Expression of cell cycle regulators and frequency of TP53 mutations in high risk gastrointestinal stromal tumors prior to adjuvant imatinib treatment.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science

Mutation*; Antineoplastic Agents/*therapeutic use ; Cell Cycle Proteins/*genetics ; Gastrointestinal Neoplasms/*drug therapy ; Gastrointestinal Neoplasms/*genetics ; Gastrointestinal Stromal Tumors/*drug therapy ; Gastrointestinal Stromal Tumors/*genetics ; Imatinib Mesylate/*therapeutic use ; Tumor Suppressor Protein p53/*genetics; Adult ; Aged ; Aged, 80 and over ; Apoptosis Regulatory Proteins/genetics ; Apoptosis Regulatory Proteins/metabolism ; Cell Cycle Proteins/metabolism ; Chemotherapy, Adjuvant ; Disease-Free Survival ; Female ; Gastrointestinal Neoplasms/metabolism ; Gastrointestinal Stromal Tumors/metabolism ; Humans ; Immunohistochemistry ; Male ; Middle Aged ; Neoplasm Recurrence, Local/genetics ; Neoplasm Recurrence, Local/metabolism ; Prognosis ; Risk Factors ; Young Adult

Despite of multitude investigations no reliable prognostic immunohistochemical biomarkers in GIST have been established so far with added value to predict the recurrence risk of high risk GIST besides mitotic count, primary location and size. In this study, we analyzed the prognostic relevance of eight cell cycle and apoptosis modulators and of TP53 mutations for prognosis in GIST with high risk of recurrence prior to adjuvant treatment with imatinib. In total, 400 patients with high risk for GIST recurrence were randomly assigned for adjuvant imatinib either for one or for three years following laparotomy. 320 primary tumor samples with available tumor tissue were immunohistochemically analyzed prior to treatment for the expression of cell cycle regulators and apoptosis modulators cyclin D1, p21, p16, CDK4, E2F1, MDM2, p53 and p-RB1. TP53 mutational analysis was possible in 245 cases. A high expression of CDK4 was observed in 32.8% of all cases and was associated with a favorable recurrence free survival (RFS), whereas high expression of MDM2 (12.2%) or p53 (35.3%) was associated with a shorter RFS. These results were independent from the primary KIT or PDGFRA mutation. In GISTs with higher mitotic counts was a significantly increased expression of cyclin D1, p53 and E2F1. The expression of p16 and E2F1 significantly correlated to a non-gastric localization. Furthermore, we observed a significant higher expression of p21 and E2F1 in KIT mutant GISTs compared to PDGFRA mutant and wt GISTs. The overall frequency of TP53 mutations was low (n = 8; 3.5%) and could not be predicted by the immunohistochemical expression of p53. In summary, mutation analysis in TP53 plays a minor role in the subgroup of high-risk GIST before adjuvant treatment with imatinib. Strong expression of MDM2 and p53 correlated with a shorter recurrence free survival, whereas a strong expression of CDK4 correlated to a better recurrence free survival.

Oncotarget. 2016 Nov 15;7(46):75328-75338. (PMID: 27659536)
Clin Cancer Res. 2005 Jan 15;11(2 Pt 1):638-45. (PMID: 15701851)
Cancer Med. 2016 Sep;5(9):2268-75. (PMID: 27484851)
J Clin Oncol. 2006 Oct 10;24(29):4764-74. (PMID: 16954519)
Mol Cell. 2009 Feb 27;33(4):462-71. (PMID: 19250907)
Cancer Gene Ther. 2011 Jan;18(1):2-11. (PMID: 20966976)
Histopathology. 2005 Mar;46(3):270-9. (PMID: 15720412)
Cell. 1994 Mar 25;76(6):1013-23. (PMID: 8137420)
Clin Cancer Res. 2005 Sep 15;11(18):6589-97. (PMID: 16166437)
Breast Cancer Res. 2013 Jan 21;15(1):R5. (PMID: 23336272)
Gene. 2001 Oct 17;277(1-2):15-30. (PMID: 11602342)
Clin Cancer Res. 2009 Jun 15;15(12):4191-8. (PMID: 19509155)
Oncogene. 2013 Mar 7;32(10):1252-65. (PMID: 22580601)
J Clin Oncol. 2004 Sep 15;22(18):3813-25. (PMID: 15365079)
Cell. 1995 May 5;81(3):323-30. (PMID: 7736585)
Histol Histopathol. 2014 Jan;29(1):127-38. (PMID: 23852861)
J Pathol. 2008 Oct;216(2):225-35. (PMID: 18729075)
Am J Clin Pathol. 2016 Dec;146(6):718-726. (PMID: 28028119)
Nucleic Acids Res. 2014 Jan;42(Database issue):D749-55. (PMID: 24316576)
Cancer Discov. 2016 Apr;6(4):353-67. (PMID: 26658964)
Hum Mutat. 2014 Jun;35(6):672-88. (PMID: 24665023)
BMC Cancer. 2008 Jul 23;8:204. (PMID: 18651966)
Clin Cancer Res. 2001 Oct;7(10):2984-97. (PMID: 11595686)
Dig Dis Sci. 2010 Sep;55(9):2561-7. (PMID: 20108043)
J Clin Oncol. 2003 May 1;21(9):1688-97. (PMID: 12721243)
J Clin Oncol. 2012 Oct 10;30(29):3633-9. (PMID: 22965953)
Nat Cell Biol. 2013 Jan;15(1):2-8. (PMID: 23263379)
Nat Rev Cancer. 2011 Jul 14;11(8):541-57. (PMID: 21753790)
J Clin Oncol. 2003 Oct 15;21(20):3814-25. (PMID: 14551300)
Semin Cancer Biol. 2003 Feb;13(1):49-58. (PMID: 12507556)
Hum Pathol. 2006 Jun;37(6):648-55. (PMID: 16733203)
J Clin Oncol. 2012 Oct 10;30(29):3648-50. (PMID: 22965952)
BMC Cancer. 2014 Jan 10;14 :13. (PMID: 24410877)
Semin Diagn Pathol. 2006 May;23(2):70-83. (PMID: 17193820)
Cancer Metastasis Rev. 2016 Jun;35(2):151-63. (PMID: 26669603)
Cancer Res. 1994 Mar 15;54(6):1556-60. (PMID: 8137263)
Histopathology. 2007 Sep;51(3):379-89. (PMID: 17727479)
JAMA. 2012 Mar 28;307(12):1265-72. (PMID: 22453568)
PLoS One. 2012;7(5):e37776. (PMID: 22662219)
Int J Surg Pathol. 2000 Apr;8(2):133-144. (PMID: 11493978)
World J Gastroenterol. 2012 May 28;18(20):2569-75. (PMID: 22654456)
Histopathology. 2010 Feb;56(3):305-18. (PMID: 20459531)
JAMA Oncol. 2017 Jun 1;3(6):793-800. (PMID: 28253390)
Ann Surg Oncol. 2015 Dec;22 Suppl 3:S362-9. (PMID: 25791792)
Nat Rev Cancer. 2011 Nov 17;11(12):865-78. (PMID: 22089421)
Clin Cancer Res. 2002 May;8(5):1117-24. (PMID: 12006527)
Cancer Genomics Proteomics. 2013 May-Jun;10(3):115-23. (PMID: 23741027)
Lancet. 2007 May 19;369(9574):1731-41. (PMID: 17512858)
Am J Surg Pathol. 2013 Nov;37(11):1648-59. (PMID: 24061512)
Sci Rep. 2016 Oct 19;6:35383. (PMID: 27759034)
Curr Drug Targets. 2014 Jan;15(1):80-9. (PMID: 24387333)
Cancer. 2013 Mar 1;119(5):1013-22. (PMID: 23165797)
Am J Pathol. 1997 Dec;151(6):1531-9. (PMID: 9403703)
Biochem Pharmacol. 2012 Jul 1;84(1):1-10. (PMID: 22387046)
Histopathology. 2012 Jul;61(1):59-68. (PMID: 22394371)
Nat Rev Cancer. 2006 Dec;6(12 ):909-23. (PMID: 17128209)
Eur Urol. 2006 Sep;50(3):506-15; discussion 515. (PMID: 16624482)
Mol Cell Biol. 2007 Dec;27(23 ):8284-95. (PMID: 17908790)
Hum Mutat. 2007 Jun;28(6):622-9. (PMID: 17311302)

0 (Antineoplastic Agents)
0 (Apoptosis Regulatory Proteins)
0 (Cell Cycle Proteins)
0 (TP53 protein, human)
0 (Tumor Suppressor Protein p53)
8A1O1M485B (Imatinib Mesylate)

Date Created: 20180217 Date Completed: 20180521 Latest Revision: 20220408

20250114

PMC5815598

10.1371/journal.pone.0193048

29451912