Purpose
This study aimed to conduct a comprehensive genetic analysis of patients with Langerhans cell histiocytosis (LCH), focusing on the frequency of MAPK pathway mutations, detailed mutation profiles of MAPK pathway genes, and their correlation with clinical features and prognosis in Korean LCH patients.
Materials and Methods
We performed targeted next-generation sequencing, capable of capturing exons from 382 cancer-related genes, on genomic DNA extracted from formaldehyde-fixed and paraffin-embedded samples of 45 pathologically confirmed LCH patients.
Results
The majority of patients (91.1%) exhibited single-system disease, with bone being the most common location (84.4%). Initial treatments varied, and no patients died during a median follow-up of 6.8 years. Our genetic assays revealed that all patients had MAPK pathway alterations, including BRAF mutations in 51.2%, MAP2K1 mutations in 42.2%, RAF1 mutations in 4.4%, and a KRAS mutation in 2.2%. These mutations were mutually exclusive. Detailed mutation profiles indicated that among the BRAF mutations, there were 18 point mutations and 5 in-frame deletions, while most MAP2K1 mutations were in-frame deletions, with only one missense mutation. We detected previously unreported variations of point mutations in BRAF, MAP2K1, KRAS, and the first instance of a RAF1-KLC1 fusion in LCH. MAP2K1 mutations occurred more frequently in older patients, whereas BRAF V600 mutations were commonly associated with unifocal bone disease. Genetic mutations did not correlate with high-risk features or event-free survival.
Conclusion
This study identified mutually exclusive MAPK pathway mutations in every LCH patient through comprehensive genetic analysis, highlighting the importance of inclusive testing in understanding the disease's genetics.
Young-Bem Se, Seung Hyun Kim, Ji Young Kim, Ja Eun Kim, Yun-Sik Dho, Jin Wook Kim, Yong Hwy Kim, Hyun Goo Woo, Se-Hyuk Kim, Shin-Hyuk Kang, Hak Jae Kim, Tae Min Kim, Soon-Tae Lee, Seung Hong Choi, Sung-Hye Park, Il Han Kim, Dong Gyu Kim, Chul-Kee Park
Cancer Res Treat. 2017;49(2):387-398. Published online July 19, 2016
Purpose
Homeobox (HOX) genes are essential developmental regulators that should normally be in the silenced state in an adult brain. The aberrant expression of HOX genes has been associated with the prognosis of many cancer types, including glioblastoma (GBM). This study examined the identity and role of HOX genes affecting GBM prognosis and treatment resistance.
Materials and Methods
The full series of HOX genes of five pairs of initial and recurrent human GBM samples were screened by microarray analysis to determine the most plausible candidate responsible for GBM prognosis. Another 20 newly diagnosed GBM samples were used for prognostic validation. In vitro experiments were performed to confirm the role of HOX in treatment resistance. Mediators involved in HOX gene regulation were searched using differentially expressed gene analysis, gene set enrichment tests, and network analysis.
Results
The underexpression of HOXA11 was identified as a consistent signature for a poor prognosis among the HOX genes. The overall survival of the GBM patients indicated a significantly favorable prognosis in patients with high HOXA11 expression (31±15.3 months) compared to the prognoses in thosewith lowHOXA11 expression (18±7.3 months, p=0.03). When HOXA11 was suppressed in the GBM cell lines, the anticancer effect of radiotherapy and/or temozolomide declined. In addition, five candidate mediators (TGFBR2, CRIM1, TXNIP, DPYSL2, and CRMP1) that may confer an oncologic effect after HOXA11 suppression were identified.
Conclusion
The treatment resistance induced by the underexpression of HOXA11 can contribute to a poor prognosis in GBM. Further investigation will be needed to confirm the value of HOXA11 as a potential target for overcoming the treatment resistance by developing chemo- or radiosensitizers.
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Pazopanib is a potent multitargeted tyrosine kinase inhibitor that has been shown to have good efficacy in patients with renal cell carcinoma. A previous phase II trial demonstrated that short-term pazopanib administration was generally well tolerated and showed antitumor activity in patients with early-stage non-small cell lung cancer. Herein, we report on the case of a 66-year-old man with simultaneous metastatic squamous cell carcinoma of the lung and renal cell carcinoma who was treated with pazopanib. The patient showed an unexpected partial response and experienced a 10-month progression-free survival without significant toxicity. To the best of the authors’ knowledge, this is the first report of pazopanib treatment in a non-small cell lung cancer patient in Korea. The results in this patient suggest that pazopanib may be a valid treatment option for advanced non-small cell lung cancer.
PURPOSE To investigate the effects of polyamines on tumor necrosis factor alpha (TNFalpha)-or tamoxifen (TAM)-induced apoptosis in estrogen receptor (ER)-positive MCF- 7 and ER-negative MDA-MB-231 human breast cancer cells. MATERIALS AND METHODS Cell viability was assessed by using MTT assay. Reactive oxygen species (ROS) generation was measured using 2', 7'-dichlorofluorescin diacetste (DCFDA) by fluorescence plate reader. DNA fragmentation was assessed by 1.5% agarose gel electrophoresis. RESULTS TNFalpah and TAM showed significant dose- and time- dependent inhibitory effects on the growth of MCF-7 human cells. However, the growth of MDA-MB-231 cells were not inhibited by TNFalpha or TAM treatment. The generation of ROS was increased in dose-and time-dependent manner by TNFalpha treatment in MCF-7 cells. Polyamines, especially spermine suppressed TNFalpha-induced ROS generation in MCF-7 cells. Antioxidant effects of polyamines were also demonstrated by DNA fragmentation, cell morphology as well as ROS generation assay. Polyamines also blocked TAM-induced cell death in MCF-7 cell. However, MDA-MB-231 cells showed resistance to the cytotoxic effects of TNFalpha or TAM. CONCLUSION These results suggest that polyamines may prevent TNFalpha or TAM-induced apoptosis in MCF-7 human breast cancer cells.
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