Department of Molecular Biology, Ariel University, Ariel, Israel.
Department of Pediatric Oncology, Schneider Children's Medical Center of Israel, Petah-Tikva, Israel.
Cancer Genomics Proteomics. 2021 May-Jun;18(3):335-347. doi: 10.21873/cgp.20264.
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.
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.
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).
Our results help towards finding new treatable molecular targets for these types of medulloblastomas.
背景/目的： sonic hedgehog（SHH）通路中的 PTCH1 或 SUFU 种系突变会导致 Gorlin 综合征，从而增加 SHH 亚组髓母细胞瘤的发病风险。由于多发性基底细胞癌的发生，Gorlin 综合征排除了放疗（治疗的标准组成部分）的使用。此外，目前的 SHH 抑制剂对 SUFU 突变的髓母细胞瘤无效，因为它们抑制上游基因。在这项研究中，我们旨在检测 SUFU 和 PTCH1 突变的 SHH 髓母细胞瘤之间基因和 microRNA 表达的差异，这可能暗示着新的治疗方向。
我们对两个患有遗传性 Gorlin 综合征的患者的肿瘤进行了 RNA 和 microRNA 测序 - 一个患有 PTCH1 突变，另一个患有 SUFU 突变 - 然后进行生物信息学分析，以检测这两个肿瘤中基因和 microRNA 表达的变化。使用 qRT-PCR 验证表达变化。进行了 Ingenuity 通路分析，以寻找可靶向的通路。
与 PTCH1 肿瘤相比，SUFU 肿瘤表现出 miR-301a-3p 和 miR-181c-5p、基质金属蛋白酶 11（MMP11）和 OTX2 的表达降低，miR-7-5p 的表达升高，其靶向基因connexin 30（GJB6）的表达降低。我们提出了解释两种类型肿瘤之间表型差异的机制，并了解为什么 PTCH1 和 SUFU 肿瘤往往会局部复发（而不是像其他髓母细胞瘤亚组那样转移）。
我们的结果有助于为这些类型的髓母细胞瘤找到新的可治疗的分子靶点。
