Bcl-xL as a poor prognostic biomarker and predictor of response to adjuvant chemotherapy specifically in BRAF-mutant stage II and III colon cancer.
Bcl-xL as a poor prognostic biomarker and predictor of response to adjuvant chemotherapy specifically in BRAF-mutant stage II and III colon cancer.
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DOI：
10.18632/oncotarget.24481
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发表时间：
2018-03-02
期刊：
影响因子：
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通讯作者：
Lawler M
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文献类型：
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作者：
Dunne PD;Coleman HG;Bankhead P;Alderdice M;Gray RT;McQuaid S;Bingham V;Loughrey MB;James JA;McCorry AMB;Gilmore A;Holohan C;Klingbiel D;Tejpar S;Johnston PG;McArt DG;Di Nicolantonio F;Longley DB;Lawler M
BRAF突变发生在8-15%的结肠癌（CC）中，并且与转移性疾病的不良预后相关。与野生型BRAF（BRAFWT）疾病相比，患有BRAF突变（BRAFMT）肿瘤的II/III期CC患者复发后的总生存期较短;然而，复发时间无显著差异。本研究的目的是确定和验证II/III期BRAFMT CC复发的新预测因子。我们使用来自460名患者（GSE 39582）的队列的基因表达数据，基于BRAFMT II/III期CC内的复发风险进行监督分类分析，以鉴定与该基因型内的预后相关的转录组生物标志物。在一个独立的基于人群的II/III期CC队列（n = 691）中使用免疫组化验证了这些结果，应用考克斯比例风险分析确定与生存期的相关性。Bcl-xL（细胞凋亡的关键调节因子）的高基因表达水平与复发风险增加相关，特别是在BRAFMT肿瘤中（HR = 8.3，95% CI 1.7-41.7），但与KRASMT/BRAFWT或KRASWT/BRAFWT肿瘤无关。在一个独立队列中，BRAFMT、未治疗、II/III期CC中的高Bcl-xL蛋白表达被证实与死亡风险增加相关（HR = 12.13，95%CI 2.49-59.13）。此外，具有高水平Bcl-xL蛋白表达的BRAFMT肿瘤似乎受益于辅助化疗（相互作用P = 0.006），表明Bcl-xL表达在这种情况下的潜在预测价值。这些发现提供了Bcl-xL基因和/或蛋白表达鉴定BRAFMT II/III期CC患者预后不良亚组的证据，这些患者可能受益于辅助化疗。
BRAF mutation occurs in 8–15% of colon cancers (CC), and is associated with poor prognosis in metastatic disease. Compared to wild-type BRAF (BRAFWT) disease, stage II/III CC patients with BRAF mutant (BRAFMT) tumors have shorter overall survival after relapse; however, time-to-relapse is not significantly different. The aim of this investigation was to identify, and validate, novel predictors of relapse of stage II/III BRAFMT CC. We used gene expression data from a cohort of 460 patients (GSE39582) to perform a supervised classification analysis based on risk-of-relapse within BRAFMT stage II/III CC, to identify transcriptomic biomarkers associated with prognosis within this genotype. These findings were validated using immunohistochemistry in an independent population-based cohort of Stage II/III CC (n = 691), applying Cox proportional hazards analysis to determine associations with survival. High gene expression levels of Bcl-xL, a key regulator of apoptosis, were associated with increased risk of relapse, specifically in BRAFMT tumors (HR = 8.3, 95% CI 1.7–41.7), but not KRASMT/BRAFWT or KRASWT/BRAFWT tumors. High Bcl-xL protein expression in BRAFMT, untreated, stage II/III CC was confirmed to be associated with an increased risk of death in an independent cohort (HR = 12.13, 95% CI 2.49–59.13). Additionally, BRAFMT tumors with high levels of Bcl-xL protein expression appeared to benefit from adjuvant chemotherapy (P for interaction = 0.006), indicating the potential predictive value of Bcl-xL expression in this setting. These findings provide evidence that Bcl-xL gene and/or protein expression identifies a poor prognostic subgroup of BRAFMT stage II/III CC patients, who may benefit from adjuvant chemotherapy.