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Chenguang Li
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MA21 - Molecular Subtyping, CBL3, and Non Coding RNA (ID 924)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 15:15 - 16:45, Room 205 BD
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MA21.05 - Comprehensive Genomic Characterization and Prognostic Nomogram Developed by 295-Gene Panel Targeted Sequencing (ID 13664)
15:45 - 15:50 | Author(s): Chenguang Li
- Abstract
- Presentation
Background
The genomic landscape of lung cancer has been thoroughly studied in the western population. But comprehensive genetic profiling reports have been limited for the Chinese patients. Here we conducted deep targeted sequencing on a large cohort of Chinese treatment-naïve lung cancer patients and identified novel molecular patterns. We developed nomogram models for prognosis prediction by integrating genetic and clinical characteristics and aim to explore more precise models for risk stratification beyond TNM staging.
a9ded1e5ce5d75814730bb4caaf49419 Method
This was a retrospective study, enrolling diagnosed lung cancer patients at Tianjin Medical University Cancer Institute & Hospital from 2009 to 2012. We developed genomic landscape by targeted sequencing using a panel consisting of exons and critical introns of 295 cancer-related genes. Nomogram models were established to provide risk stratification in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) patients
4c3880bb027f159e801041b1021e88e8 Result
513 tumor tissue samples were collected at very beginning of treatment (stage I, n=193; stage II, n=140; stage IIIA, n=140; stage IIIB, n=5; stage IV, n=28; unknown, n=7). The most frequently mutated oncogenic genes in LUAD were EGFR (55%) and KRAS (11%), compared to 14% and 33% in TCGA. Heterogeneity existed in terms of mutual exclusive and co-occurrent mutated gene pairs between LUAD and LUSC. In LUAD, pairs with most significant exclusivity was EGFR/KRAS and co-occurrent was NOTCH3/GRIN2A, whereas the most significant concurrent gene pair in LUSC was ZNF703/FGFR1. To predict survival, our nomograms identified that, in stage I-IIIA LUAD and LUSC, mutated TET2 contributed to more favorable DFS while mutations in EPHA3 and ETV5 indicated better OS. Stage and mutated KRAS were associated with inferior DFS and OS (DFS, n=222, c-index=0.714; OS, n=308, c-index=0.706). In the T1+2&N0&M0 subgroup, which is considered clinically low risk for relapse, older patients who carry BRCA2 mutations were found to strongly correlate with poor DFS (n=121, c-index=0.709), while age and mutated KRAS were distinct indicators of inferior OS (n=163, c-index=0.725). The calibration for survival probability displayed well agreement between nomogram prediction and actual outcomes. Stratification of different risk groups based on nomogram prediction displayed significant differences among Kaplan-Meier curves for survival outcomes (p<0.0001).
8eea62084ca7e541d918e823422bd82e Conclusion
This is the so far largest cohort of Chinese lung cancer patients with comprehensive genomic profiling reported. We revealed unique molecular profiles than TCGA and distinct mutual exclusivity and co-occurrence patterns between LUAD and LUSC. In addition, the nomogram models show promise of more precise prognostic prediction of NSCLC patients when integrating genetic information with clinical characteristics.
6f8b794f3246b0c1e1780bb4d4d5dc53Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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P3.13 - Targeted Therapy (Not CME Accredited Session) (ID 979)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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P3.13-14 - Identification of Novel Mutations by High-Throughout Sequencing in T790M Wildtype/cMET Unamplified NSCLC with Acquired Resistance to EGFR TKIs (ID 12481)
12:00 - 13:30 | Presenting Author(s): Chenguang Li
- Abstract
Background
Lung cancer remains the leading cause of cancer-related death worldwide. Though most patients with EGFR activating mutations are sensitive to EGFR tyrosine kinase inhibitors (TKIs), tumors will inevitably acquire resistance to first generation EGFR TKIs. EGFR T790M mutation and cMET amplification are common mechanisms. Further study is needed to explore unknown genomic alterations contributing to drug resistance.
a9ded1e5ce5d75814730bb4caaf49419 Method
In the screening period of ASTRIS (D5160C00022) study of single center, tumor and blood samples from 69 stage ⅢB-Ⅳ NSCLC patients defined as acquired resistance to first generation EGFR TKIs (Gefitinib, Elortinib or Ecotinib) were collected. The cobas® and Droplet digital PCR (ddPCR) were used to detect T790M mutations in tumor samples and plasma ctDNA. cMET amplification were evaluated by Fluorescence in situ Hybridization (FISH). Exome sequencing were performed in four T790M wildtype/cMET unamplified samples.
4c3880bb027f159e801041b1021e88e8 Result
The T790M mutation rate of FFPE tissue cobas, plasma cobas and plasma ddPCR testing were 54.5%, 21.3% and 30.4% respectively. Taking all testing methods into account, the T790M positive rate was 52.2%. In 21 samples which tumor re-biopsy was performed, 14 were T790M positive (66.7%). cMET amplification were identified in 3 out of 7 T790M negative samples. Exome sequencing in 4 T790M wildtype/cMET unamplified samples and paired white blood cells identified a cohort of candidate key mutated genes including BRAF, FGFR1, PAK1, PCNT, PEBP4 and SOX3.
8eea62084ca7e541d918e823422bd82e Conclusion
EGFR T790M mutation and cMET amplification are main mechanisms leading to EGFR TKI resistant in lung adenocarcinoma. These key mutated genes identified in the present study would need further functional study validation.
6f8b794f3246b0c1e1780bb4d4d5dc53
