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S. Xu
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P1.15 - SCLC/Neuroendocrine Tumors (ID 701)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.15-008 - Clinical Features and Gene Mutation Profiling of Pulmonary Carcinoid Tumors (ID 7440)
09:30 - 09:30 | Author(s): S. Xu
- Abstract
Background:
Carcinoid tumors of the lung are an uncommon group of pulmonary neoplasms. Carcinoid tumors represent the most indolent form of a spectrum of bronchopulmonary neuroendocrine tumors, however little is known about its molecular features. We analyzed pulmonary carcinoid tumors to identify biologically relevant genomic alterations.
Method:
We reviewed all the patient data from 2006 to 2016 in our hospital and collected 20 cases of lung carcinoid tumors. We summarized their clinical features and imaging data. Among 20 cases of lung carcinoid tumors, quality control was passed for 6 patients. We performed targeted capture sequencing of 56 cancer-related genes. Moreover, we made a literature review of pulmonary carcinoid tumors and summarized the clinical features and gene mutations.
Result:
Among the 20 pulmonary carcinoid tumors cases, which include 9 typical carcinoid and 11 atypical carcinoid tumors, there was a male predominance of this disease (Male vs Female: 15 vs 5). The range of age is 14 to 71 with the median age of 48. For gene mutation profiling on 6 pulmonary carcinoid tumors, we detected 27 mutations in 21 genes, including 22 missense mutations, 2 deletion mutations, 1 frameshift mutation and two others. Among the 21 genes, there are 11 proto-oncogenes and 6 tumor suppressor genes, which were reported to participate in the tumorigenesis, growth, invasion and metastasis of tumor.
Conclusion:
Through the next generation sequencing, we detected 27 mutations in 21 gene on the 6 pulmonary carcinoid tumors. Among these genes, the mutation of gene IGF1R, ERBB4, KIT and TSC2 showed the most frequent. We supposed that these genes might be involved in the tumorigenesis of pulmonary carcinoid tumors and the potential targets of therapy. Further functional studies of these genes are worthy of being explored.
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P3.01 - Advanced NSCLC (ID 621)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.01-002 - Concurrent EGFR T790M Secondary Mutation and EMT in a Lung Adenocarcinoma Patient with EGFR TKI Drug Resistance (ID 7373)
09:30 - 09:30 | Author(s): S. Xu
- Abstract
Background:
Almost all EGFR-mutant lung cancers develop resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). Several mechanisms for this acquired resistance have been identified, including development of an EGFR T790M mutation, MET amplification, hepatocyte growth factor (HGF) overexpression, loss of PTEN expression, epithelial to mesenchymal transition (EMT) and transformation to small cell lung cancer.
Method:
We presented a lung cancer patient with EGFR exon 19 deletion who was resistant to EGFR TKI treatment during disease progression. The original lung tumor started to enlarge and bred a secondary growing nodule adjacently. A left upper lobectomy plus systematic mediastinal lymphadenectomy by VATS was performed after a whole body evaluation which had no sign of extrapulmonary abnormalities. The pathological examination, genetic sequencing, and histological staining of E-cadherin and Vimentin were performed on the TKI resistant postoperative specimens.
Result:
The original lung tumor was confirmed to be adenocarcinoma according to the typical morphology and positivity of TTF1 and CK7. The secondary lung tumor has sarcomatoid histology showing a more spindle-like mesenchymal morphology with CK and Vimentin positivity. Next generation sequencing (NGS) test confirmed that the original lung adenocarcinoama retained EGFR exon 19 deletion but was also found T790M mutation in EGFR exon 20. The secondary sarcomatoid carcinoma retained EGFR exon 19 deletion as well. Besides, sarcomatoid carcinoma had genetic mutation on FANCL and BCL2L2, and amplification on CDK4, MDM2, APFRP1, GNAS, CIC, FANCE, Notch4 and AKT2. In addition, in comparison with adenocarcinoma from biopsy and postoperative specimens, the second growing sarcomatoid tumor is strongly positive for Vimentin and nearly negative for E-cadherin, indicating that sarcomatoid histology probably underwent EMT.
Conclusion:
The clinical implication of this case provides significant insights into our understanding that two or more mechanisms might be involved simultaneously in the EGFR TKI resistance. Therefore, if possible, it is necessary to perform tumor biopsies after the development of resistance to identify the best treatment options for patients.
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P3.02 - Biology/Pathology (ID 620)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 2
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.02-095 - Basic Transcription Factor 3 Is Involved in Lung Cancer Growth and Progression (ID 7395)
09:30 - 09:30 | Author(s): S. Xu
- Abstract
Background:
Basic transcription factor 3 (BTF3) which is a general RNA polymerase II transcription factor plays a crucial role in the regulation of various biological processes. Evidence has demonstrated that BTF3 is aberrantly expressed and involved in the development and progression of gastric cancer and colorectal cancer. However, the role of BTF3 in lung cancer is not clear. The present study is to investigate the expression of BTF3 in non-small cell lung caner (NSCLC), its role in tumor growth as well as the underlying mechanisms.
Method:
BTF3 shRNA lentiviral vector was constructed and transfected in human NSCLC cells NCI-H1299 and A549. The cell proliferation, viability and apoptosis were evaluated by Celigo, MTT and AnnexinV-APC assays. The immunohistochemical stainings of BTF3 were performed on ten NSCLC tumors and matched adjacent lung tissues. Xenograft tumor model was established to evaluate the role of BTF3 in tumor formation in vivo. To further explore the underlying mechanism, a gene array was performed in BTF3 knockdowned A549 cells and pathway/network analyses was performed with Ingenuity Pathway Analysis (IPA).
Result:
Knockdown of BTF3 inhibited the proliferation and viability and increased apoptosis significantly in NSCLC cells. The BTF3 expression was much higher in NSCLC tumors compared to the adjacent lung tissues. A549 with BTF3 shRNA lentiviral transfection could not form subcutaneous tumors in immune-deficient mice in vivo. After BTF3 was inhibited in A549 cells, it was observed 489 upregulated and 148 downregulated genes (FC>1.5). IPA core analysis of these proteins revealed that acute phase response pathway was significantly enriched among other canonical pathways, and played a role in cell death, cell movement of myeloid cells and organismal death. We further utilized IPA upstream regulator analysis and found two transcriptional regulators XBP1 and NUPR1 that are predicted to be the key regulators of proteins changed in the BTF3 inhibited A549 cells. Western blot analysis verified that HK2, DUSP5 and KLF4 were significantly downregulated in BTF3 inhibited A549 cells.
Conclusion:
These results suggest, for the first time, that BTF3 is over-expressed in lung cancer and favors tumor growth, suggesting that BTF3 might play a role in the progression of lung cancer. The investigation of BTF3 in NSCLC survival and prognosis and further regulatory mechanisms are ongoing.
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P3.02-097 - Clinicopathological Features and Genetic Landscape of Pulmonary Large Cell Carcinoma under 2015 WHO Classification of NSCLC (ID 7461)
09:30 - 09:30 | Author(s): S. Xu
- Abstract
Background:
Pulmonary large cell carcinoma (LCC) was re-defined by 2015 WHO classification of non-small cell lung cancer (NSCLC) by excluding the tumors with adenocarcinoma, squamous and neuroendocrine features. The clinicopathological features and genetic landscape of pulmonary large cell carcinoma (LCC) with new classification were barely investigated.
Method:
Twenty-four LCC patients previously diagnosed under WHO 2004 criteria at Tianjin Medical University General Hospital were collected and re-classfied by 2015 WHO classification criteria. The specimen with more than 1% positivity of TTF-1/napsin A and 10% positivity of p40/p63/ CK5/6 expression was excluded from LCCs under WHO 2015 criteria in this study. The specimens with CgA and Syn positivity, the feature of neuroendocrine tumor, were excluded too. The genetic analysis was performed by the next-generation sequencing (NGS) of 46 cancer-related genes on the newly re-classified LCCs. The correlation of clinicopathological and genetic data was further analyzed on these samples.
Result:
All 8 patients re-defined as LCCs under WHO 2015 criteria were male and 7 patients were smokers. None of significant difference was found between the LCCs patients and excluded patients under WHO 2015 criteria in terms of age, gender, smoking status, primary site and TNM staging. Although lower OS time was presented in LCCs under WHO 2015 criteria compared with the excluded ones, no significant difference was detected between these two groups (LCC under WHO 2015 criteria vs excluded specimens = 698.75±62.83 vs 1301.03 ±245.40 days, P=0.738). Ten of 46 candidate genes including EGFR, KRAS, TP53, KIT, PIK3CA, PTEN, IDH1, APC, ATM and BRAF were detected in all 24 specimens. Four of all 8 LCC patients under WHO 2015 criteria presented TP53 mutation and two showed concurrent TP53 and KRAS mutations. None of any somatic mutation was detected in the rest 4 of 8 LCCs. LCCs under 2015 criteria showed a lower heterogeneity and lower incidence of TP53 mutation compared to the with excluded specimens (TP53 mutation: LCCs vs excluded specimens=4/8 vs 15/16, p=0.015; Detected mutations: LCCs vs excluded specimens = 2/46 vs 10/46, p=0.030).
Conclusion:
LCCs re-classified by the new criteria remain the features of higher incidence in male and tobacco exposure. No significant difference change in terms of other clinical characteristics. The lower heterogeneity of somatic mutation in LCCs under WHO 2015 criteria might reflect the precision and uniformity of the new classification on the genetic level.
