Sivan Gershanov1, Helen Toledano2,3, Nomi Pernicone1, Suzana Fichman3,4, Shalom Michowiz3,5, Albert Pinhasov1, Nitza Goldenberg-Cohen6,7,8, Tamar Listovsky9,10, Mali Salmon-Divon9,10. 1. Department of Molecular Biology, Ariel University, Ariel, Israel. 2. Department of Pediatric Oncology, Schneider Children's Medical Center of Israel, Petah-Tikva, Israel. 3. Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. 4. Department of Pathology, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel. 5. Department of Pediatric Neurosurgery, Schneider Children's Medical Center of Israel, Petah-Tikva, Israel. 6. Department of Ophthalmology, Bnai Zion Medical Center, Haifa, Israel. 7. The Krieger Eye Research Laboratory, Felsenstein Medical Research Center, Medical Center, Petah-Tikva, Israel. 8. The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel. 9. Department of Molecular Biology, Ariel University, Ariel, Israel; malisa@ariel.ac.il tamary@ariel.ac.il. 10. Adelson School of Medicine, Ariel University, Ariel, Israel.
Abstract
BACKGROUND/AIM: Germline mutations in PTCH1 or SUFU in the sonic hedgehog (SHH) pathway cause Gorlin's syndrome with increased risk of developing SHH-subgroup medulloblastoma. Gorlin's syndrome precludes the use of radiotherapy (a standard component of treatment) due to the development of multiple basal cell carcinomas. Also, current SHH inhibitors are ineffective against SUFU-mutated medulloblastoma, as they inhibit upstream genes. In this study, we aimed to detect differences in the expression of genes and microRNAs between SUFU- and PTCH1-mutated SHH medulloblastomas which may hint at new treatment directions. PATIENTS AND METHODS: We sequenced RNA and microRNA from tumors of two patients with germline Gorlin's syndrome - one having PTCH1 mutation and one with SUFU mutation - followed by bioinformatics analysis to detect changes in genes and miRNAs expression in these two tumors. Expression changes were validated using qRT-PCR. Ingenuity pathway analysis was performed in search for targetable pathways. RESULTS: Compared to the PTCH1 tumor, the SUFU tumor demonstrated lower expression of miR-301a-3p and miR-181c-5p, matrix metallopeptidase 11 (MMP11) and OTX2, higher expression of miR-7-5p and corresponding lower expression of its targeted gene, connexin 30 (GJB6). We propose mechanisms to explain the phenotypic differences between the two types of tumors, and understand why PTCH1 and SUFU tumors tend to relapse locally (rather than metastatically as in other medulloblastoma subgroups). CONCLUSION: Our results help towards finding new treatable molecular targets for these types of medulloblastomas. Copyright
BACKGROUND/AIM: Germline mutations in PTCH1 or SUFU in the sonic hedgehog (SHH) pathway cause Gorlin's syndrome with increased risk of developing SHH-subgroup medulloblastoma. Gorlin's syndrome precludes the use of radiotherapy (a standard component of treatment) due to the development of multiple basal cell carcinomas. Also, current SHH inhibitors are ineffective against SUFU-mutated medulloblastoma, as they inhibit upstream genes. In this study, we aimed to detect differences in the expression of genes and microRNAs between SUFU- and PTCH1-mutated SHH medulloblastomas which may hint at new treatment directions. PATIENTS AND METHODS: We sequenced RNA and microRNA from tumors of two patients with germline Gorlin's syndrome - one having PTCH1 mutation and one with SUFU mutation - followed by bioinformatics analysis to detect changes in genes and miRNAs expression in these two tumors. Expression changes were validated using qRT-PCR. Ingenuity pathway analysis was performed in search for targetable pathways. RESULTS: Compared to the PTCH1 tumor, the SUFU tumor demonstrated lower expression of miR-301a-3p and miR-181c-5p, matrix metallopeptidase 11 (MMP11) and OTX2, higher expression of miR-7-5p and corresponding lower expression of its targeted gene, connexin 30 (GJB6). We propose mechanisms to explain the phenotypic differences between the two types of tumors, and understand why PTCH1 and SUFU tumors tend to relapse locally (rather than metastatically as in other medulloblastoma subgroups). CONCLUSION: Our results help towards finding new treatable molecular targets for these types of medulloblastomas. Copyright
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