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KLLN as Tumor Suppressor in Cowden Syndrome and Sporadic Breast Cancers

Nizialek, Emily A
http://rave.ohiolink.edu/etdc/view?acc_num=case1409778932

Abstract Details

2014, Doctor of Philosophy, Case Western Reserve University, Genetics.
KLLN and PTEN, on 10q23, share a bidirectional promoter and are transcribed in opposite directions. Cowden syndrome (CS) is an autosomal dominant disorder with a high risk of cancers. While PTEN is believed to be the major CS gene, our recent study of 3042 probands with classic CS or CS-like (CSL) phenotypes revealed 25% of CS and 5% of CSL probands have germline PTEN mutations. In our pilot study, we found KLLN germline DNA hypermethylation in 37% of 123 PTEN mutation-negative CS/CSL patients revealing KLLN as a novel predisposition gene for cancer. We sought to prove and further characterize this association between KLLN and CS/CSL. Significantly increased KLLN promoter DNA methylation was found in 1012 PTEN mutation-negative CS/CSL patients compared to 111 controls (p<0.001). We further analyzed CS patients for KLLN mutations and found only 1 patient out of 136 (0.7%) with a KLLN mutation, indicating CS is likely not causally associated to KLLN mutations. Interestingly, 13 of 438 (3%) patients with apparently sporadic breast cancer have KLLN mutations not found in 128 controls. These mutations were all observed to significantly impact KLLN’s function. Patients with breast cancer and KLLN mutations had a significant family history of breast cancer, which suggests that KLLN is a low/moderate penetrant breast cancer susceptibility gene. We wanted to further understand the mechanism by which KLLN is acting as a tumor suppressor. Through genome-wide studies, we discovered a novel mechanism for KLLN in genome stability. Germline KLLN alterations may be an important mechanism for CS/CSL and sporadic breast cancer.
Zhenghe Wang, PhD (Committee Chair)
David Serre, PhD (Committee Member)
Ruth Keri, PhD (Committee Member)
Charis Eng, PhD MD (Advisor)
119 p.
Genetics
Cowden Syndrome, hereditary cancer syndromes, epigenetics

Recommended Citations

Citations

  • Nizialek, E. A. (2014). KLLN as Tumor Suppressor in Cowden Syndrome and Sporadic Breast Cancers [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1409778932

    APA Style (7th edition)

  • Nizialek, Emily. KLLN as Tumor Suppressor in Cowden Syndrome and Sporadic Breast Cancers. 2014. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1409778932.

    MLA Style (8th edition)

  • Nizialek, Emily. "KLLN as Tumor Suppressor in Cowden Syndrome and Sporadic Breast Cancers." Doctoral dissertation, Case Western Reserve University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=case1409778932

    Chicago Manual of Style (17th edition)

case1409778932
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© 2014, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.