Abstract 1424: KCNJ2 comprises a marker of poor prognosis and a therapeutic target in non-WNT/non-SHH medulloblastoma
Bibliographic record
Abstract
Abstract Medulloblastoma comprises the most common malignant brain tumor in childhood. Recently, integrated genomic approaches revealed four major biological disease variants: WNT (wingless), SHH (sonic hedgehog), group 3, and group 4. Treatment failure mainly occurs in children harboring metastatic tumors, which typically carry an isochromosome 17 or gain of 17q, a common hallmark of intermediate and high-risk non-WNT/non-SHH medulloblastoma. Thus, novel therapeutic options for these patients are urgently warranted. Through mRNA expression profiling of 64 primary tumor samples, we identified potassium inwardly-rectifying channel J2 (KCNJ2) as one of the most upregulated genes on chromosome 17q in tumors with 17q gain. Notably, recent reports have linked deregulation of voltage-dependent ion channels to the development of other types of cancer. We first validated our microarray findings on KCNJ2 transcript levels using quantitative real-time PCR. High KCNJ2 transcript levels were significantly associated with non-WNT/non-SHH grouping, anaplastic histology, metastatic dissemination, and poor clinical outcome. KCNJ2 protein expression was analyzed by immunohistochemistry in a large cohort of patients (n=199), and high protein expression levels were found to be strongly correlated with 17q gain, metastatic dissemination, and inferior overall and progression-free survival (p<0.0001). To functionally validate the potential role of KCNJ2 in medulloblastoma biology, we performed knockdown experiments by small interfering RNA-mediated silencing in two well characterized medulloblastoma cell lines. Knockdown of KCNJ2 resulted in a reduced proliferation rate and induction of apoptosis. Furthermore, treatment of the medulloblastoma cell lines with Amiodarone and SR 59230A, two inhibitors of this class of Kir channels, phenocopied these promising anti-proliferative and pro-apoptotic effects in a time- and dose-dependent manner. Whole cell patch clamp results revealed a remarkable current reduction upon inhibitor treatment with SR 59230A. In summary, we could delineate KCNJ2 immunopositivity as an independent biomarker for medulloblastoma with dismal prognosis. Thus, pharmacological inhibition of this candidate gene may constitute a new therapeutic option for patients with high-risk medulloblastomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1424. doi:1538-7445.AM2012-1424
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".