Identifying the Appropriate FISH Criteria for Defining MET Copy Number-Driven Lung Adenocarcinoma through Oncogene Overlap Analysis.
Identifying the Appropriate FISH Criteria for Defining MET Copy Number-Driven Lung Adenocarcinoma through Oncogene Overlap Analysis.
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DOI：
10.1016/j.jtho.2016.04.033
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发表时间：
2016-08
期刊：
影响因子：
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通讯作者：
Camidge DR
中科院分区：
文献类型：
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作者：
Noonan SA;Berry L;Lu X;Gao D;Barón AE;Chesnut P;Sheren J;Aisner DL;Merrick D;Doebele RC;Varella-Garcia M;Camidge DR
MET基因拷贝数增加（CNG）可能是肺癌中MET抑制的预测性生物标志物，但定义MET阳性的最合适方法和标准尚不确定。荧光原位杂交（FISH）检测肺腺癌组织中MET拷贝数。阳性标准包括平均MET/细胞≥5（低水平≥5 - <6，中等水平≥6 -<7，高水平≥7）和MET/CEP 7比值≥1.8（低水平≥1.8 - ≤2.2，中等水平>2.2 - < 5，高水平≥5）。捕获相关的临床和分子特征。99/686例（14%）的平均MET/细胞≥ 5，52/1164例（4.5%）的MET/CEP 7 ≥1.8。在56%的平均MET/细胞≥ 5组和47%的MET/CEP 7比值≥1.8组中可检测到其他致癌驱动因子（EGFR、KRAS、ALK、ERBB 2、BRAF、NRAS、ROS 1或RET），表明许多MET“阳性”病例并非真正的MET成瘾。平均MET/细胞的低、不确定和高类别中的伴随驱动因素分别为32/52（62%）、12/19（63%）和11/27（41%）（p=0.2），MET/CEP 7中分别为15/29（52%）、9/18（50%）和0/4（0%）（p=0.04）。MET/CEP 7 ≥1.8，在不存在其他癌基因的情况下，与肾上腺转移率较高相关（p=0.03），但与从不吸烟状态无关。FISH MET/CEP 7 ≥ 5定义MET“阳性”组，无致癌重叠。由于该方法和标准也与MET抑制的最高响应率相关，因此其代表MET CNG成瘾状态的最清晰定义。然而，当没有其他癌基因重叠发生时，MET/CEP 7 ≥ 1.8的病例中也可能存在MET相关表型。
MET gene copy number gain (CNG) may be a predictive biomarker for MET inhibition in lung cancer, but the most appropriate method and criteria for defining MET positivity are uncertain. MET copy number was assessed by fluorescence in situ hybridization (FISH) in lung adenocarcinoma. Positivity criteria included mean MET/cell ≥5 (low ≥5 – <6, intermediate ≥6 –<7, high ≥7) and MET/CEP7 ratio ≥1.8 (low ≥1.8 – ≤2.2, intermediate >2.2 – < 5, high ≥5). Associated clinical and molecular characteristics were captured. 99/686 cases (14%) had mean MET/cell ≥ 5, 52/1164 (4.5%) had MET/CEP7 ≥1.8. Other oncogenic drivers (in EGFR, KRAS, ALK, ERBB2, BRAF, NRAS, ROS1 or RET) were detectable in 56% of the mean MET/cell ≥ 5 group and 47% of the MET/CEP 7 ratio ≥1.8 group, suggesting many MET ‘positive’ cases are not truly MET-addicted. Concomitant drivers in low, indeterminate and high categories of mean MET/cell were 32/52 (62%), 12/19 (63%) and 11/27 (41%) (p=0.2) and in MET/CEP7: 15/29 (52%), 9/18 (50%) and 0/4 (0%) respectively (p=0.04). MET/CEP7 ≥1.8, in the absence of other oncogenes, was associated with a higher rate of adrenal metastases (p=0.03), but not with never smoking status. FISH MET/CEP7 ≥ 5 defined a MET ‘positive’ group with no oncogenic overlap. As this method and criteria are also associated with the highest response rate to MET inhibition it represents the clearest definition of a MET CNG-addicted state. However, a MET-associated phenotype may also exist across MET/CEP7 ≥ 1.8 cases when no other oncogene overlap occurs.