Association between molecular subtype of esophageal squamous cell carcinoma and survival of patients

Autor: Denis S. Kutilin, Aleksey Yurievich Maksimov, Evgeniy N. Kolesnikov, Mikhail A Kozhushko, Sergey V. Sanamyants, Natalia A. Petrusenko, Tatiana Yu. Myagkova, Oleg I. Kit
Rok vydání: 2019
Předmět:
Zdroj: Journal of Clinical Oncology. 37:e15520-e15520
ISSN: 1527-7755
0732-183X
Popis: e15520 Background: Esophageal squamous cell carcinoma (ESCC) comprises a group of heterogeneous tumors with various prognoses which does not depend on clinical signatures (TNM, tumor location). In recent years, different molecular subtypes of ESCC have been identified in different populations; however, such studies have not been conducted in the population of Southern Russia. The purpose of the study was the molecular typing of ESCC in patients of the Southern Russia, and the assessment of survival of patients with different molecular subtypes of ESCC. Methods: Tissue sections from FFPE blocks from 124 ESCC patients were studied. Tumor and normal cells were isolated using laser microdissection (Palm MicroBeam, Carl Zeiss). Molecular typing of ESCC was performed by the determination of copy number variation (CNV) of 8 genes ( CUL3, ATG7, SOX2, TP63, YAP1, VGLL4, CDK6, KDM6А) using Real-Time qPCR and 7 somatic mutations (SNP) ( NFE2L2 (c.85G > A), NOTCH1 (c.1379C > T), NOTCH1 (c.1451G > T), ZNF750 (c.414C > A), ZNF750 (c.1621G > A), SMARCA4 (p.Q758*, c.2272C > T), KMT2D (Q5170* , c.15508C > T)) using Sanger direct sequencing method. The differences were assessed by the Mann-Whitney test. For the cluster analysis (Hierarchical Clustering, Euclidean distance), we used R scripts. Survival of patients was analyzed by the Kaplan–Meier method, and differences between survivals in groups were assessed by the log-rank test. Results: Cluster analysis allowed determination of 3 clusters of ESCC samples different in CNV (p < 0.005): cluster 1 (n = 39) demonstrated increased CNV of SOX2, TP63, YAP1 and decreased CNV of CUL3, ATG7 and VGLL4, cluster 2 (n = 82) – increased CNV of CDK6 and decreased CNV of KDM6А, cluster 3 (n = 3) – decreased CNV of ATG7. Samples of cluster 1 showed c.85G > A mutation in the NFE2L2 gene, cluster 2 - c.1379C > T and c.1451G > T in NOTCH1, c.414C > A and c.1621G > A in ZNF750, and cluster 3 - p.Q758* and Q5170* in SMARCA4 and KMT2D, respectively. Thus, we differentiated 3 molecular subtypes of ESCC (1,2,3). Overall survival rates were higher in ESCC2 (16.1±2.0 months), the lowest ones – in ESCC3 (0.88±0.56 months), with intermediate values in ESCC1 (4.6±0.74 months). Differences between the groups were statistically significant (p = 0.00001). Conclusions: Based on the differential distinctions in SNP and CNV of the genes, we verified 3 molecular subtypes of ESCC with different overall survival of patients.
Databáze: OpenAIRE
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