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Jia-Tao Zhang
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FP01 - Early Stage/Localized Disease (ID 111)
- Event: WCLC 2020
- Type: Posters (Featured)
- Track: Early Stage/Localized Disease
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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FP01.03 - Genetic Predisposition for Pre-Invasive Lung Adenocarcinoma Manifesting as Ground-Glass Nodules with Family History of Lung Cancer (ID 1512)
00:00 - 00:00 | Author(s): Jia-Tao Zhang
- Abstract
Introduction
Lung cancer with family history have been increasing gradually of late years in East Asian, especially those presenting as pulmonary ground-glass nodules (GGNs). The predisposition of GGN with lung cancer family history remains baffling.
Methods
This prospective study (NCT04220268) enrolled patients with pulmonary pre-invasive or invasive adenocarcinoma, which presenting as GGN in computer tomography (CT) scans. We used extreme phenotype approach to select 50 GGN patients with a family history of lung cancer (FHLC) in one or more first-degree relatives. Blood samples were collected and sequenced by whole exome sequencing (WES) to investigate rare but potential pathogenic germline mutations with a stepwise filtering strategy including: variant quality and classification, minor allele frequency (MAF) < 0.01 in public and local database, functional prediction and family segregation.
Results
In total, 2325 single nucleotide variants (SNVs) and 238 frameshift mutations with MAF <0.01 were finally identified through the filter. The number of these rare, damaging germline mutations in non-smoking patients were significantly higher than those in smoking patients (Spearman’s ρ= -0.33, p=0.02). Fifty-nine SNVs and 10 frameshifts were not only rare and deleterious but also presented in more than two families. Importantly, twenty of them had been reported to be associated with higher risk or carcinogenesis of lung cancer. Two of them were validated in 126 nonoverlapping susceptibility loci for lung carcinogenesis identified by genome-wide association studies (GWAS).
Conclusion
Patients with GGNs and FHLC may have inheritable carcinogenesis mutations. These variants may potentially contribute to the risk of pulmonary pre-invasive adenocarcinoma susceptibility in Chinese population. Non-smoking patients with GGN probably had higher genetic predisposition than the smoking patients.
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MA13 - Tumor Biology: Focus on EGFR Mutation, DNA Repair and Tumor Microenvironment (ID 214)
- Event: WCLC 2020
- Type: Mini Oral
- Track: Tumor Biology and Systems Biology - Basic and Translational Science
- Presentations: 1
- Moderators:
- Coordinates: 1/31/2021, 16:45 - 17:45, Scientific Program Auditorium
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MA13.09 - Heterogeneous Genomic Evolution and Immune Microenvironments in Metastatic Lung Cancer (ID 1155)
16:45 - 17:45 | Author(s): Jia-Tao Zhang
- Abstract
Introduction
The comprehensive insights into the genomic evolution and immune microenvironments of lung cancer metastasis remain unknown. Furthermore, whether non-stochastic patterns of lung cancer metastases to different sites exist is elusive.
Methods
We investigated the genomic evolution and immune microenvironments of paired primary-metastatic (P-M) tumors by employing multi-region whole-exome sequencing and immunohistochemistry in 179 samples from 51 lung cancer patients with metastases to the pleura, bone, adrenal gland, brain and additional lymph nodes.
Results
Our data revealed differences in genomic landscapes, molecular determinants, seeding patterns, and lymphocyte infiltration among different metastatic sites. Metastatic lymph nodes showed the highest P-M genomic divergence, followed by pleura, brain, bone, and adrenal gland. We identified MYC amplification as a selected event driving metastasis and associated with worse overall survival (P = 0.013). Interestingly, EGFR amplification and TP53 mutations were preferably selected in distant metastases whereas RICTOR amplification was selected in regional metastases (pleura and lymph nodes). Based on spatial tumor growth model, we demonstrated commonly late arising of metastatic seeding (61.1%) of lung cancer with quantitative evidence. However, mutation rate and timing of dissemination varied among different metastatic sites. Metastases at regional tissues were more frequently infiltrated with CD8+ tumor-infiltrating lymphocytes (TILs) than those at distant organs, among which bone metastases were merely infiltrated with CD8+ TILs. Furthermore, monoclonal and polyclonal seeding were associated with rapid and attenuated progression (P = 0.013), respectively, which supports the potential value as a prognostic predictor. Immune-heterogeneity and -homogeneity were primarily driven by arm-level and focal copy number events in primary tumors, respectively, indicating distinct mechanisms of tumor immune escape during metastasis.
Conclusion
These findings implied the combinatorial role of multiple factors in shaping patterns of dissemination and advanced the clinical evaluation and intervention of lung cancer metastasis.
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P59 - Tumor Biology and Systems Biology - Basic and Translational Science - Genomics (ID 197)
- Event: WCLC 2020
- Type: Posters
- Track: Tumor Biology and Systems Biology - Basic and Translational Science
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P59.03 - Intratumoral Heterogeneity and Clonal Evolution in Large Non-Small Cell Lung Cancer (>7cm) Delineated by Multiregion Sequencing (ID 1305)
00:00 - 00:00 | Presenting Author(s): Jia-Tao Zhang
- Abstract
Introduction
T4N0M0 (size > 7cm) non-small cell lung cancer (NSCLC) represent relatively favorable prognosis in stage IIIA category, probably due to the limited metastatic potential. The intratumor genomic profile of these oversize tumors have not been well studied.
Methods
T4N0M0 surgical NSCLC patients were enrolled. Whole-exome sequencing on three regions of each surgical tumor was performed. Single nucleotide variation (SNV), small insertion and deletions (Indels), and copy number variation were called and used for the analysis of intratumoral heterogeneity (ITH). Driver genes were identified by a gene list from the research of Matthew H. Bailey 2018. Tumor mutation burden (TMB) was calculated using all somatic nonsynonymous mutations (variant allele frequency > 0.03). Phylogenetic trees were constructed by regionally shared and private alterations.
Results
Five NSCLC were enrolled, including three adenocarcinoma and two squamous cell carcinoma. 15 tumor regions were sequenced successfully, with a median coverage of 452×. Interestingly, two distant ITH/TMB phenotypes were found, ITHlow/TMBhi (P1,P4,P5) andITHhi/TMBlow (P2,P3). The average heterogeneous somatic mutations in these two categories were 36% vs 98%, while the TMB was 154 vs 19. The ITHlow/TMBhi type had higher proportion of trunk SNV and Indels (62.2%, 53.2, and 65.5%, respectively), while ITHhi/TMBlow had lower of trunk (0% and 3.2%). In total, 11 driver mutations were identified and 72.73% of the driver mutations located on the trunks of tumor phylogenetic trees, including KEAP1, TP53, FAT1, CDKN2A, SMARCA4, and FAT1.
Conclusion
Our data implied two distant ITH/TMB phenotypes in the T4N0M0 NSCLC (>7cm). It may contribute to our need for further understanding of tumor indolent growth pattern.
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P85 - Targeted Therapy - Clinically Focused - MET (ID 262)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P85.02 - NGS could not Replace FISH Regarding to MET Amplification as an Optimal Biomarker (ID 1581)
00:00 - 00:00 | Author(s): Jia-Tao Zhang
- Abstract
Introduction
MET amplification (MET amp) is known as an important mechanism of resistance to EGFR-TKIs in NSCLC. We investigated the association between survival benefits and MET status identified by different methods, to explore the appropriate biomarker to select patient for MET-TKIs treatment in advanced NSCLC.
Methods
Method: FISH (fluorescence in situ hybridization), IHC (immunohistochemistry) and NGS (next generation sequences) were performed prospectively from FFPE/liquid samples with NSCLC. MET amplification by FISH was defined as MET/CEP7 ratio＞2 or CN(copy number )＞6 and served as the standard reference for over-express by IHC and copy number gain (CNG) by NGS. Objective response (OR) and PFS were used to confirm optimal biomarker for MET inhibitor.
Results
We identified MET dysregulation of 37 NSCLC patients by FISH, IHC and NGS before MET-TKIs administration and assessing the survival benefits of 33 cases treated MET inhibitor. The consistence of FISH, IHC and NGS was only 54%. They are the different population. MET amplification identified by FISH proved the best predictive efficiency for survival benefits. The PR rate was 82% (18/22) and median PFS was 4.8 months in MET amp, compared to 1.0 months for cases with non-MET amp (P= 0.004). Both MET dysregulations identified by NGS or IHC failed to distinguish the significant survival difference in patients with MET-TKIs. Comparing with MET amplification by FISH, effective cases were more seen in patients with CNG > 4.0 or IHC score ＞290 . Based on these two cut-off values：CNG > 4.0 or IHC score ＞290 still did not predict efficacy of MET inhibitors, suggesting CNG by NGS had no significant associations with efficacy benefits.
Conclusion
Compared to MET amplification identified by FISH, CNG dysregulation by NGS or MET protein over-express by IHC could not serves as the predictive biomarker for MET inhibitors.
