Thirty-one patients with SCBC and available treatment-naïve tumor specimens were identified from an institutional database (23 limited stage [LS], 8 extensive stage [ES]). Small cell carcinoma specimens were microdissected and subjected to tumor next-generation whole-exon sequencing with a 592 gene panel. Kaplan-Meier techniques and Cox proportional hazards models were used to evaluate genomic aberration association with relapse-free survival (RFS) and overall survival (OS) in the limited stage cohort.
The most common pathogenic gene variants included ARID1A (48%), TP53 (48%) and RB1 (48%). Mutations in genes with potential therapeutic targets not routinely evaluated in SCBC included BRCA1/2 (16%), POLE (13%), JAK2 (13%), PDGFB (13%) and FGFR3 (3%). Multiple novel biomarker candidates showed trends for improvements in OS in the LS subset including ERCC2 (HR 0.322, P = 0.122) and RB1 (HR 0.481, P = 0.182), while LS patients with TP53 mutations (HR 2.730, P = 0.056), and MCL1 gene amplification (HR 4.183, P = 0.018) suggested inferior OS. Additionally, gene or copy number variants with potential prognostic benefit included UBR5 and DAXX (P = 0.02, [hazard ratios nonestimable due to zero events in biomarker positive groups]).
These results support the role for tumor genomic profiling in SCBC and identify multiple potential novel biomarkers and therapeutic targets in this rare disease. Efforts to validate these findings should lead to improved decision-making and treatment outcomes in SCBC.
从机构数据库中确定了31名SCBC患者和可用的未治疗肿瘤标本(23个有限阶段[LS],8广泛阶段[ES])。对小细胞癌标本进行显微解剖,并使用592基因组对肿瘤进行下一代全外显子测序。Kaplan-Meier技术和Cox比例风险模型用于评估有限阶段队列中基因组畸变与无复发生存期(RFS)和总生存期(OS)的关联。
最常见的致病基因变异包括ARID1A(48%),TP53(48%)和RB1(48%)。在SCBC中未常规评估的具有潜在治疗靶标的基因突变包括BRCA1/2(16%),POLE(13%),JAK2(13%),PDGFB(13%)和FGFR3(3%)。多个新的生物标志物候选物显示LS子集的OS改善趋势,包括ERCC2(HR0.322,P=0.122)和RB1(HR0.481,P=0.182),而LS患者TP53突变(HR2.730,P=0.056),MCL1基因扩增(HR4.183,P=0.018)提示OS较差。此外,具有潜在预后获益的基因或拷贝数变异包括UBR5和DAXX(P=0.02,[由于生物标志物阳性组中的零事件,风险比不可估计]).
这些结果支持肿瘤基因组分析在SCBC中的作用,并在这种罕见疾病中确定了多种潜在的新型生物标志物和治疗靶标。努力验证这些发现应导致改善SCBC的决策和治疗结果。