Co-mutation pattern, clonal hierarchy, and clone size concur to determine disease phenotype of SRSF2P95-mutated neoplasms
Co-mutation pattern, clonal hierarchy, and clone size concur to determine disease phenotype of SRSF2P95-mutated neoplasms
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共突变模式、克隆层次和克隆大小共同确定 SRSF2P95 突变肿瘤的疾病表型
DOI：
10.1038/s41375-020-01106-z
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发表时间：
2020
期刊：
影响因子：
11.4
通讯作者：
Ogawa Seishi et al.
中科院分区：
文献类型：
--
作者：
Todisco Gabriele;Ogawa Seishi et al.
剪接因子基因的体细胞突变经常发生在髓系肿瘤中。SRSF2P95突变与环状铁母细胞所致的骨髓增生异常综合征(MDS)有关，而SRSF2P95突变可见于不同的疾病类别，包括MDS、骨髓增生性肿瘤(MPN)、骨髓增生异常/骨髓增殖性肿瘤(MDS/MPN)和急性髓系白血病(AML)。为了确定这种表型异质性的分子决定因素，我们研究了从2663例髓系肿瘤患者中挑选的279SRSF2P95突变病例的分子和临床特征。多因素回归分析显示共突变基因与临床表型相关，包括JAK2或MPL型与骨髓纤维化(OR = 26.9)，TET2与单核细胞增多症(OR = 5.2)，RAS途径基因与白细胞增多症(OR = 5.1)，以及STAG2、RUNX1或IDH1/2与原始表型(MDS或AML)相关(OR = 分别为3.4、1.9和2.1)。在SRSF2-JAK2共突变患者中，JAK2基因突变与MPN的临床特征一致，而在MDS/MPN患者中以SRSF2突变为主。在SRSF2-TET2共突变患者中，单核细胞增多症的临床表现与共突变克隆大小呈正相关。这项研究提供的证据表明，共突变模式、克隆大小和层级一致决定临床表型，追踪疾病实体之间的相关基因-表型关联，并洞察当前世卫组织分类类别中不可解释的临床异质性。
Somatic mutations in splicing factor genes frequently occur in myeloid neoplasms. WhileSF3B1mutations are associated with myelodysplastic syndromes (MDS) with ring sideroblasts,SRSF2P95mutations are found in different disease categories, including MDS, myeloproliferative neoplasms (MPN), myelodysplastic/myeloproliferative neoplasms (MDS/MPN), and acute myeloid leukemia (AML). To identify molecular determinants of this phenotypic heterogeneity, we explored molecular and clinical features of a prospective cohort of 279SRSF2P95-mutated cases selected from a population of 2663 patients with myeloid neoplasms. Median number of somatic mutations per subject was 3. Multivariate regression analysis showed associations between co-mutated genes and clinical phenotype, includingJAK2orMPLwith myelofibrosis (OR = 26.9);TET2with monocytosis (OR = 5.2); RAS-pathway genes with leukocytosis (OR = 5.1); andSTAG2,RUNX1, orIDH1/2with blast phenotype (MDS or AML) (OR = 3.4, 1.9, and 2.1, respectively). Within patients withSRSF2–JAK2co-mutation, JAK2dominance was invariably associated with clinical feature of MPN, whereasSRSF2mutation was dominant in MDS/MPN. Within patients withSRSF2–TET2co-mutation, clinical expressivity of monocytosis was positively associated with co-mutated clone size. This study provides evidence that co-mutation pattern, clone size, and hierarchy concur to determine clinical phenotype, tracing relevant genotype–phenotype associations across disease entities and giving insight on unaccountable clinical heterogeneity within current WHO classification categories.
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影响因子：
20.3
作者：
B. Saez;M. Walter;T. Graubert
通讯作者：
B. Saez;M. Walter;T. Graubert
DOI：
10.1056/nejmoa1103283
发表时间：
2011-10-13
期刊：
The New England journal of medicine
影响因子：
--
作者：
Papaemmanuil E;Cazzola M;Boultwood J;Malcovati L;Vyas P;Bowen D;Pellagatti A;Wainscoat JS;Hellstrom-Lindberg E;Gambacorti-Passerini C;Godfrey AL;Rapado I;Cvejic A;Rance R;McGee C;Ellis P;Mudie LJ;Stephens PJ;McLaren S;Massie CE;Tarpey PS;Varela I;Nik-Zainal S;Davies HR;Shlien A;Jones D;Raine K;Hinton J;Butler AP;Teague JW;Baxter EJ;Score J;Galli A;Della Porta MG;Travaglino E;Groves M;Tauro S;Munshi NC;Anderson KC;El-Naggar A;Fischer A;Mustonen V;Warren AJ;Cross NC;Green AR;Futreal PA;Stratton MR;Campbell PJ;Chronic Myeloid Disorders Working Group of the International Cancer Genome Consortium
通讯作者：
Chronic Myeloid Disorders Working Group of the International Cancer Genome Consortium
影响因子：
20.3
作者：
Pellagatti, Andrea;Armstrong, Richard N.;Boultwood, Jacqueline
通讯作者：
Boultwood, Jacqueline
影响因子：
20.3
作者：
Yue Yang;H. Akada;Dipmoy Nath;R. Hutchison;G. Mohi
通讯作者：
Yue Yang;H. Akada;Dipmoy Nath;R. Hutchison;G. Mohi
JAK2 V617F 等位基因负荷在区分慢性粒单核细胞白血病与单核细胞增多的原发性骨髓纤维化中的效用。
影响因子：
3.3
作者：
Z. Hu;C. Ramos;L. Medeiros;Chong Zhao;C. Yin;Shaoying Li;Shimin Hu;Wei Wang;B. Thakral;Jie Xu;S. Verstovsek;P. Lin
通讯作者：
P. Lin