647647672648

    Chicago Manual of Style (17th edition)

case1512647647672648
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© 2017, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.