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Full text release has been delayed at the author's request until January 19, 2026

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NON-CANONICAL PTEN SIGNALING MODIFIERS OF AUTISM VERSUS CANCER PHENOTYPES IN PTEN HAMARTOMA TUMOR SYNDROME

Wei, Ruipeng
http://rave.ohiolink.edu/etdc/view?acc_num=case1701707629648779

Abstract Details

2024, Doctor of Philosophy, Case Western Reserve University, Systems Biology and Bioinformatics.
Cancer and autism spectrum disorder/developmental delay (ASD/DD) are two common clinical phenotypes in individuals with germline PTEN variants (PTEN hamartoma tumor syndrome, PHTS). However, the accurate prediction of these two disparate phenotypes (cancer vs. ASD/DD) for PHTS at the individual level remains unestablished, despite the availability of population level prevalence estimates. Burgeoning studies have shown that genomic and metabolomic factors may act as modifiers of ASD/DD versus cancer in PHTS. We also found that mitochondrial complex II variants occurring in 10% of PHTS individuals modify breast cancer risk and thyroid cancer histology. Therefore, mitochondrial pathways could act as important factors in PHTS phenotype development. As such, in the first project, we investigated the mtDNA landscape extracted from whole genome sequencing data from 498 PHTS individuals, including 164 with ASD/DD (PHTS-onlyASD/DD), 184 with cancer (PHTS-onlyCancer), 132 with neither ASD/DD nor cancer (PHTS-neither), and 18 with both ASD/DD and cancer (PHTS-ASDCancer). We demonstrate that PHTS-onlyASD/DD have significantly higher mtDNA copy number compared to the PHTS-onlyCancer group. Additionally, the PHTS-neither group has significantly higher mtDNA variant burden than the PHTSASDCancer group. 1 Relatedly, maintenance of genome integrity is one of the key biological functions of PTEN; however no integrative studies have been conducted to quantify the DNA damage response (DDR) in individuals with PHTS and to relate the cellular phenotype to organismal phenotypes and genotypes. Therefore, in the second project, we used 43 PHTS patient-derived lymphoblastoid cell lines (LCLs) to investigate the associations between DDR and PTEN genotypes and/or the clinical (organismal) phenotypes of ASD/DD vs. cancer. We found that PTEN nonsense variants are associated with inefficient DNA damage repair. In contrast, we observed the fastest DNA damage repairing rates in LCLs from individuals with ASD/DD, irrespective of PTEN genotype. We applied the reactiondiffusion partial differential equation mathematical model for integrative analyses, a tumor cell growth model with a DNA damage term to accurately describe the DDR process in the LCLs. At lower DNA damage level, live cell density is the highest in PHTS-ASD/DD subgroup than in the other phenotypes, while when DNA damage increases, PHTSASD/DD live cell density was lower than in the PHTS-cancer and PHTS-neither subgroups. Collectively, our studies implicate that mtDNA and DDR may act as modifiers of PHTS phenotype manifestation, ASD/DD vs cancer.
Charis Eng (Advisor)
Jacob Scott (Advisor)
Alexandru Almasan (Committee Member)
Daniela Calvetti (Committee Member)
Mehmet Koyutürk (Committee Chair)
159 p.
Bioinformatics; Biomedical Research
PTEN, DNA damage response, mitochondrial genome, mathematical modelling

Recommended Citations

Citations

  • Wei, R. (2024). NON-CANONICAL PTEN SIGNALING MODIFIERS OF AUTISM VERSUS CANCER PHENOTYPES IN PTEN HAMARTOMA TUMOR SYNDROME [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1701707629648779

    APA Style (7th edition)

  • Wei, Ruipeng. NON-CANONICAL PTEN SIGNALING MODIFIERS OF AUTISM VERSUS CANCER PHENOTYPES IN PTEN HAMARTOMA TUMOR SYNDROME. 2024. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1701707629648779.

    MLA Style (8th edition)

  • Wei, Ruipeng. "NON-CANONICAL PTEN SIGNALING MODIFIERS OF AUTISM VERSUS CANCER PHENOTYPES IN PTEN HAMARTOMA TUMOR SYNDROME." Doctoral dissertation, Case Western Reserve University, 2024. http://rave.ohiolink.edu/etdc/view?acc_num=case1701707629648779

    Chicago Manual of Style (17th edition)

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© 2024, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.
Release 3.2.12