NRAS G12S驅動的慢性粒單核細胞白血病精準治療
病人的突變情況如下：
ZRSR2: R126X/N155fs
TET2: T1809fs
ASXL1: Q757X
NRAS: G12S
坦白說，這四個基因的突變在慢性粒單核細胞白血病CMML裡面都很常見， 從治療角度來講，需要找出主次。
如果醫生了解CMML的基因組學，就會知道TET2和ASXL1的單拷貝失活不足以驅動，但是卻對預後有不良影響。 ZRSR2 應該是出現了兩個不同的突變克隆，不太像兩個突變位於同一個細胞的兩條染色體上。最關鍵的一點，是NRAS G12S 突變單一就足夠驅動CMML/JMML.
我 先給出COSMIC資料庫的NRAS G12S出現頻率：
白血病是最高頻率出現的，有190例， 第二高的食道腫瘤才剛剛超過20例，白血病裡面這個突變的分布基本上就是CMML/JMML/MDS/AML.
僅從COSMIC的數據，基本就可以判斷NRAS G12S這個突變是主要矛盾。
作為對比，看一下患者ASXL1的突變記錄， 就2例：
下面談談NRAS G12突變具體的血液學病例和相關醫學研究：
2006年， Blood雜誌就發表NRAS G12D足以驅動CMML.
在 CMML病人中檢測也發現NRAS G12D是一個主要驅動突變，而NRAS G12S突變的頻率相對要低很多。
2012年， Blood雜誌報道了兩個青年粒單核細胞白血病的病例分析， 這兩個病人是嵌合體，一個是NRAS G12D驅動，另外一個是NRAS G12S驅動。
Blood. 2012 Aug 16;120(7):1485-8. doi: 10.1182/blood-2012-02-406090. Epub 2012 Jul 2.
Somatic mosaicism for oncogenic NRAS mutations in juvenile myelomonocytic leukemia.
Doisaki S1, Muramatsu H, Shimada A, Takahashi Y, Mori-Ezaki M, Sato M, Kawaguchi H, Kinoshita A, Sotomatsu M, Hayashi Y, Furukawa-Hibi Y, Yamada K, Hoshino H, Kiyoi H, Yoshida N, Sakaguchi H, Narita A, Wang X, Ismael O, Xu Y, Nishio N, Tanaka M, Hama A, Koike K, Kojima S.
Abstract
Juvenile myelomonocytic leukemia (JMML) is a rare pediatric myeloid neoplasm characterized by excessive proliferation of myelomonocytic cells. Somatic mutations in genes involved in GM-CSF signal transduction, such as NRAS, KRAS, PTPN11, NF1, and CBL, have been identified in more than 70% of children with JMML. In the present study, we report 2 patients with somatic mosaicism for oncogenic NRASmutations (G12D and G12S) associated with the development of JMML. The mutated allele frequencies quantified by pyrosequencing were various and ranged from 3%-50% in BM and other somatic cells (ie, buccal smear cells, hair bulbs, or nails). Both patients experienced spontaneous improvement of clinical symptoms and leukocytosis due to JMML without hematopoietic stem cell transplantation. These patients are the first reported to have somatic mosaicism for oncogenic NRAS mutations. The clinical course of these patients suggests that NRAS mosaicism may be associated with a mild disease phenotype in JMML.說到這裡，我想那麼對於NRAS G12S是主要驅動應該沒有什麼意見。下面的問題是如何治療？
由於NRAS G12S的血液病案例極為罕見，我沒有找到合適的病例報道，所以退而求其次尋找NRAS G12D的治療方案。
2014年，Blood雜誌發表了使用MAPK抑製劑治療NRAS突變驅動的AML的基礎研究：
MAPK抑製劑曲美替尼Trametinib對動物模型有效：
這個研究影響到了臨床，所以一年多以後有醫生使用曲美替尼治療NRAS G12D驅動的非典型CML, 臨床上控制病情的時間達到14個月。
The patient was started on treatment with trametinib, an MEK1/2 inhibitor with Food and Drug Administration approval for malignant melanoma. Therapy with trametinib resulted in exceptional improvements in his blood counts and continued disease control with 14 months of follow-up. This case highlights the need for clinical trials evaluating the safety and efficacy of MEK1/2 as a therapeutic target for the treatment of patients with NRAS-mutated aCML/CNL.
所以我給病人的建議是觀察， 一旦攜帶NRAS G12S的突變細胞出現顯著增長，就需要考慮使用MAPK抑製劑曲美替尼進行針對性的靶向治療。
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