Abstract
e21103 Background: Small cell lung cancer (SCLC) is a type of aggressive malignancy with poor prognosis, accounting for 15% of lung cancers. Intratumoral heterogeneity (ITH) has been investigated in lung adenocarcinoma or squamous cell carcinoma, but its role in SCLC still remains unclear. Exploring ITH and tumor evolution of SCLC is essential for its treatment and prognosis. Methods: 102 multi-regional tumor tissues were collected from 34 operative SCLC patients (pts) before systemic therapy during Sep. 2009 to Sep.2018 from Sun Yat-sen University Cancer Center. All of the enrolled cases were confirmed as SCLC by immunohistochemistry. We performed whole-exome sequencing (WES) of all the tumor tissues and assessed the ITH using clonal and subclonal somatic mutations or copy number variants. ITH was defined as the proportion of subclonal genetic alterations of all. The relationship between ITH and overall survival (OS) was also explored. Results: Among the enrolled 34 SCLC pts, the median age was 64 year. 28 pts had the smoking history. 23 pts received adjuvant therapy after surgery. Stage I-II and III-IV pts accounted for 50% respectively. The most frequent mutated genes were TP53 (88%), RB1 (70%), TTN (68%), TCEB3CL (65%), MUC16 (56%), and all of them were clonal. The median overall ITH was 0.36 (ranging from 0 to 1), while the mutational ITH and the CNV ITH were 0.50 (0.22 to 1) and 0.49 (0.22 to 1). Univariate analysis revealed that postoperative treatment (HR = 0.27, 0.07-0.97, p= 0.006) and higher CNV ITH (HR = 0.28, 0.08-0.99, p= 0.009) were significant positive predictors of OS, while higher mutational heterogeneity was not associated with OS (HR = 3.34, 0.91-12.25, p= 0.21) significantly. Conclusions: TP53, RB1, TTN, TCEB3CL and MUC16 were probably clonal mutations as early events in SCLC evolution. CNV ITH might be a prognostic predictor in SCLC, which should be verified in a large-sample cohort.
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