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首页> 外文期刊>BMC Medical Genomics >Association of candidate single nucleotide polymorphisms with somatic mutation of the epidermal growth factor receptor pathway
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Association of candidate single nucleotide polymorphisms with somatic mutation of the epidermal growth factor receptor pathway

机译：候选单核苷酸多态性与表皮生长因子受体途径的体细胞突变的关联

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Background Tumour growth in colorectal cancer and other solid cancers is frequently supported by activating mutations in the epidermal growth factor receptor (EGFR) signaling pathway (Patholog Res Int 2011:932932, 2011). Treatment of metastatic colorectal cancer with targeted anti-EGFR therapeutics such as cetuximab extends survival in only 25% of patients who test wild-type for KRAS, while the majority of patients prove resistant (J Clin Oncol 28(7):1254–1261, 2010). Prediction of cetuximab responsiveness for KRAS wild-type colorectal cancers is currently not well defined, and prognostic biomarkers would help tailor treatment to individual patients. Somatic mutation of the EGFR signalling pathway is a prevalent mechanism of resistance to cetuximab (Nature 486(7404):532–536, 2012). If the human genome harbours variants that influence susceptibility of the EGFR pathway to oncogenic mutation, such variants could also be prognostic for cetuximab responsiveness. Methods We assessed whether patient genetic variants may associate with somatic mutation of the EGFR signalling pathway. We combined tumour mutation data from the Cancer Genome Atlas with matched patient genetic data, and tested for germline variants that associate with somatic mutation of the EGFR pathway (including EGFR, KRAS, BRAF, PTEN and PIK3CA). Results Two single nucleotide polymorphisms (SNPs) located 90?kb upstream of the TERT oncogene associated with somatic mutation of the EGFR pathway beyond the threshold of genome-wide significance: rs7736074 (P?=?4.64 × 10-9) and rs4975596 (P?=?5.69 × 10-9). We show that allelic variants of rs7736074 and rs4975596 modulate TERT expression levels in multiple cancer types, and exhibit preliminary prognostic value for response to cetuximab. Conclusions We have identified two germline SNPs that associate with somatic mutation of the EGFR pathway, and may be prognostic for cetuximab responsiveness. These variants could potentially contribute to a panel of prognostic biomarkers for assessing whether metastatic colorectal cancer patients are likely to derive benefit from cetuximab treatment. Genotyping of a large cohort of cetuximab-treated colorectal cancer patients is called for to further clarify the association.
机译：背景技术大肠癌和其他实体癌中的肿瘤生长通常通过激活表皮生长因子受体（EGFR）信号传导途径的突变来支持（Patholog Res Int 2011：932932，2011）。使用靶向抗EGFR治疗药物（例如西妥昔单抗）治疗转移性结直肠癌，仅25％的野生型KRAS测试患者延长了生存期，而大多数患者证明具有耐药性（J Clin Oncol 28（7）：1254–1261， 2010）。目前尚未很好地确定西妥昔单抗对KRAS野生型结直肠癌的反应性，并且预后生物标志物将有助于为个体患者量身定制治疗方案。 EGFR信号通路的体细胞突变是对西妥昔单抗耐药的普遍机制（Nature 486（7404）：532-536，2012）。如果人类基因组中存在影响EGFR途径对致癌突变敏感性的变异体，那么这些变异体也可能预示了西妥昔单抗的反应性。方法我们评估了患者的遗传变异是否可能与EGFR信号通路的体细胞突变有关。我们将来自癌症基因组图谱的肿瘤突变数据与匹配的患者遗传数据相结合，并测试了与EGFR途径（包括EGFR，KRAS，BRAF，PTEN和PIK3CA）的体细胞突变相关的种系变异。结果TERT致癌基因上游90？kb处的两个单核苷酸多态性（SNP）与EGFR途径的体细胞突变相关，超出了全基因组范围的阈值：rs7736074（P？=？4.64×10 -9 ）和rs4975596（P？=？5.69×10 -9 ）。我们显示，rs7736074和rs4975596的等位基因变体在多种癌症类型中调节TERT表达水平，并显示出对西妥昔单抗的反应的初步预后价值。结论我们确定了两个与EGFR途径的体细胞突变相关的种系SNP，它们可能预示了西妥昔单抗的反应性。这些变体可能有助于建立一组预后生物标志物，以评估转移性结直肠癌患者是否可能从西妥昔单抗治疗中受益。大量西妥昔单抗治疗的结直肠癌患者需要进行基因分型，以进一步阐明这种关联。

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