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Koenig Dissertation Final.pdf (3.8 MB)

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LKB1 Loss in Lung Adenocarcinoma

Koenig, Michael J
http://rave.ohiolink.edu/etdc/view?acc_num=osu1555503848137523

Abstract Details

2019, Doctor of Philosophy, Ohio State University, Biomedical Sciences.
LKB1 is the fourth-most frequently mutated gene in lung adenocarcinoma, with loss-of-function observed in up to 30% of all cases (Collisson et al. 2014; Kaufman et al. 2014). Our previous work identified a 16-gene signature for LKB1 loss of function through not just mutation, but deletion and epigenetic silencing, which occurs relatively frequently (Lee et al. 2013; Kaufman et al. 2014). We applied this genetic signature to lung adenocarcinoma samples in the Cancer Genome Atlas (TCGA) and discovered a novel association between LKB1 loss and widespread CpG demethylation. LKB1-loss tumors also expressed significantly less DNA methyl transferase (DNMT1) and show depletion of S-Adenosyl-Methionine (SAM-e), which is the primary substrate for DNMT1 activity. Repetitive element transcriptional start sites are demethylated and sensitivity to azacytidine is lower in LKB1 loss. Mechanistically, demethylated CpGs are enriched for FOXA1/2/3 consensus binding sites, and we further identified that FOXA localization and turnover is dependent upon LKB1 and the downstream kinase SIK. Overall, these findings demonstrate that a large number of lung adenocarcinoma patients have a unique epigenetic profile driven by LKB1 loss which could play a role in lung tumorigenicity and resistance to immunotherapy.
David Carbone (Advisor)
Christopher Oakes (Committee Member)
Matthew Ringel (Committee Member)
Susan Cole (Committee Member)
Sameek Roychowdhury (Committee Member)
Bioinformatics; Biology; Biomedical Research; Genetics; Oncology
Cancer; Lung Cancer; NSCLC; Lung Adenocarcinoma; LKB1; STK11; Epigenetics; DNA Methylation; Chromatin; extracellular vesicles; exosome

Recommended Citations

Citations

  • Koenig, M. J. (2019). LKB1 Loss in Lung Adenocarcinoma [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1555503848137523

    APA Style (7th edition)

  • Koenig, Michael. LKB1 Loss in Lung Adenocarcinoma. 2019. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1555503848137523.

    MLA Style (8th edition)

  • Koenig, Michael. "LKB1 Loss in Lung Adenocarcinoma." Doctoral dissertation, Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1555503848137523

    Chicago Manual of Style (17th edition)

osu1555503848137523
103
© 2019, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.