These data corroborate the involvement of three lncRNAs (HOTAIR, H19 and KCNQ1OT1) in breast tumourigenesis and support lncRNA CISH as a potential clinical assay. Importantly, CISH allows identification of the tissue compartment expressing lncRNA.
C-MET proto-oncogene is a tyrosine kinase situated on chromosome 7. C-MET and its ligand hepatocyte growth factor/scatter factor (HGF/SF) play a role in proliferation, differentiation and organ development. C-MET genetic aberrations are found associated with driving tumorigenesis. In this retrospective study, we reviewed molecular analysis data gathered from a cancer institute during a two-year period (2010-2012). Upon detection of tumors harboring c-MET mutations, we determined the status of the other mutations tested and evaluated c-MET expression by fluorescent in-situ hybridization (FISH). Our search resulted in identification of 134 c-MET mutations, 44% of which had mutations of at least one of the other genes tested. No c-MET expression aberrancy was detected in this subset by FISH. Survival amongst the patients with surgically resected metastatic colorectal cancers (CRC) was slightly better in those with only a c-MET mutation compared to those with no mutation detected, although the difference was not statistically significant. When c-MET inhibition becomes an integrated part of chemotherapy practice, our observed frequency of co-mutations will be an argument for utilizing c-MET targeted treatment in combination with other targeted drugs and therapeutic strategies. Larger studies can aid to further parse out c-MET prognostic and therapeutic significance.
A 59-year-old male with past medical history significant for non-Hodgkin's lymphoma status after chemotherapy presented with acute onset of neck pain, odynophagia, and dysphagia associated with subjective fever, chills, and dyspnea. Physical findings included a temperature of 38.4°C, hypertension, and tachycardia. Patient was found to have anterior neck tenderness. Laboratory evaluation revealed neutropenia. The patient was started on empiric antibacterial and antiviral therapy and continued on home prophylactic antifungal treatment. Thyroid function tests revealed overt hyperthyroidism. A thyroid ultrasound showed heterogeneous echotexture without discrete nodules. Subacute thyroiditis was treated with methylprednisolone, metoprolol, and opiate analgesics. Patient's antibacterial, antifungal, and antiviral treatments were broadened. A fine needle aspiration was not conducted. The patient's condition deteriorated rapidly over his brief hospital course and he expired. Autopsy showed fungal thyroiditis secondary to disseminated invasive Aspergillus. This report describes the presentation of fungal thyroiditis secondary to disseminated invasive Aspergillus originating from the respiratory tract. The authors review the diagnostic challenges, pathophysiology, and treatment of this condition.
Background: Long non-coding RNAs (lncRNAs) participate in a spectrum of biological activities by diverse mechanisms. LncRNA dysregulation has been reported for many cancers. Some lncRNAs may function as oncogenes (OG) and others as tumor suppressor genes (TSG). To date, lncRNA has been investigated primarily by qRT-PCR. In this study we have examined the relationship of lncRNA expression patterns to breast tumor pathology by chromogenic in situ hybridization (CISH). Methods: Expression of six lncRNAs, HOTAIR (OG), H19 (OG), Kcnq1ot1 (OG), Meg3 (TSG), Malat1 (OG), and ZFas1 (TSG), plus HER2 and MKI67 mRNAs was examined by RNAscope® CISH using tissue microarrays (TMAs) comprising normal epithelia, ductal carcinoma in situ (DCIS), and invasive carcinoma (IC) from 45 patients. HOTAIR/H19-mediated protein EZH2 was evaluated by immunohistochemistry (IHC). CISH and IHC results were scored in terms of the percentage of stained cells (<2%=0, 2-10%=1, 10-50%=2, >50%=3) and staining intensity (low=1, medium=2, high=3). Staining grade (SG) values were calculated as SG= proportion x intensity (SG value range=1-9). Results: The TMAs contained 36 normal epithelia (N), 34 DCIS (D) and 43 IC tissue punches. HOTAIR expression was common: at SG≥1, expression was detected in N:85%; D:97%; IC:100% (p>0.05). HOTAIR SG mean values (N 4.0, D 5.7, IC 6.2) were significantly higher in DCIS and IC than in normal tissues (N:D p<0.05; N:IC p<0.01; D:IC p>0.05). IC HOTAIR SGs correlated with Nottingham grade (p<0.01), HER2 CISH (p<0.01) and MKI67 CISH (p<0.05). HOTAIR expression levels in DCIS were associated with MKI67 CISH (p<0.01). H19 was rarely expressed in normal epithelial or tumor cells but was strongly expressed especially in inter-lobular stromal cells around invasive growths. At SG≥1 H19 was detected in N:38%; D:55%; IC:90% (p<0.01). H19 SG means (N 1.3, D 2.3, IC 3.7) were significantly higher among IC than normal or DCIS tissues (N:D p>0.05; N:IC p<0.01; D:IC p<0.05). IC H19 expression showed a positive correlation with Nottingham grade (p<0.05) and with MKI67 expression (p<0.01). H19 in DCIS showed a correlation with MKI67 CISH (p<0.01). Kcnq1ot1 staining was more common in DCIS and IC than in normal tissues: at SG≥1, N:77%; D:96%; IC:94% (p<0.01). Both the DCIS and IC SGs correlated with MKI67 expression (p<0.05). Meg3 expression was associated with normal breast; at SG≥1, N:46%; D:2%; IC:0%, [p<0.01]). Malat1 stained strongly in all cells in all specimens. Zfas1 specimen staining was absent or weak. IC and DCIS EZH2 IHC staining correlated positively with both HOTAIR and H19 expression (p<0.05). Conclusions: These data demonstrate the utility of CISH for investigating and demonstrating pathologic lncRNA expression. HOTAIR and H19 in particular and possibly Kncq1ot1 and Meg3 are potential breast cancer biomarkers. H19 may be a marker for DCIS at increased risk of progression to invasive cancer. Citation Format: Zhouwei Zhang, Zhihua Peng, Daniel Olsen, James deKay, Donald L. Weaver, Mark F. Evans. Long non-coding RNA in situ hybridization signal patterns correlate with breast tumor pathology. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1498. doi:10.1158/1538-7445.AM2014-1498
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