高率に変異を起こす遺伝子ARID1A：NEJM続報

先日卵巣の明細胞癌で高率に変異を起こす遺伝子ARID1Aについてサイエンスの報告をnoteしたが、NEJMにも同様の報告が載っていた。こちらも55/119 (46%) であり、この遺伝子は知られている癌関連遺伝子の中でも極めて高率に再現性良く（といっても2報）変異を起こす遺伝子ということになるかもしれないね。追加であるがendometorioid carcinoma（卵巣）でも10/33 (30%)と高率に変異を起こしている。

ARID1A Mutations in Endometriosis-Associated Ovarian Carcinomas

Kimberly C. Wiegand, B.Sc., Sohrab P. Shah, Ph.D., Osama M. Al-Agha, M.D., Yongjun Zhao, D.V.M., Kane Tse, B.Sc., Thomas Zeng, M.Sc., Janine Senz, B.Sc., Melissa K. McConechy, B.Sc., Michael S. Anglesio, Ph.D., Steve E. Kalloger, B.Sc., Winnie Yang, B.Sc., Alireza Heravi-Moussavi, Ph.D., Ryan Giuliany, B.Sc., Christine Chow, B.M.L.Sc., John Fee, B.Sc., Abdalnasser Zayed, B.Sc., Leah Prentice, Ph.D., Nataliya Melnyk, B.Sc., Gulisa Turashvili, M.D., Ph.D., Allen D. Delaney, Ph.D., Jason Madore, M.Sc., Stephen Yip, M.D., Ph.D., Andrew W. McPherson, B.A.Sc., Gavin Ha, B.Sc., Lynda Bell, R.T., Sian Fereday, B.Sc., Angela Tam, B.Sc., Laura Galletta, B.Sc., Patricia N. Tonin, Ph.D., Diane Provencher, M.D., Dianne Miller, M.D., Steven J.M. Jones, Ph.D., Richard A. Moore, Ph.D., Gregg B. Morin, Ph.D., Arusha Oloumi, Ph.D., Niki Boyd, Ph.D., Samuel A. Aparicio, B.M., B.Ch., Ph.D., Ie-Ming Shih, M.D., Ph.D., Anne-Marie Mes-Masson, Ph.D., David D. Bowtell, Ph.D., Martin Hirst, Ph.D., Blake Gilks, M.D., Marco A. Marra, Ph.D., and David G. Huntsman, M.D.

N Engl J Med 2010; 363:1532-1543October 14, 201

Background

Ovarian clear-cell and endometrioid carcinomas may arise from endometriosis, but the molecular events involved in this transformation have not been described.

Methods

We sequenced the whole transcriptomes of 18 ovarian clear-cell carcinomas and 1 ovarian clear-cell carcinoma cell line and found somatic mutations in ARID1A (the AT-rich interactive domain 1A [SWI-like] gene) in 6 of the samples. ARID1A encodes BAF250a, a key component of the SWI–SNF chromatin remodeling complex. We sequenced ARID1A in an additional 210 ovarian carcinomas and a second ovarian clear-cell carcinoma cell line and measured BAF250a expression by means of immunohistochemical analysis in an additional 455 ovarian carcinomas.

Results

ARID1A mutations were seen in 55 of 119 ovarian clear-cell carcinomas (46%), 10 of 33 endometrioid carcinomas (30%), and none of the 76 high-grade serous ovarian carcinomas. Seventeen carcinomas had two somatic mutations each. Loss of the BAF250a protein correlated strongly with the ovarian clear-cell carcinoma and endometrioid carcinoma subtypes and the presence of ARID1A mutations. In two patients, ARID1A mutations and loss of BAF250a expression were evident in the tumor and contiguous atypical endometriosis but not in distant endometriotic lesions.

Conclusions

These data implicate ARID1A as a tumor-suppressor gene frequently disrupted in ovarian clear-cell and endometrioid carcinomas. Since ARID1A mutation and loss of BAF250a can be seen in the preneoplastic lesions, we speculate that this is an early event in the transformation of endometriosis into cancer. (Funded by the British Columbia Cancer Foundation and the Vancouver General Hospital–University of British Columbia Hospital Foundation.)