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Liyan Ji
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FP10 - Small Cell Lung Cancer/NET (ID 231)
- Event: WCLC 2020
- Type: Posters (Featured)
- Track: Small Cell Lung Cancer/NET
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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FP10.03 - Multi-Region Exome Sequencing Reveals the Intratumoral Heterogeneity of Surgically Resected Small Cell Lung Cancer (ID 2079)
00:00 - 00:00 | Author(s): Liyan Ji
- Abstract
Introduction
Small cell lung cancer (SCLC) is a highly malignant tumor with extensive genomic alterations detected by single-region sequencing. But the intratumoral heterogeneity (ITH) of SCLC remains unknown. Elucidating the heterogeneity of SCLC by multi-region sequencing help the understanding of disease and the improvement of clinical outcomes.
Methods
Multi-region exome sequencing was performed on 120 FFPE samples from 40 staged I-III SCLC patients (three regions for each patient). All the tissue samples were collected by surgical resection from Sun Yat-sen University Cancer Center and confirmed as SCLC by immunohistochemistry. Intratumoral heterogeneity (ITH) was defined as percentage of branch/subclonal somatic non-silent mutations or copy number variations. We further analyzed the correlation of ITH and clinical phenotype to evaluate the impact of genomic alterations on outcome, including disease-free survival and overall survival.
Results
We subjected 120 FFPE SCLC samples to multi-regional whole-exome sequencing. In total, 48818 somatic mutations were identified with average 239x sequencing depth. The most significantly and frequently mutant genes were TP53 (88%) and RB1 (70%), which dominate truncal mutations (Fig.1A). In addition to a medium tumor mutation burden (TMB, 15/Mb range 2~66), SCLC exhibited somatic copy number variation (CNV) across all patients. Using CNV ITH, an average of 0.49 (range 0.22~1 per sector) was found in SCLC (Fig.1B). The age-associated, tobacco-associated, and aflatoxin-associated signatures were major mutational signatures in these patients (Fig.1C). We found a medium mutational heterogeneity (0.50, range 0.22~1) in our SCLC cohort, in contrast to low ITH in previous reported NSCLC and LUAD cohort (Fig.1C). Combined SCLC patients behaved in much the same way as pure SCLC patients, both in terms of mutation distribution, ITH, TMB, mclone (number of tumor molecular clones) and gene signatures (Fig. 1D). This condition is also present in smoker patients and those with EGFR mutations. A higher CNV ITH was observed in stage I-II of SCLC than stage III (p < 0.001) (Fig.1E). Less mClone were associated with better DFS of SCLC (Fig. 1E).
Conclusion
Despite moderate mutation burden, SCLC showed a medium intratumoral heterogeneity with high genomic instability. CNV exhibited a high heterogeneity at early stage and mclone may serve as a prognostic biomarker for SCLC.
