MDSにおけるスプライス蛋白変異(2)： サンガーからNEJM

MDSにおけるスプライス蛋白変異について今度はサンガー研究所からNEJMに報告が出た。前回の東大小川さんの報告と違うのは、

1. スプライス関連蛋白パスウェイが変異を受けるという捉え方ではなく、その中の一つSFB１が(比較的)高頻度に変異を受けるという報告になっていること。(72/354 20%)
   
   
2. MDSのサブタイプでsideroblastsを伴うグループに変異が多いこと（53/82: 65%)
   
   
3. そのグループ（SFB１変異陽性群）は比較的予後がよろしいとのこと
   
   
4. MDS以外の広範な腫瘍群へ解析が及んでいること。他のタイプの白血病、乳癌を初めとする固形癌には５％以下の頻度で（例外的に）変異を認める程度であり、この変異はMDSに集中していることを示している。

スプライス蛋白変異というのが確かにある種の癌化に関連していることは間違いなさそうである。

Original Article

Somatic SF3B1 Mutation in Myelodysplasia with Ring Sideroblasts

E. Papaemmanuil, M. Cazzola, J. Boultwood, L. Malcovati, P. Vyas, D. Bowen, A. Pellagatti, J.S. Wainscoat, E. Hellstrom-Lindberg, C. Gambacorti-Passerini, A.L. Godfrey, I. Rapado, A. Cvejic, R. Rance, C. McGee, P. Ellis, L.J. Mudie, P.J. Stephens, S. McLaren, C.E. Massie, P.S. Tarpey, I. Varela, S. Nik-Zainal, H.R. Davies, A. Shlien, D. Jones, K. Raine, J. Hinton, A.P. Butler, J.W. Teague, E.J. Baxter, J. Score, A. Galli, M.G. Della Porta, E. Travaglino, M. Groves, S. Tauro, N.C. Munshi, K.C. Anderson, A. El-Naggar, A. Fischer, V. Mustonen, A.J. Warren, N.C.P. Cross, A.R. Green, P.A. Futreal, M.R. Stratton, and P.J. Campbell for the Chronic Myeloid Disorders Working Group of the International Cancer Genome Consortium

September 26, 2011 (10.1056/NEJM　　oa1103283)

Background

Myelodysplastic syndromes are a diverse and common group of chronic hematologic cancers. The identification of new genetic lesions could facilitate new diagnostic and therapeutic strategies.

Methods

We used massively parallel sequencing technology to identify somatically acquired point mutations across all protein-coding exons in the genome in 9 patients with low-grade myelodysplasia. Targeted resequencing of the gene encoding RNA splicing factor 3B, subunit 1 (SF3B1), was also performed in a cohort of 2087 patients with myeloid or other cancers.

Results

We identified 64 point mutations in the 9 patients. Recurrent somatically acquired mutations were identified in SF3B1. Follow-up revealed SF3B1 mutations in 72 of 354 patients (20%) with myelodysplastic syndromes, with particularly high frequency among patients whose disease was characterized by ring sideroblasts (53 of 82 [65%]). The gene was also mutated in 1 to 5% of patients with a variety of other tumor types. The observed mutations were less deleterious than was expected on the basis of chance, suggesting that the mutated protein retains structural integrity with altered function. SF3B1 mutations were associated with down-regulation of key gene networks, including core mitochondrial pathways. Clinically, patients with SF3B1 mutations had fewer cytopenias and longer event-free survival than patients without SF3B1 mutations.

Conclusions

Mutations in SF3B1 implicate abnormalities of messenger RNA splicing in the pathogenesis of myelodysplastic syndromes. (Funded by the Wellcome Trust and others.)