Diagnostic value of a novel fully automated immunochemistry assay for detection of ALK rearrangement in primary lung adenocarcinoma

Mitofusin-2 (MFN2) is a mitochondrial protein associated with mitochondrial fusion process. It was initially identified as a hyperplasia suppressor and implicated in Charcot-Marie-Tooth disease. Recent studies showed that MFN2 played important roles in the development of multiple tumors. Here we examined MFN2 expression in 30 lung adenocarcinoma samples and revealed that the expression of MFN2 was significantly higher in lung adenocarcinoma tissues as compared to adjacent normal tissues. We then investigated the impact of MFN2 knockdown on A549 human lung adenocarcinoma cells and showed that cell proliferation, cell cycle and invasion behavior were all deregulated by MFN2 knockdown. And deregulation of cell cycle pathway after MFN2 knockdown was confirmed by microarray analysis. Furthermore, microarray analysis also revealed that different oncogenes such as RAP1A, RALB and ITGA2 were oppositely regulated by MFN2, which provided molecular clues for the paradoxical functions of MFN2 in tumor development. Taken together, our study unraveled the tumor-promoting functions of MFN2 in lung adenocarcinoma and implicated that the role of MFN2 in cancer development might be more complicated than expected and should be explored in detail in the future.

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“…?, moderate cytoplasmic reactivity) and 3 (?? ?, granular cytoplasmic reactivity of strong intensity in C10 % of tumor cells) [17].…”

Section: Methodsmentioning

confidence: 99%

Mitofusin-2 over-expresses and leads to dysregulation of cell cycle and cell invasion in lung adenocarcinoma

Lou

Liu

et al. 2015

Med Oncol

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“…Among them, FISH was approved as a gold standard by the Food and Drug Administration (FDA) with the Vysis ALK Break Apart FISH Probe Kit. ALK rearrangement could also detected by IHC, an auto-mated the Ventana ALK assay kit with D5F3 antibody (Ventana Medical Systems Inc., Tucson, Ariz) coupled with an ultrasensitive amplification and detection system have been verified in ALK protein detection (6,7). Besides that, RT-PCR is a more sensitive and specific method that can allows the detection of even a few molecules of chimeric ALK transcripts.…”

Section: Introductionmentioning

confidence: 99%

High concordance of ALK rearrangement between primary tumor and paired metastatic lymph node in patients with lung adenocarcinoma

Hou

Ren

Su³

et al. 2016

J. Thorac. Dis.

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Background: Lung cancer has heterogeneous features. It remains unclear whether ALK rearrangement was distributed heterogeneously in tumor from different anatomic sites. To address this issue, we investigate the concordance of ALK rearrangement between primary tumors and paired metastatic lymph nodes in pulmonary adenocarcinoma patients. Results: A total of 101 patients were enrolled into this study with a median age of 60 years old (range, 35-78 years). ALK rearrangement was found in 20 primary lesions, while in 18 paired metastatic lymph nodes. ALK rearrangement was more frequently happened in younger (P<0.001), Nonsmokers (P=0.012), high-stage disease (P=0.021) and predominantly solid growth pattern (P=0.024). The concordance rate between primary tumor and paired metastatic lymph nodes was 98%. Two patients with ALK rearrangement on primary tumor didn't show ALK gene fusion on paired metastatic lymph nodes. Sixty-eight cases had more than two stations of metastatic lymph nodes. ALK rearrangement in the different station of metastatic lymph nodes of the same patient was consistent.Conclusions: High concordant rate of ALK rearrangement between primary tumors and paired metastatic lymph nodes were found in this study. The authors concluded that specimens from metastatic lesions and primary tumors are equally suitable for detection ALK rearrangement.

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“…Robust and reliable laboratory tests for predictive biomarkers are critical to select appropriate patients for targeted therapy. Patients with improved performance status and EML4-ALK translocation have an increased overall survival time compared with patients treated with conventional chemotherapy (17,48). There is no significant difference in clinical factors and survival outcome between the patients harboring variant 1 and those harboring non-variant 1 EML4-ALK fusion genes (49).…”

Section: Discussionmentioning

confidence: 98%

“…The subtle changes may be challenging to interpret by FISH analysis, and have led to false-negative results (15,16). IHC has been considered as an alternative to FISH for the detection of ALK rearrangement, and Ventana IHC for ALK fusion gene has been approved by the European Union (17).…”

Section: Introductionmentioning

confidence: 99%

Expression level of CRKL and AXL combined with exon 19 deletion in EGFR and ALK status confer differential prognosis of lung adenocarcinoma subtypes

Cai

Dong

et al. 2016

Oncology Letters

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Abstract. Non-small cell lung cancer (NSCLC) is a lethal cancer-related disease in population. Adenocarcinoma (AC) is subclassified into several subtypes based on the new classification by the International Association for the Study of Lung Cancer, American Thoracic Society and European Respiratory Society in 2011. Correlation between original expression of Crk-like (CRKL) and anaplastic lymphoma receptor tyrosine kinase in diverse histological components of AC and epidermal growth factor receptor (EGFR) or ALK status was evaluated by immunohistochemistry and sequencing in present study. A total of 106 cases, including 83 patients (78.3%) with mixed-type ACs, were assessed in the present study using eligible follow-up data. The ACs consisted of 32 acinar, 12 papillary, 5 mucinous, 11 micropapillary and 46 solid-predominant ACs. In total, 69.8% samples were composed of 2 or 3 histological components, with different expression levels of CRKL and AXL. ACs with EGFR mutation had a higher level of AXL expression compared with ACs without mutation (P=0.019). Multivariate survival analysis showed that AC subtypes and EGFR mutation subtypes were significantly associated with the progression-free survival (PFS) time. Acinar AC was the subtype with the most notable PFS time (30.6 months), which was significantly different from the PFS time of papillary, mucinous, micropapillary and solid-predominant ACs (hazard ratio, 0.4; 95% CI, 0.21-0.75; P=0.005). Among the ACs with exon 19 mutation, the median PFS time (28.8 months) of patients with a lower level of AXL protein expression was increased compared with the PFS time of patients with the L858R mutation and wild-type EGFR (9.1 months and 11 months, respectively; P=0.03), whereas no significant difference in ACs with an increased level of AXL expression. However, AC patients with higher level of CRKL expression had better PFS (28.8 months) than patients with the L858R mutation and wild-type EGFR (9.1 months and 11.3 months, respectively). Exon 19 deletion is an important status that is associated with an improved response to conventional chemotherapy. The identification of EGFR mutations combined with CRKL and AXL status may potentially alter the way that lung AC is treated.

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Diagnostic value of a novel fully automated immunochemistry assay for detection of ALK rearrangement in primary lung adenocarcinoma

Abstract: The novel fully automated IHC assay is a reliable screening tool in routine pathologic laboratories for identification of patients with ALK rearrangement for targeted therapy in lung ADC.

Cited by 113 publications

References 23 publications

Mitofusin-2 over-expresses and leads to dysregulation of cell cycle and cell invasion in lung adenocarcinoma

Mitofusin-2 over-expresses and leads to dysregulation of cell cycle and cell invasion in lung adenocarcinoma

High concordance of ALK rearrangement between primary tumor and paired metastatic lymph node in patients with lung adenocarcinoma

Expression level of CRKL and AXL combined with exon 19 deletion in EGFR and ALK status confer differential prognosis of lung adenocarcinoma subtypes

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