A 3'-UTR KRAS-variant is associated with cisplatin resistance in patients with recurrent and/or metastatic head and neck squamous cell carcinoma
A 3'-UTR KRAS-variant is associated with cisplatin resistance in patients with recurrent and/or metastatic head and neck squamous cell carcinoma
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DOI：
10.1093/annonc/mdu367
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发表时间：
2014-11-01
影响因子：
50.5
通讯作者：
Weidhaas, J. B.
中科院分区：
文献类型：
--
作者：
Chung, C. H.;Lee, J. W.;Weidhaas, J. B.
KRAS的3 '-非翻译区中的种系突变（rs61764370，KRAS变体：TG/GG）破坏microRNA调节，先前已与各种癌症中改变的患者结果和药物敏感性相关。我们的研究表明，KRAS变异体是复发/转移性头颈部鳞状细胞癌患者铂类药物疗效差的潜在预测生物标志物。KRAS 3 '非翻译区的生殖系突变（rs61764370，KRAS变异体：TG/GG）与多种癌症患者预后和耐药/敏感性改变相关。我们研究了这种变异在复发/转移（R/M）头颈部鳞状细胞癌（HNSCC）中的预后和预测意义。我们对从三个已完成的临床试验中收集的103例HNSCC进行了回顾性研究。对这些样品和8个HNSCC细胞系进行KRAS变体基因分型。通过免疫组化测定26例口咽部肿瘤中p16的表达。微阵列分析也用于阐明KRAS变异和非变异肿瘤之间的差异表达基因。在95/103（92%）的HNSCC肿瘤样品中确定了KRAS变体状态，TG/GG等位基因频率为32%（30/95）。研究的三种HNSCC细胞系（3/8）具有KRAS变体。在口咽部亚组中未观察到KRAS变异状态与p16表达之间的相关性（Fisher精确检验，P = 1.0）。就患者结局而言，KRAS变异患者接受顺铂治疗时无进展生存期较差（对数秩P = 0.002）。相反，当将西妥昔单抗添加到其基于铂的方案中时，KRAS变体患者似乎经历了疾病控制的一些改善（对数秩P = 0.04）JG/GG rs61764370 KRAS变体是R/M HNSCC患者中铂应答差的潜在预测生物标志物。
A germline mutation in the 3'-untranslated region of KRAS (rs61764370, KRAS-variant: TG/GG) which disrupts microRNA regulation has previously been associated with altered patient outcome and drug sensitivity in various cancers. Our study suggests this KRAS-variant is a potential predictive biomarker for poor platinum response in recurrent/metastatic head and neck squamous cell carcinoma patients.A germline mutation in the 3'-untranslated region of KRAS (rs61764370, KRAS-variant: TG/GG) has previously been associated with altered patient outcome and drug resistance/sensitivity in various cancers. We examined the prognostic and predictive significance of this variant in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).We conducted a retrospective study of 103 HNSCCs collected from three completed clinical trials. KRAS-variant genotyping was conducted for these samples and 8 HNSCC cell lines. p16 expression was determined in a subset of 26 oropharynx tumors by immunohistochemistry. Microarray analysis was also utilized to elucidate differentially expressed genes between KRAS-variant and non-variant tumors. Drug sensitivity in cell lines was evaluated to confirm clinical findings.KRAS-variant status was determined in 95/103 (92%) of the HNSCC tumor samples and the allelic frequency of TG/GG was 32% (30/95). Three of the HNSCC cell lines (3/8) studied had the KRAS-variant. No association between KRAS-variant status and p16 expression was observed in the oropharynx subset (Fisher's exact test, P = 1.0). With respect to patient outcome, patients with the KRAS-variant had poor progression-free survival when treated with cisplatin (log-rank P = 0.002). Conversely, KRAS-variant patients appeared to experience some improvement in disease control when cetuximab was added to their platinum-based regimen (log-rank P = 0.04).The TG/GG rs61764370 KRAS-variant is a potential predictive biomarker for poor platinum response in R/M HNSCC patients.NCT00503997, NCT00425750, NCT00003809.