子宮筋腫で変異率の高いMED12が今度はCellに・・・

子宮筋腫で変異率の高いことで当ブログで紹介したMED12が今度はCellの論文になっている。いろいろな腫瘍での薬剤耐性に関与するとの報告のようだ。良性疾患である子宮筋腫で極めて変異率が高い遺伝子として報告されたMED12である。小生は気になって仕方がないのである。

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2011年8月27日土曜日 

子宮筋腫の7割にMED12遺伝子の突然変異がある：フィンランドのAaltonenの報告 

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 Cell, Volume 151, Issue 5, 937-950, 21 November 2012

MED12 Controls the Response to Multiple Cancer Drugs through Regulation of TGF-β Receptor Signaling

Authors 

Sidong Huang, Michael Hölzel, Theo Knijnenburg, Andreas Schlicker, Paul Roepman, Ultan McDermott, Mathew Garnett, Wipawadee Grernrum, Chong Sun, Anirudh Prahallad, Floris H. Groenendijk, Lorenza Mittempergher, Wouter Nijkamp, Jacques Neefjes, Ramon Salazar, Peter ten Dijke, Hidetaka Uramoto, Fumihiro Tanaka, Roderick L. Beijersbergen, Lodewyk F.A. Wessels, René Bernards

（著者の中に産業医科大学の先生がいるのは誰だ？）

Summary

Inhibitors of the ALK and EGF receptor tyrosine kinases provoke dramatic but short-lived responses in lung cancers harboring EML4-ALK translocations or activating mutations of EGFR, respectively. We used a large-scale RNAi screen to identify MED12, a component of the transcriptional MEDIATOR complex that is mutated in cancers, as a determinant of response to ALK and EGFR inhibitors. MED12 is in part cytoplasmic where it negatively regulates TGF-βR2 through physical interaction. MED12 suppression therefore results in activation of TGF-βR signaling, which is both necessary and sufficient for drug resistance. TGF-β signaling causes MEK/ERK activation, and consequently MED12 suppression also confers resistance to MEK and BRAF inhibitors in other cancers. MED12 loss induces an EMT-like phenotype, which is associated with chemotherapy resistance in colon cancer patients and to gefitinib in lung cancer. Inhibition of TGF-βR signaling restores drug responsiveness in MED12KD cells, suggesting a strategy to treat drug-resistant tumors that have lost MED12. 

過去二年のMED12について参考文献を掲載しておく。

1. Makinen N, Mehine M, Tolvanen J, et al.:  MED12, the mediator complex subunit 12 gene, is mutated at high frequency in uterine leiomyomas. Science; 334:252-255,2011
2. Makinen N, Heinonen HR, Moore S, et al.:  MED12 exon 2 mutations are common in uterine leiomyomas from South African patients. Oncotarget; 2:966-969,2011
3. Barbieri CE, Baca SC, Lawrence MS, et al.:  Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nature genetics; 44:685-689,2012
4. Markowski DN, Bartnitzke S, Loning T, et al.:  MED12 mutations in uterine fibroids--their relationship to cytogenetic subgroups. International journal of cancer; 131:1528-1536,2012
5. McGuire MM, Yatsenko A, Hoffner L, et al.:  Whole exome sequencing in a random sample of North American women with leiomyomas identifies MED12 mutations in majority of uterine leiomyomas. PloS one;7: e33251,2012
6. Perot G, Croce S, Ribeiro A, et al.:  MED12 alterations in both human benign and malignant uterine soft tissue tumors. PloS one; 7:e40015,2012
   
   3番目の論文は前立腺癌であり・・・

Nat Genet. 2012 May 20;44(6):685-9.

Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. 

Barbieri CE, Baca SC, Lawrence MS, Demichelis F, Blattner M, Theurillat JP, White TA, Stojanov P, Van Allen E, Stransky N, Nickerson E, Chae SS, Boysen G, Auclair D, Onofrio RC, Park K, Kitabayashi N, MacDonald TY, Sheikh K, Vuong T, Guiducci C, Cibulskis K, Sivachenko A, Carter SL, Saksena G, Voet D, Hussain WM, Ramos AH, Winckler W, Redman MC, Ardlie K, Tewari AK, Mosquera JM, Rupp N, Wild PJ, Moch H, Morrissey C, Nelson PS, Kantoff PW, Gabriel SB, Golub TR, Meyerson M, Lander ES, Getz G, Rubin MA, Garraway LA. Source Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York, USA.

Abstract

 Prostate cancer is the second most common cancer in men worldwide and causes over 250,000 deaths each year. Overtreatment of indolent disease also results in significant morbidity. Common genetic alterations in prostate cancer include losses of NKX3.1 (8p21) and PTEN (10q23), gains of AR (the androgen receptor gene) and fusion of ETS family transcription factor genes with androgen-responsive promoters. Recurrent somatic base-pair substitutions are believed to be less contributory in prostate tumorigenesis but have not been systematically analyzed in large cohorts. Here, we sequenced the exomes of 112 prostate tumor and normal tissue pairs. New recurrent mutations were identified in multiple genes, including MED12 and FOXA1. SPOP was the most frequently mutated gene, with mutations involving the SPOP substrate-binding cleft in 6-15% of tumors across multiple independent cohorts. Prostate cancers with mutant SPOP lacked ETS family gene rearrangements and showed a distinct pattern of genomic alterations. Thus, SPOP mutations may define a new molecular subtype of prostate cancer.