融合遺伝子の作られかた：最新のサイエンスより

Published Online October 29, 2009 Science DOI: 10.1126/science.1178124

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Brevia

Submitted on June 23, 2009
Accepted on October 21, 2009

Induced Chromosomal Proximity and Gene Fusions in Prostate Cancer

Ram-Shankar Mani ¹, Scott A. Tomlins ¹, Kaitlin Callahan ¹, Aparna Ghosh ¹, Mukesh K. Nyati ², Sooryanarayana Varambally ³, Nallasivam Palanisamy ⁴, Arul M. Chinnaiyan ^5*

¹ Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
² Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.; Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
³ Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.; Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
⁴ Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.; Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
⁵ Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.; Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.; Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, MI 48109, USA.; Department of Urology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.

Gene fusions play a critical role in cancer progression. The mechanisms underlying their genesis and cell type specificity are not well understood. About 50% of human prostate cancers display a gene fusion involving the 5’untranslated region of TMPRSS2, an androgen-regulated gene, and the protein-coding sequences of ERG, which encodes an ETS transcription factor. Studying human prostate cancer cells by fluorescence in situ hybridization, we show that androgen signaling induces proximity of the TMPRSS2 and ERG genomic loci, both located on chromosome 21q22.2. Subsequent exposure of the cells to gamma-irradiation, which causes DNA double strand breaks, facilitates the formation of the TMPRSS2-ERG gene fusion. These results may help explain why TMPRSS2-ERG fusions are restricted to the prostate, which is dependent on androgen signaling.

TMPRSS2ーERG融合遺伝子は固形癌で見出された初めてのrecurrent gene fusionであり、言われるところをそのまま信じれば約５０％の前立腺癌で融合蛋白が検出されることになる。診断学的にも治療ターゲットとしても強烈なポテンシャルをもつ分子標的であろう。なぜか日本での関心は今ひとつのようで、これほどの”逸材”なのになぜに関心を呼ばないのか不思議（不思議）（（不思議））である。

アンドロジェン感受性の前立腺細胞のみにこの融合蛋白が生じる仕組みのひとつとして、ゲノムDNAが折れ曲がる、近づく、すりすりする、TMPRSS2とERGゲノムのランデブー状態が起こりやすくなる状態をandrogen signalingが作るということを示しているらしい。その後放射線によりDSBが起こり融合が完成するという仕組みのようだ。

ゲノムの3次元構造の変化が癌化に大事であるとボクは信じているが、これまでゲノムレベルで3次元構造のゆがみと癌化について述べた論文を余り見たことがない。もちろんゲノムが核膜に固定されているattached region研究やゲノムの端の方なら今年のノーベル賞のテロメアなどの研究は80年代から知られているが、今ひとつピントこなかった。

今回の論文は一見嘘っぽい。がしかし・・・夢があるなあ。でもホントかね？？？？面白いといえば、今年のトップ５の論文だな、ボクにとっては。