MET receptor sequence variants R970C and T992I lack transforming capacity.
MET receptor sequence variants R970C and T992I lack transforming capacity.
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DOI：
10.1158/0008-5472.can-10-0429
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发表时间：
2010-08-01
期刊：
影响因子：
11.2
通讯作者：
Loriaux MM
中科院分区：
文献类型：
--
作者：
Tyner JW;Fletcher LB;Wang EQ;Yang WF;Rutenberg-Schoenberg ML;Beadling C;Mori M;Heinrich MC;Deininger MW;Druker BJ;Loriaux MM
高通量测序有望加速序列变异的发现，但区分致癌突变和无关的“乘客”突变仍然是一个重大挑战。在这里，我们提出了MET受体(肝细胞生长因子受体)R970C和T992I(也称为R988C和T1010I)的两个序列变体的分析。以前的报道表明，这些序列变异正在转化，并有助于肿瘤的发生。我们筛选了慢性淋巴细胞白血病(CLL)、急性髓系白血病(AML)、慢性单核细胞白血病(CMML)、结直肠癌、子宫内膜癌、甲状腺癌或黑色素瘤患者以及非癌症患者，发现这些变异在大多数队列中出现频率较低，包括正常个体。没有发现任何一种序列变异体增加磷酸化或转化能力的证据。由于MET的小分子抑制剂目前正在开发中，区分致癌序列变异和罕见的单核苷酸多态将非常重要，以避免使用不必要的和潜在有毒的癌症治疗药物。
High-throughput sequencing promises to accelerate the discovery of sequence variants, but distinguishing oncogenic mutations from irrelevant "passenger" mutations remains a major challenge. Here we present an analysis of two sequence variants of the MET receptor (hepatocyte growth factor receptor) R970C and T992I (also designated R988C and T1010I). Previous reports indicated these sequence variants are transforming and contribute to oncogenesis. We screened patients with chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML), colorectal cancer, endometrial cancer, thyroid cancer, or melanoma as well as individuals without cancer and found these variants at low frequencies in most cohorts, including normal individuals. No evidence of increased phosphorylation or transformative capacity by either sequence variant was found. Since small-molecule inhibitors for MET are currently in development, it will be important to distinguish between oncogenic sequence variants and rare single-nucleotide polymorphisms to avoid the use of unnecessary and potentially toxic cancer therapy agents.