title: p14(ARF) methylation is a common event in the pathogenesis and progression of myxoid and pleomorphic liposarcoma.
abstract: Liposarcoma represents the most frequent group of soft tissue sarcomas. The group can be divided into three different classes: (1) differentiated/undifferentiated (WDLPS/DDLPS), (2) myxoid/round cell (MLPS/RCLPS) and (3) pleomorphic liposarcoma (PLS). It has become apparent that p53-p14 and Rb-p16 pathways play important roles in the pathogenesis of various sarcoma types. Molecular studies of the genes involved in these two pathways showed wide variations between the liposarcoma subtypes or even within the same subtype. We sought to examine mutational status of p53 and methylation status of p16 (INK4a) /p14 (ARF) genes in primary and recurrent liposarcoma tumors. There were twelve myxoid (12/18, 66.7 %) and six pleomorphic liposarcoma (6/18, 33.3 %) samples. Immunohistochemical analysis revealed that p53 protein was overexpressed in 3/12 MLPS (25 %) and 6/6 PLS (100 %). Mutational analysis showed that 2/11 MLPS (18.2 %) and 2/6 PLS (33.3 %) contained mutated p53 gene. On the other hand, 3/18 samples (16.7 %) had methylated p16 promoter. However, the frequencies of the p14 (ARF) gene methylation were 83.3 % (10/12) and 50 % (3/6) in myxoid and pleomorphic group, respectively. Overall, 15 out of 18 (83.3 %) samples had either p53 gene mutation or methylated p14 (ARF) promoter. The results from the current study suggest significant impact of the p14 (ARF) gene methylation on the pathogenesis and progression of myxoid and to a lesser extent pleomorphic liposarcoma. Despite the limited number of samples, our study points to necessity of further investigation of p53-p14 and Rb-p16 pathways in liposarcoma.
authors.affiliation: Department for Radiobiology and Molecular Genetics, Institute of Nuclear Sciences Vinča, University of Belgrade, Mike Alasa 12-14, 11000, Belgrade, Serbia. radoslav@vinca.rs
authors.forename: Radoslav
authors.initials: R
authors.lastname: Davidović
authors.forename: Jelena
authors.initials: J
authors.lastname: Sopta
authors.forename: Vesna
authors.initials: V
authors.lastname: Mandušić
authors.forename: Milena
authors.initials: M
authors.lastname: Krajnović
authors.forename: Maja
authors.initials: M
authors.lastname: Stanojević
authors.forename: Goran
authors.initials: G
authors.lastname: Tulić
authors.forename: Bogomir
authors.initials: B
authors.lastname: Dimitrijević
mesh_terms: D000368:Aged; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D006801:Humans; D008080:Liposarcoma / Q000235:genetics* / Q000473:pathology*; D018208:Liposarcoma, Myxoid / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000235:genetics; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53
references.citation: Carcinogenesis. 2000 Nov;21(11):2057-64
references.pmid: 11062168
references.citation: Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9821-6
references.pmid: 8790415
references.citation: Sarcoma. 2011;2011:538085
references.pmid: 22190864
references.citation: J Gastroenterol Hepatol. 2002 Mar;17(3):301-7
references.pmid: 11982701
references.citation: Mod Pathol. 2012 Mar;25(3):465-70
references.pmid: 22080060
references.citation: Clin Cancer Res. 2001 Dec;7(12):3977-87
references.pmid: 11751490
references.citation: Cancer. 2007 Jun 15;109(12):2522-31
references.pmid: 17510918
references.citation: Genet Res Int. 2011;2011:497148
references.pmid: 22567356
references.citation: Exp Gerontol. 2004 Nov-Dec;39(11-12):1751-9
references.pmid: 15582292
references.citation: Pathol Res Pract. 2009;205(6):386-94
references.pmid: 19186005
references.citation: J Pathol. 1997 Jan;181(1):8-13
references.pmid: 9071997
references.citation: Cancer. 2006 Apr 1;106(7):1602-9
references.pmid: 16502411
references.citation: Rev Recent Clin Trials. 2009 Jan;4(1):12-26
references.pmid: 19149759
references.citation: Lab Invest. 2006 Jun;86(6):591-8
references.pmid: 16534497
references.citation: EMBO J. 1998 Sep 1;17(17):5001-14
references.pmid: 9724636
references.citation: Am J Pathol. 2010 Oct;177(4):2080-90
references.pmid: 20884963
references.citation: Am J Pathol. 1997 Dec;151(6):1531-9
references.pmid: 9403703
references.citation: Int J Cancer. 2000 Sep 1;87(5):654-8
references.pmid: 10925358
references.citation: J Pathol. 2005 Dec;207(4):410-21
references.pmid: 16177957
references.citation: Mol Med. 1997 Jan;3(1):5-20
references.pmid: 9132280
references.citation: Nucleic Acids Res. 1991 Dec 25;19(24):6977
references.pmid: 1762941
references.citation: Exp Cell Res. 2001 Mar 10;264(1):42-55
references.pmid: 11237522
references.citation: Ann Diagn Pathol. 2000 Aug;4(4):252-66
references.pmid: 10982304
references.citation: Cell. 2006 Oct 20;127(2):265-75
references.pmid: 17055429
references.citation: Sarcoma. 2011;2011:483154
references.pmid: 21253554
references.citation: Oncogene. 2007 Apr 2;26(15):2157-65
references.pmid: 17401424
references.citation: J Clin Oncol. 2006 Apr 10;24(11):1770-83
references.pmid: 16603719
references.citation: Clin Cancer Res. 2003 Sep 15;9(11):4132-8
references.pmid: 14519636
references.citation: Nat Genet. 2010 Aug;42(8):715-21
references.pmid: 20601955