化学療法後再発の脳腫瘍からはp53やATRXなどの突然変異が脱落している？：Science 2013 Dec

Science
Published online 12 December 2013 

Mutational Analysis Reveals the Origin and Therapy-Driven Evolution of Recurrent Glioma

Brett E. Johnson, Tali Mazor, and others, Koki Aihara, Shogo Yamamoto, Hiroki Ueda, Kenji Tatsuno, Nobuhito Saito, Hiroyuki Aburatani, Akitake Mukasa, Barry S. Taylor, and Joseph F. Costello

1. Department of Neurological Surgery, University of California, San Francisco, CA 94158, USA.
2. ²Department of Pathology, University of California, San Francisco, CA 94158, USA.
3. ³Genome Science Laboratory, Research Center for Advanced Science and Technology, University of Tokyo, Meguro-ku, Tokyo 153-8904, Japan.
4. ⁴Department of Neurosurgery, University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
     等々

Received for publication 2 May 2013
Accepted for publication 27 November 2013

Abstract

Tumor recurrence is a leading cause of cancer mortality. Therapies for recurrent disease may fail, at least in part, because the genomic alterations driving the growth of recurrences are distinct from those in the initial tumor. To explore this hypothesis, we sequenced the exomes of 23 initial low-grade gliomas and recurrent tumors resected from the same patients. In 43% of cases, at least half of the mutations in the initial tumor were undetected at recurrence, including driver mutations in TP53, ATRX, SMARCA4, and BRAF, suggesting recurrent tumors are often seeded by cells derived from the initial tumor at a very early stage of their evolution. Notably, tumors from 6 of 10 patients treated with the chemotherapeutic drug temozolomide (TMZ) followed an alternative evolutionary path to high-grade glioma. At recurrence, these tumors were hypermutated and harbored driver mutations in the RB and AKT-mTOR pathways that bore the signature of TMZ-induced mutagenesis. 


グリオーマ23例の症例報告である。治療経過とともに構成遺伝子変異が変化していく。グリオーマで変異頻度が高い遺伝子はIDH1,TP53,ATRX,SMARCA4であり、その変異頻度は本研究では以下のグラフである。

症例１では図のような変異経過をたどったという。当初はastorocytoma、その後の治療でglioblastoma multiforme (GBM) に変化

このevolutional treeの中で次々に新たなクローンが生まれ、ドミナントになっていくが、最初に認められたTP53,ATRX,SMARCA4変異が途中から認められなくなるというのだ。

「ドライバーって何なの？」とその根本の意味を再度問いかける面白い研究だ。

さはさりながらである、もう少し詳細に慎重に読んでみたい。






PS：武笠さん、油谷さん等による日本語のプレスリリースはこちら。