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Published in: BMC Cancer 1/2010

Open Access 01-12-2010 | Research article

Cyclin H expression is increased in GIST with very-highrisk of malignancy

Authors: Julian Dorn, Hanno Spatz, Michael Schmieder, Thomas FE Barth, Annette Blatz, Doris Henne-Bruns, Uwe Knippschild, Klaus Kramer

Published in: BMC Cancer | Issue 1/2010

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Abstract

Background

Risk estimation of gastrointestinal stromal tumours (GIST) is based on tumour size and mitotic rate according to the National Institutes of Health consensus classification. The indication for adjuvant treatment of patients with high risk GIST after R0 resection with small molecule inhibitors is still a controversial issue, since these patients represent a highly heterogeneous population. Therefore, additional prognostic indicators are needed. Here, we evaluated the prognostic value of cyclin H expression in GIST.

Methods

In order to identify prognostic factors of GIST we evaluated a single centre cohort of ninety-five GIST patients. First, GISTs were classified with regard to tumour size, mitotic rate and localisation according to the NIH consensus and to three additional suggested risk classifications. Second, Cyclin H expression was analysed.

Results

Of ninety-five patients with GIST (53 female/42 male; median age: 66.78a; range 17-94a) risk classification revealed: 42% high risk, 20% intermediate risk, 23% low risk and 15% very low risk GIST. In patients with high risk GIST, the expression of cyclin H was highly predictive for reduced disease-specific survival (p = 0.038). A combination of cyclin H expression level and high risk classification yielded the strongest prognostic indicator for disease-specific and disease-free survival (p ≤ 0.001). Moreover, in patients with tumour recurrence and/or metastases, cyclin H positivity was significantly associated with reduced disease-specific survival (p = 0.016) regardless of risk-classification.

Conclusion

Our data suggest that, in addition to high risk classification, cyclin H expression might be an indicator for "very-high risk" GIST.
Appendix
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Literature
1.
go back to reference Fletcher CD, Berman JJ, Corless C, Gorstein F, Lasota J, Longley BJ, Miettinen M, O'Leary TJ, Remotti H, Rubin BP, et al: Diagnosis of gastrointestinal stromal tumors: A consensus approach. Hum Pathol. 2002, 33: 459-465. 10.1053/hupa.2002.123545.CrossRefPubMed Fletcher CD, Berman JJ, Corless C, Gorstein F, Lasota J, Longley BJ, Miettinen M, O'Leary TJ, Remotti H, Rubin BP, et al: Diagnosis of gastrointestinal stromal tumors: A consensus approach. Hum Pathol. 2002, 33: 459-465. 10.1053/hupa.2002.123545.CrossRefPubMed
2.
go back to reference Miettinen M, Lasota J: Gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential diagnosis. Arch Pathol Lab Med. 2006, 130: 1466-1478.PubMed Miettinen M, Lasota J: Gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential diagnosis. Arch Pathol Lab Med. 2006, 130: 1466-1478.PubMed
3.
4.
go back to reference Hornick JL, Fletcher CD: The role of KIT in the management of patients with gastrointestinal stromal tumors. Hum Pathol. 2007, 38: 679-687. 10.1016/j.humpath.2007.03.001.CrossRefPubMed Hornick JL, Fletcher CD: The role of KIT in the management of patients with gastrointestinal stromal tumors. Hum Pathol. 2007, 38: 679-687. 10.1016/j.humpath.2007.03.001.CrossRefPubMed
5.
go back to reference Hou YY, Lu SH, Zhou Y, Xu JF, Ji Y, Hou J, Qi WD, Shi Y, Tan YS, Zhu XZ: Predictive values of clinical and pathological parameters for malignancy of gastrointestinal stromal tumors. Histol Histopathol. 2009, 24: 737-747.PubMed Hou YY, Lu SH, Zhou Y, Xu JF, Ji Y, Hou J, Qi WD, Shi Y, Tan YS, Zhu XZ: Predictive values of clinical and pathological parameters for malignancy of gastrointestinal stromal tumors. Histol Histopathol. 2009, 24: 737-747.PubMed
6.
go back to reference Joensuu H: Risk stratification of patients diagnosed with gastrointestinal stromal tumor. Hum Pathol. 2008, 39: 1411-1419. 10.1016/j.humpath.2008.06.025.CrossRefPubMed Joensuu H: Risk stratification of patients diagnosed with gastrointestinal stromal tumor. Hum Pathol. 2008, 39: 1411-1419. 10.1016/j.humpath.2008.06.025.CrossRefPubMed
7.
go back to reference Miettinen M, Sobin LH, Lasota J: Gastrointestinal stromal tumors of the stomach: a clinicopathologic, immunohistochemical, and molecular genetic study of 1765 cases with long-term follow-up. Am J Surg Pathol. 2005, 29: 52-68. 10.1097/01.pas.0000146010.92933.de.CrossRefPubMed Miettinen M, Sobin LH, Lasota J: Gastrointestinal stromal tumors of the stomach: a clinicopathologic, immunohistochemical, and molecular genetic study of 1765 cases with long-term follow-up. Am J Surg Pathol. 2005, 29: 52-68. 10.1097/01.pas.0000146010.92933.de.CrossRefPubMed
8.
go back to reference Wente MN, Buchler MW, Weitz J: [Gastrointestinal stromal tumors (GIST). Surgical therapy]. Chirurg. 2008, 79: 638-643. 10.1007/s00104-008-1527-5.CrossRefPubMed Wente MN, Buchler MW, Weitz J: [Gastrointestinal stromal tumors (GIST). Surgical therapy]. Chirurg. 2008, 79: 638-643. 10.1007/s00104-008-1527-5.CrossRefPubMed
9.
go back to reference Hohenberger P: Adjuvant imatinib in GIST: a self-fulfilling prophecy, or more?. Lancet. 2009, 373: 1058-1060. 10.1016/S0140-6736(09)60562-6.CrossRefPubMed Hohenberger P: Adjuvant imatinib in GIST: a self-fulfilling prophecy, or more?. Lancet. 2009, 373: 1058-1060. 10.1016/S0140-6736(09)60562-6.CrossRefPubMed
10.
go back to reference DeMatteo RP, Ballman KV, Antonescu CR, Maki RG, Pisters PW, Demetri GD, Blackstein ME, Blanke CD, von Mehren M, Brennan MF, et al: Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet. 2009, 373: 1097-1104. 10.1016/S0140-6736(09)60500-6.CrossRefPubMedPubMedCentral DeMatteo RP, Ballman KV, Antonescu CR, Maki RG, Pisters PW, Demetri GD, Blackstein ME, Blanke CD, von Mehren M, Brennan MF, et al: Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet. 2009, 373: 1097-1104. 10.1016/S0140-6736(09)60500-6.CrossRefPubMedPubMedCentral
11.
go back to reference Johansson M, Persson JL: Cancer therapy: targeting cell cycle regulators. Anticancer Agents Med Chem. 2008, 8: 723-731.CrossRefPubMed Johansson M, Persson JL: Cancer therapy: targeting cell cycle regulators. Anticancer Agents Med Chem. 2008, 8: 723-731.CrossRefPubMed
12.
go back to reference Malumbres M: Cyclins and related kinases in cancer cells. J BUON. 2007, 12 (Suppl 1): S45-52.PubMed Malumbres M: Cyclins and related kinases in cancer cells. J BUON. 2007, 12 (Suppl 1): S45-52.PubMed
13.
go back to reference Ali S: Role of c-kit/SCF in cause and treatment of gastrointestinal stromal tumors (GIST). Gene. 2007, 401: 38-45. 10.1016/j.gene.2007.06.017.CrossRefPubMed Ali S: Role of c-kit/SCF in cause and treatment of gastrointestinal stromal tumors (GIST). Gene. 2007, 401: 38-45. 10.1016/j.gene.2007.06.017.CrossRefPubMed
14.
go back to reference Bauer S, Duensing A, Demetri GD, Fletcher JA: KIT oncogenic signaling mechanisms in imatinib-resistant gastrointestinal stromal tumor: PI3-kinase/AKT is a crucial survival pathway. Oncogene. 2007, 26: 7560-7568. 10.1038/sj.onc.1210558.CrossRefPubMed Bauer S, Duensing A, Demetri GD, Fletcher JA: KIT oncogenic signaling mechanisms in imatinib-resistant gastrointestinal stromal tumor: PI3-kinase/AKT is a crucial survival pathway. Oncogene. 2007, 26: 7560-7568. 10.1038/sj.onc.1210558.CrossRefPubMed
15.
go back to reference Tornillo L, Terracciano LM: An update on molecular genetics of gastrointestinal stromal tumours. J Clin Pathol. 2006, 59: 557-563. 10.1136/jcp.2005.031112.CrossRefPubMedPubMedCentral Tornillo L, Terracciano LM: An update on molecular genetics of gastrointestinal stromal tumours. J Clin Pathol. 2006, 59: 557-563. 10.1136/jcp.2005.031112.CrossRefPubMedPubMedCentral
16.
go back to reference Shirin H, Kravtsov V, Shahmurov M, Shabat VS, Krinshpon I, Alin A, Avinoach I, Avni Y: The cyclin-dependent kinase inhibitor, p27, has no correlation with the malignant potential of GIST. Digestion. 2007, 75: 4-9. 10.1159/000101457.CrossRefPubMed Shirin H, Kravtsov V, Shahmurov M, Shabat VS, Krinshpon I, Alin A, Avinoach I, Avni Y: The cyclin-dependent kinase inhibitor, p27, has no correlation with the malignant potential of GIST. Digestion. 2007, 75: 4-9. 10.1159/000101457.CrossRefPubMed
17.
go back to reference Nemoto Y, Mikami T, Hana K, Kikuchi S, Kobayashi N, Watanabe M, Okayasu I: Correlation of enhanced cell turnover with prognosis of gastrointestinal stromal tumors of the stomach: relevance of cellularity and p27kip1. Pathol Int. 2006, 56: 724-731. 10.1111/j.1440-1827.2006.02038.x.CrossRefPubMed Nemoto Y, Mikami T, Hana K, Kikuchi S, Kobayashi N, Watanabe M, Okayasu I: Correlation of enhanced cell turnover with prognosis of gastrointestinal stromal tumors of the stomach: relevance of cellularity and p27kip1. Pathol Int. 2006, 56: 724-731. 10.1111/j.1440-1827.2006.02038.x.CrossRefPubMed
18.
go back to reference Sabah M, Cummins R, Leader M, Kay E: Altered expression of cell cycle regulatory proteins in gastrointestinal stromal tumors: markers with potential prognostic implications. Hum Pathol. 2006, 37: 648-655. 10.1016/j.humpath.2006.01.023.CrossRefPubMed Sabah M, Cummins R, Leader M, Kay E: Altered expression of cell cycle regulatory proteins in gastrointestinal stromal tumors: markers with potential prognostic implications. Hum Pathol. 2006, 37: 648-655. 10.1016/j.humpath.2006.01.023.CrossRefPubMed
19.
go back to reference Nakamura N, Yamamoto H, Yao T, Oda Y, Nishiyama K, Imamura M, Yamada T, Nawata H, Tsuneyoshi M: Prognostic significance of expressions of cell-cycle regulatory proteins in gastrointestinal stromal tumor and the relevance of the risk grade. Hum Pathol. 2005, 36: 828-837. 10.1016/j.humpath.2005.03.012.CrossRefPubMed Nakamura N, Yamamoto H, Yao T, Oda Y, Nishiyama K, Imamura M, Yamada T, Nawata H, Tsuneyoshi M: Prognostic significance of expressions of cell-cycle regulatory proteins in gastrointestinal stromal tumor and the relevance of the risk grade. Hum Pathol. 2005, 36: 828-837. 10.1016/j.humpath.2005.03.012.CrossRefPubMed
20.
go back to reference Koon N, Schneider-Stock R, Sarlomo-Rikala M, Lasota J, Smolkin M, Petroni G, Zaika A, Boltze C, Meyer F, Andersson L, et al: Molecular targets for tumour progression in gastrointestinal stromal tumours. Gut. 2004, 53: 235-240. 10.1136/gut.2003.021238.CrossRefPubMedPubMedCentral Koon N, Schneider-Stock R, Sarlomo-Rikala M, Lasota J, Smolkin M, Petroni G, Zaika A, Boltze C, Meyer F, Andersson L, et al: Molecular targets for tumour progression in gastrointestinal stromal tumours. Gut. 2004, 53: 235-240. 10.1136/gut.2003.021238.CrossRefPubMedPubMedCentral
21.
go back to reference Lolli G, Johnson LN: CAK-Cyclin-dependent Activating Kinase: a key kinase in cell cycle control and a target for drugs?. Cell Cycle. 2005, 4: 572-577.CrossRefPubMed Lolli G, Johnson LN: CAK-Cyclin-dependent Activating Kinase: a key kinase in cell cycle control and a target for drugs?. Cell Cycle. 2005, 4: 572-577.CrossRefPubMed
22.
go back to reference Bondi J, Husdal A, Bukholm G, Nesland JM, Bakka A, Bukholm IR: Expression and gene amplification of primary (A, B1, D1, D3, and E) and secondary (C and H) cyclins in colon adenocarcinomas and correlation with patient outcome. J Clin Pathol. 2005, 58: 509-514. 10.1136/jcp.2004.020347.CrossRefPubMedPubMedCentral Bondi J, Husdal A, Bukholm G, Nesland JM, Bakka A, Bukholm IR: Expression and gene amplification of primary (A, B1, D1, D3, and E) and secondary (C and H) cyclins in colon adenocarcinomas and correlation with patient outcome. J Clin Pathol. 2005, 58: 509-514. 10.1136/jcp.2004.020347.CrossRefPubMedPubMedCentral
23.
go back to reference Kayaselcuk F, Erkanli S, Bolat F, Seydaoglu G, Kuscu E, Demirhan B: Expression of cyclin H in normal and cancerous endometrium, its correlation with other cyclins, and association with clinicopathologic parameters. Int J Gynecol Cancer. 2006, 16: 402-408. 10.1111/j.1525-1438.2006.00407.x.CrossRefPubMed Kayaselcuk F, Erkanli S, Bolat F, Seydaoglu G, Kuscu E, Demirhan B: Expression of cyclin H in normal and cancerous endometrium, its correlation with other cyclins, and association with clinicopathologic parameters. Int J Gynecol Cancer. 2006, 16: 402-408. 10.1111/j.1525-1438.2006.00407.x.CrossRefPubMed
24.
go back to reference Dirnhofer S, Leyvraz S: Current standards and progress in understanding and treatment of GIST. Swiss Med Wkly. 2009, 139: 90-102.PubMed Dirnhofer S, Leyvraz S: Current standards and progress in understanding and treatment of GIST. Swiss Med Wkly. 2009, 139: 90-102.PubMed
25.
go back to reference Di Vizio D, Demichelis F, Simonetti S, Pettinato G, Terracciano L, Tornillo L, Freeman MR, Insabato L: Skp2 expression is associated with high risk and elevated Ki67 expression in gastrointestinal stromal tumours. BMC Cancer. 2008, 8: 134-10.1186/1471-2407-8-134.CrossRefPubMedPubMedCentral Di Vizio D, Demichelis F, Simonetti S, Pettinato G, Terracciano L, Tornillo L, Freeman MR, Insabato L: Skp2 expression is associated with high risk and elevated Ki67 expression in gastrointestinal stromal tumours. BMC Cancer. 2008, 8: 134-10.1186/1471-2407-8-134.CrossRefPubMedPubMedCentral
26.
go back to reference Liu FY, Qi JP, Xu FL, Wu AP: Clinicopathological and immunohistochemical analysis of gastrointestinal stromal tumor. World J Gastroenterol. 2006, 12: 4161-4165.CrossRefPubMedPubMedCentral Liu FY, Qi JP, Xu FL, Wu AP: Clinicopathological and immunohistochemical analysis of gastrointestinal stromal tumor. World J Gastroenterol. 2006, 12: 4161-4165.CrossRefPubMedPubMedCentral
27.
go back to reference Yang J, Du X, Lazar AJ, Pollock R, Hunt K, Chen K, Hao X, Trent J, Zhang W: Genetic aberrations of gastrointestinal stromal tumors. Cancer. 2008, 113: 1532-1543. 10.1002/cncr.23778.CrossRefPubMedPubMedCentral Yang J, Du X, Lazar AJ, Pollock R, Hunt K, Chen K, Hao X, Trent J, Zhang W: Genetic aberrations of gastrointestinal stromal tumors. Cancer. 2008, 113: 1532-1543. 10.1002/cncr.23778.CrossRefPubMedPubMedCentral
28.
go back to reference Schmieder M, Wolf S, Danner B, Stoehr S, Juchems MS, Wuerl P, Henne-Bruns D, Knippschild U, Hasel C, Kramer K: p16 expression differentiates high-risk gastrointestinal stromal tumor and predicts poor outcome. Neoplasia. 2008, 10: 1154-1162.CrossRefPubMedPubMedCentral Schmieder M, Wolf S, Danner B, Stoehr S, Juchems MS, Wuerl P, Henne-Bruns D, Knippschild U, Hasel C, Kramer K: p16 expression differentiates high-risk gastrointestinal stromal tumor and predicts poor outcome. Neoplasia. 2008, 10: 1154-1162.CrossRefPubMedPubMedCentral
29.
go back to reference Schneider-Stock R, Boltze C, Lasota J, Peters B, Corless CL, Ruemmele P, Terracciano L, Pross M, Insabato L, Di Vizio D, et al: Loss of p16 protein defines high-risk patients with gastrointestinal stromal tumors: a tissue microarray study. Clin Cancer Res. 2005, 11: 638-645.PubMed Schneider-Stock R, Boltze C, Lasota J, Peters B, Corless CL, Ruemmele P, Terracciano L, Pross M, Insabato L, Di Vizio D, et al: Loss of p16 protein defines high-risk patients with gastrointestinal stromal tumors: a tissue microarray study. Clin Cancer Res. 2005, 11: 638-645.PubMed
30.
go back to reference Agaimy A, Haller F, Gunawan B, Wunsch PH, Fuzesi L: Distinct biphasic histomorphological pattern in gastrointestinal stromal tumours (GISTs) with common primary mutations but divergent molecular cytogenetic progression. Histopathology. 2009, 54: 295-302. 10.1111/j.1365-2559.2008.03214.x.CrossRefPubMed Agaimy A, Haller F, Gunawan B, Wunsch PH, Fuzesi L: Distinct biphasic histomorphological pattern in gastrointestinal stromal tumours (GISTs) with common primary mutations but divergent molecular cytogenetic progression. Histopathology. 2009, 54: 295-302. 10.1111/j.1365-2559.2008.03214.x.CrossRefPubMed
31.
go back to reference Bachet JB, Hostein I, Le Cesne A, Brahimi S, Beauchet A, Tabone-Eglinger S, Subra F, Bui B, Duffaud F, Terrier P, et al: Prognosis and predictive value of KIT exon 11 deletion in GISTs. Br J Cancer. 2009, 101: 7-11. 10.1038/sj.bjc.6605117.CrossRefPubMedPubMedCentral Bachet JB, Hostein I, Le Cesne A, Brahimi S, Beauchet A, Tabone-Eglinger S, Subra F, Bui B, Duffaud F, Terrier P, et al: Prognosis and predictive value of KIT exon 11 deletion in GISTs. Br J Cancer. 2009, 101: 7-11. 10.1038/sj.bjc.6605117.CrossRefPubMedPubMedCentral
32.
go back to reference Hoeben A, Schoffski P, Debiec-Rychter M: Clinical implications of mutational analysis in gastrointestinal stromal tumours. Br J Cancer. 2008, 98: 684-688. 10.1038/sj.bjc.6604217.CrossRefPubMedPubMedCentral Hoeben A, Schoffski P, Debiec-Rychter M: Clinical implications of mutational analysis in gastrointestinal stromal tumours. Br J Cancer. 2008, 98: 684-688. 10.1038/sj.bjc.6604217.CrossRefPubMedPubMedCentral
33.
go back to reference Rubin BP, Heinrich MC, Corless CL: Gastrointestinal stromal tumour. Lancet. 2007, 369: 1731-1741. 10.1016/S0140-6736(07)60780-6.CrossRefPubMed Rubin BP, Heinrich MC, Corless CL: Gastrointestinal stromal tumour. Lancet. 2007, 369: 1731-1741. 10.1016/S0140-6736(07)60780-6.CrossRefPubMed
34.
go back to reference Schildhaus HU, Merkelbach-Bruse S, Buttner R, Wardelmann E: Pathology and molecular biology of gastrointestinal stromal tumors (GIST). Radiologe. 2009, 49 (12): 1104-8. 10.1007/s00117-009-1850-y.CrossRefPubMed Schildhaus HU, Merkelbach-Bruse S, Buttner R, Wardelmann E: Pathology and molecular biology of gastrointestinal stromal tumors (GIST). Radiologe. 2009, 49 (12): 1104-8. 10.1007/s00117-009-1850-y.CrossRefPubMed
Metadata
Title
Cyclin H expression is increased in GIST with very-highrisk of malignancy
Authors
Julian Dorn
Hanno Spatz
Michael Schmieder
Thomas FE Barth
Annette Blatz
Doris Henne-Bruns
Uwe Knippschild
Klaus Kramer
Publication date
01-12-2010
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2010
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-10-350

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