Frequent functional activation of RAS signalling not explained by RAS/RAF mutations in relapsed/refractory multiple myeloma.
Frequent functional activation of RAS signalling not explained by RAS/RAF mutations in relapsed/refractory multiple myeloma.
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复发/难治性多发性骨髓瘤中 RAS 信号传导的频繁功能激活不能用 RAS/RAF 突变来解释
DOI：
10.1038/s41598-018-31820-9
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发表时间：
2018-09-10
影响因子：
4.6
通讯作者：
Chim CS
中科院分区：
文献类型：
--
作者：
Wong KY;Yao Q;Yuan LQ;Li Z;Ma ESK;Chim CS
RAS基因突变在复发/难治性多发性骨髓瘤(RRMM)中很常见，但对原始样本的功能研究很少。本研究用磷酸化ERK1/2(磷酸化ERK1/2)的Western印迹法研究了17例疑似RRMM的原代骨髓瘤浆细胞中RAS信号的功能激活。此外，还利用聚合酶链式反应和双向直接测序的方法研究了KRAS、NRAS、BRAF和ALK的激活突变。此外，利用甲基化特异的聚合酶链式反应分析了负性RAS信号调节基因RASSF1A和RASD1的甲基化。磷酸化ERK1/2过表达表明，12例(75.0%)RRMM有功能性RAS激活。在RAS功能激活的患者中，只有7例(58.3%)患者存在NRAS Q61H、NRAS Q61K、KRAS G12D、KRAS G12V、KRAS G13D、KRAS Q61P或BRAF V600E突变，而5例(41.7%)患者无RAS/RAF突变。相反，无功能性RAS激活的患者无RAS/RAF突变。此外，功能RAS激活的患者中没有ALK突变，也没有RASSF1A和RASD1的甲基化。总的来说，RAS信号的功能激活存在于大多数RRMM中，但只有大约一半(58.3%)是由RAS/RAF突变引起的。如果在更大的研究中得到证实，无论RAS/RAF突变如何，MEK抑制剂的临床研究都是合理的。
RAS mutations are frequent in relapsed/refractory multiple myeloma (RRMM) but functional study in primary samples is scanty. Herein, in primary myeloma plasma cells of 17 suspected RRMM, functional activation of RAS signalling was studied by Western blot of phosphorylated ERK1/2 (phospho-ERK1/2). Moreover, activating mutations in KRAS, NRAS, BRAF, and ALK were studied by PCR and bidirectional direct sequencing. Furthermore, methylation of negative RAS signalling regulator genes, RASSF1A and RASD1, were analyzed by methylation-specific PCR. As evidenced by phospho-ERK1/2 over-expression, functional RAS activation was detected in 12 (75.0%) RRMM. Of patients with functional RAS activation, sequencing data showed only seven (58.3%) patients with one each had NRAS Q61H, NRAS Q61K, KRAS G12D, KRAS G12V, KRAS G13D, KRAS Q61P, or BRAF V600E mutation, whereas five (41.7%) patients had no RAS/RAF mutation. Conversely, patients without functional RAS activation had no RAS/RAF mutation. Moreover, none of the patients with functional RAS activation had ALK mutations, or methylation of RASSF1A and RASD1. Collectively, functional activation of RAS signalling was present in majority of RRMM but only about half (58.3%) accountable by RAS/RAF mutations. If verified in larger studies, clinical investigations of MEK inhibitors are warranted regardless of RAS/RAF mutations.
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复发的神经母细胞瘤显示出频繁的RAS-MAPK途径突变。
影响因子：
30.8
作者：
Eleveld TF;Oldridge DA;Bernard V;Koster J;Colmet Daage L;Diskin SJ;Schild L;Bentahar NB;Bellini A;Chicard M;Lapouble E;Combaret V;Legoix-Né P;Michon J;Pugh TJ;Hart LS;Rader J;Attiyeh EF;Wei JS;Zhang S;Naranjo A;Gastier-Foster JM;Hogarty MD;Asgharzadeh S;Smith MA;Guidry Auvil JM;Watkins TB;Zwijnenburg DA;Ebus ME;van Sluis P;Hakkert A;van Wezel E;van der Schoot CE;Westerhout EM;Schulte JH;Tytgat GA;Dolman ME;Janoueix-Lerosey I;Gerhard DS;Caron HN;Delattre O;Khan J;Versteeg R;Schleiermacher G;Molenaar JJ;Maris JM
通讯作者：
Maris JM
影响因子：
1.3
作者：
Ma ES;Wang CL;Wong AT;Choy G;Chan TL
通讯作者：
Chan TL
影响因子：
20.3
作者：
Kaiser, Martin F.;Johnson, David C.;Morgan, Gareth J.
通讯作者：
Morgan, Gareth J.
影响因子：
11.5
作者：
Nojima, Masanori;Maruyama, Reo;Shinomura, Yasuhisa
通讯作者：
Shinomura, Yasuhisa
影响因子：
11.2
作者：
Prior IA;Lewis PD;Mattos C
通讯作者：
Mattos C