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R.M. Reis
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MA 01 - SCLC: Research Perspectives (ID 650)
- Event: WCLC 2017
- Type: Mini Oral
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:John V Heymach, Eun Kyung Cho
- Coordinates: 10/16/2017, 11:00 - 12:30, Room 503
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MA 01.01 - Metastatic Behavior of Pulmonary Neuroendocrine Carcinomas Is Associated with Epithelial to Mesenchymal Transition Gene Profile (ID 9362)
11:00 - 12:30 | Author(s): R.M. Reis
- Abstract
- Presentation
Background:
The new 2015 WHO classification broadly divided pulmonary neuroendocrine tumor (NET) of the lung in low-grade typical carcinoid (TC) and atypical carcinoid (AC), to the high-grade large-cell neuroendocrine carcinoma (LCNEC) and the small-cell carcinoma (SCLC). The molecular alterations underlying the pathogenesis of these tumors have been studied showing two blocks of entities with independent cellular mechanisms. Many of the differences between the two NETs blocks can be ascribed to tobacco consumption, which induces epithelial to mesenchymal transition activation, responsible for invasive and metastatic behavior. These correlations further highlight the difference in OS for patients with low and high grade metastatic NETs. Therefore, epithelial to mesenchymal transition (EMT) genes profile emerge promise as indicator of invasion and metastasis in NETs.
Method:
Fresh frozen tissue from SCLC (n = 10), LCNEC (n = 4), AC (n = 5), TC (n = 5) and matched normal tissue samples were collected for qRT-PCR analysis carried out on StepOnePlus™ Real-Time PCR System (Applied Biosystems) with RT[2] Profiler PCR Array System for the EMT pathway with 84 target genes (Qiagen, Dusseldorf, Germany). Linear regression was done to evaluate association between gene expressions. Clinical variable such as age, gender, tobacco history, lymph node metastasis and histologic types were associated with gene expression. Differences were regarded as statistically significant at P < 0.05.
Result:
High expression of membrane receptor EGFR (p = 0.003), protein of the matrix metalloproteinase MMP3 (p = 0.044), transcriptional factor TCF3 (p = 0.022) and signaling pathway factor WNT5A (p = 0.013) were observed in patients with tobacco history. Metastatic LCNEC and SCLC presented significant lower expression of JAG1 gene and higher level of EGFR (p<0.01), transmembrane protein DSP (p = 0.03), TCF3 (p = 0.01), TGF-B3 (p = 0.04) and WNT5A (p = 0.01) compared to TC and AC. In addition to these genes, AKT1 and MAP1B were equally high expressed in metastatic NE carcinomas. Importantly, increased expression of these genes added of MMP2 gene was significantly associated with poor OS of the patients.
Conclusion:
A panel of 84 EMT genes was tested and the best biomarkers included EGFR, MMP2, MMP3, TCF3, WNT5A, JAG1, TGFB3, AKT1 and MAP1B with impact on unfavorable prognostic and overall survival of patients, highlight that EMT play a fundamental role in pathogenetic pathway of metastasis in NETs. Supported by CNPq project 301411/2016-6; FAPESP 2013/10113-7.
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P3.15 - SCLC/Neuroendocrine Tumors (ID 731)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.15-006 - Comprehensive Analysis of EMT Gene Signature in Primary and Metastatic Small Cell and Non-Small Cell Carcinomas of the Lung (ID 8182)
09:30 - 16:00 | Author(s): R.M. Reis
- Abstract
Background:
Metastasis are responsible for the death of 90% of patients with lung cancer (LC) indicating the necessity to know the multiple signaling pathways involved. Among them, high-grade neuroendocrine lung carcinomas (NELC) invade and metastasize rapidly. Therefore, biomarkers of aggressiveness in LC remain to be determined, especially in NELC. Epithelial to mesenchymal transition (EMT) genes profile emerge promise as indicator of invasion and metastasis. The aim was to investigate the expression of EMT markers and assessed their relationship with the clinicopathological features and prognosis.
Method:
Fresh frozen tissue from SCLC (n=15) and NSCLC (ADc n=23 and SqCC n=10) and matched normal tissue samples were collected for qRT-PCR analysis carried out on StepOnePlus™ Real-Time PCR with RT[2] Profiler PCR Array System for the EMT pathway with 84 target genes (Qiagen, Dusseldorf, Germany). Gene expression was correlated with clinicopathological variables in the SCLC and NSCLC groups. Survival curves were calculated using the Kaplan-Meier method and risk factors determined by multivariate Cox regression model. Differences were regarded as statistically significant at P<0.05.
Result:
Female patients presented significant higher expression of EGFR (p=0.03), ILK (p=0.05), JAG1 (p=0.01), MMP2 (p=0.04) and SNAI2 (p=0.04) genes. Tobacco history was associated with increased expression of EGFR (p<0.01), ITGAV (p=0.05), SPP1 (p<0.01) and WNT5A (p=0.02). NSCLC presented similar levels of EMT genes evaluated. Tumors from SCLC and NSCLC in advanced N and M stage expressed significant high levels of genes related to cellular membrane [EGFR (p=0.03), ILK (p<0.01), FR11 (p=0.05), ITGAV (p=0.02), ITGB1 (p<0.01), DSP (p=0.04)], extracellular matrix [COL5A2 (p=0.04), COL1A2 (p=0.04)], cytoplasm [GSK3B (p=0.01), VPS13A (p=0.02), MAP1B (p=0.01)] and nucleus SNAI2 (p=0.04). Interestingly, SCLC tumors expressed higher levels of FR11 (p=0.02), GSK3B (p=0.04), ILK (p<0.01), ITGB1 (p=0.01), JAG1 (p<0.01) and MAP1B (p=0.01) indicating more aggressiveness than NSCLC. A mathematical model controlled for N and M stage, histologic type and the gene expression showed that patients with SCLC expressing high levels of MMP2 and SPARC presented significant high risk of death (OR 5.41 and 4.94, respectively) compared to those with lower expression. Patients with NSCLC with low levels of ILK, SPP1, COL1A2, ITGB1 presented a low risk of death (OR -7.02, -0.4, -1.3 and -3.02, respectively).
Conclusion:
Different expression of EMT genes in SCLC and NSCLC, its relationship with histologic types, advanced stage, lymph node metastasis and death suggest a possible role of these markers in their malignancy, but more importantly provide a potential biomolecular marker to predict outcome.
