title: Early G₁ cyclin-dependent kinases as prognostic markers and potential therapeutic targets in esophageal adenocarcinoma.
abstract: OBJECTIVE
  Chromosomal gain at 7q21 is a frequent event in esophageal adenocarcinoma (EAC). However, this event has not been mapped with fine resolution in a large EAC cohort, and its association with clinical endpoints and functional relevance are unclear.
  
  
  METHODS
  We used a cohort of 116 patients to fine map the 7q21 amplification using SNP microarrays. Prognostic significance and functional role of 7q21 amplification and its gene expression were explored.
  
  
  RESULTS
  Amplification of the 7q21 region was observed in 35% of tumors with a focal, minimal amplicon containing six genes. 7q21 amplification was associated with poor survival and analysis of gene expression identified cyclin-dependent kinase 6 (CDK6) as the only gene in the minimal amplicon whose expression was also associated with poor survival. A low-level amplification (10%) was observed at the 12q13 region containing the CDK6 homologue cyclin-dependent kinase 4 (CDK4). Both amplification and expression of CDK4 correlated with poor survival. A combined model of both CDK6 and CDK4 expressions is a superior predictor of survival than either alone. Specific knockdown of CDK4 and/or CDK6 by siRNAs shows that they are required for proliferation of EAC cells and that their function is additive. PD-0332991 targets the kinase activity of both molecules and suppresses proliferation and anchorage independence of EAC cells through activation of the pRB pathway.
  
  
  CONCLUSIONS
  We suggest that CDK6 is the driver of 7q21 amplification and that both CDK4 and CDK6 are prognostic markers and bona fide oncogenes in EAC. Targeting these molecules may constitute a viable new therapy for this disease.
authors: Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA. amin_ismail@urmc.rochester.edu
authors: Amin
authors: A
authors: Ismail
authors: Santhoshi
authors: S
authors: Bandla
authors: Marie
authors: M
authors: Reveiller
authors: Liana
authors: L
authors: Toia
authors: Zhongren
authors: Z
authors: Zhou
authors: William E
authors: WE
authors: Gooding
authors: Irina
authors: I
authors: Kalatskaya
authors: Lincoln
authors: L
authors: Stein
authors: Mary
authors: M
authors: D'Souza
authors: Virginia R
authors: VR
authors: Litle
authors: Jeffrey H
authors: JH
authors: Peters
authors: Arjun
authors: A
authors: Pennathur
authors: James D
authors: JD
authors: Luketich
authors: Tony E
authors: TE
authors: Godfrey
references: Prostate. 1995 Jan;26(1):35-9
references: 7845865
references: Gut. 2004 Aug;53(8):1070-4
references: 15247170
references: Cancer. 2010 Jun 1;116(11):2621-34
references: 20336784
references: Oncogene. 2008 Sep 18;27(41):5511-26
references: 18794885
references: Cancer Res. 2001 Apr 15;61(8):3410-8
references: 11309301
references: Cancer Genet Cytogenet. 2009 Feb;189(1):37-42
references: 19167610
references: Mod Pathol. 2007 Jan;20(1):120-9
references: 17143264
references: Leukemia. 2008 Feb;22(2):387-92
references: 17989712
references: J Am Coll Surg. 2006 Apr;202(4):588-96; discussion 596-8
references: 16571425
references: Adv Cancer Res. 2010;107:163-224
references: 20399964
references: Cancer Lett. 2009 Jun 18;278(2):230-240
references: 19216023
references: Exp Cell Res. 1999 Apr 10;248(1):110-4
references: 10094818
references: Gynecol Oncol. 2007 May;105(2):462-9
references: 17300833
references: Oncogene. 1998 Oct 29;17(17):2235-49
references: 9811454
references: Breast Cancer Res. 2009;11(5):R77
references: 19874578
references: Cancer Control. 2007 Jul;14(3):295-304
references: 17615536
references: Cancer Res. 2009 May 15;69(10):4443-53
references: 19435910
references: Oncology. 2010;78(1):26-33
references: 20185938
references: Cancer Res. 2000 Jul 15;60(14):3689-95
references: 10919634
references: J Mammary Gland Biol Neoplasia. 2004 Jan;9(1):95-104
references: 15082921
references: Genes Chromosomes Cancer. 2008 Aug;47(8):649-56
references: 18438866
references: Curr Drug Targets. 2010 Aug;11(8):1000-17
references: 20426765
references: Cell. 2006 Oct 20;127(2):265-75
references: 17055429
references: Int J Radiat Oncol Biol Phys. 2007 Feb 1;67(2):405-9
references: 17097832
references: Cancer Res. 2010 Apr 15;70(8):3228-38
references: 20354191
references: Eur J Cancer. 2010 May;46(7):1260-70
references: 20303741
references: Mol Cancer Ther. 2004 Nov;3(11):1427-38
references: 15542782
references: Cancer Genet Cytogenet. 2006 Apr 15;166(2):157-62
references: 16631473
references: Nat Med. 2001 May;7(5):548-52
references: 11329054
references: Curr Opin Genet Dev. 2010 Feb;20(1):4-14
references: 20060285
references: Cell Cycle. 2010 May;9(9):1809-18
references: 20404570
references: Cell. 2004 Aug 20;118(4):493-504
references: 15315761
references: Ann Surg Oncol. 2006 Jan;13(1):12-30
references: 16378161
references: J Clin Oncol. 2005 Dec 1;23(34):8853-62
references: 16314645
references: Cancer Res. 1997 Apr 1;57(7):1250-4
references: 9102208
references: Cancer Prev Res (Phila). 2010 Sep;3(9):1176-86
references: 20651033
references: Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9440-5
references: 12883005
references: Mol Cancer Res. 2004 Feb;2(2):105-14
references: 14985467
references: Gastroenterology. 2010 May;138(5):1920-30
references: 20100483
references: Oncogene. 2009 Aug 20;28(33):2925-39
references: 19561645
references: J Pharmacol Exp Ther. 2005 Jan;312(1):206-13
references: 15304523
references: Prog Cell Cycle Res. 2003;5:5-18
references: 14593696
references: Trends Biochem Sci. 2005 Nov;30(11):630-41
references: 16236519
references: Breast Cancer Res. 2009;11(6):112
references: 20067604