Expression of p16INK4A in gastrointestinal stromal tumours (GISTs): Two different forms exist that independently correlate with poor prognosis

Histopathology

Volumn 56, Issue 3, 2010, Pages 305-318

  Haller, Florian ^a,f   Agaimy, Abbas ^b   Cameron, Silke ^c   Beyer, Manori ^a   Gunawan, Bastian ^a   Happel, Nicole ^d   Langer, Claus ^a   Ramadori, Giuliano ^c   Von Heydebreck, Anja ^e   Füzesi, László ^a  

^a UNIVERSITY OF GÖTTINGEN   (Germany)

^b UNIVERSITY OF ERLANGEN NUREMBERG   (Germany)

^c Department of Gastroenterology and Endocrinology ^*  (Germany)

^d Institute for Biochemistry and Molecular Cell Biology   (Germany)

^e MERCK KGAA   (Germany)

^f UNIVERSITY OF FREIBURG   (Germany)

Author keywords

E2F1; GIST; P16INK4A; Prognosis

Indexed keywords

CYCLIN DEPENDENT KINASE INHIBITOR 2A; TRANSCRIPTION FACTOR E2F1; E2F1 PROTEIN, HUMAN; ISOPROTEIN; TUMOR MARKER;

ARTICLE; CELL NUCLEUS; CYTOPLASM; DISEASE FREE SURVIVAL; FOLLOW UP; GASTROINTESTINAL STROMAL TUMOR; GENE MUTATION; HUMAN; HUMAN TISSUE; IMMUNOHISTOCHEMISTRY; MITOSIS; PRIORITY JOURNAL; PROGNOSIS; PROTEIN EXPRESSION; TUMOR GROWTH; TUMOR VOLUME; UPREGULATION; BIOSYNTHESIS; GENETICS; KAPLAN MEIER METHOD; METABOLISM; MORTALITY; POLYACRYLAMIDE GEL ELECTROPHORESIS; TISSUE MICROARRAY; WESTERN BLOTTING;

BLOTTING, WESTERN; CELL NUCLEUS; CYCLIN-DEPENDENT KINASE INHIBITOR P16; CYTOPLASM; DISEASE-FREE SURVIVAL; E2F1 TRANSCRIPTION FACTOR; ELECTROPHORESIS, POLYACRYLAMIDE GEL; GASTROINTESTINAL STROMAL TUMORS; HUMANS; IMMUNOHISTOCHEMISTRY; KAPLAN-MEIERS ESTIMATE; PROGNOSIS; PROTEIN ISOFORMS; TISSUE ARRAY ANALYSIS; TUMOR MARKERS, BIOLOGICAL;

EID: 77449118248     PISSN: 03090167     EISSN: 13652559     Source Type: Journal    
DOI: 10.1111/j.1365-2559.2010.03478.x     Document Type: Article

References (32)

1. Miettinen M, Sobin LH, Lasota J. Gastrointestinal stromal tumours 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.
2. Miettinen M, Makhlouf H, Sobin LH, Lasota J. Gastrointestinal stromal tumours of the jejunum and ileum: a clinicopathologic, immunohistochemical, and molecular genetic study of 906 cases before imatinib with long-term follow-up. Am. J. Surg. Pathol. 2006 30 477 489.
3. Serrano M. The tumour suppressor protein p16INK4a. Exp. Cell Res. 1997 237 7 13.
4. Ortega S, Malumbres M, Barbacid M. Cyclin D-dependent kinases, INK4 inhibitors and cancer. Biochim. Biophys. Acta 2002 1602 73 87.
5. Schneider-Stock R, Boltze C, Lasota J et al. High prognostic value of p16INK4 alterations in gastrointestinal stromal tumours. J. Clin. Oncol. 2003 21 1688 1697.
6. Schneider-Stock R, Boltze C, Lasota J et al. Loss of p16 protein defines high-risk patients with gastrointestinal stromal tumours: a tissue microarray study. Clin. Cancer Res. 2005 11 638 645.
7. Sabah M, Cummins R, Leader M, Kay E. Loss of heterozygosity of chromosome 9p and loss of p16INK4A expression are associated with malignant gastrointestinal stromal tumours. Mod. Pathol. 2004 17 1364 1371.
8. Ricci R, Arena V, Castri F et al. Role of p16/INK4a in gastrointestinal stromal tumour progression. Am. J. Clin. Pathol. 2004 122 35 43. (Pubitemid 38849870)
9. Perrone F, Tamborini E, Dagrada GP et al. 9p21 locus analysis in high-risk gastrointestinal stromal tumours characterized for c-kit and platelet-derived growth factor receptor alpha gene alterations. Cancer 2005 104 159 169.
10. Haller F, Löbke C, Ruschhaupt M et al. Loss of 9p leads to p16(INK4A) down-regulation and enables RB/E2F1-dependent cell cycle promotion in gastrointestinal stromal tumours (GISTs). J. Pathol. 2008 215 253 262.
11. Steigen SE, Bjerkehagen B, Haugland HK et al. Diagnostic and prognostic markers for gastrointestinal stromal tumours in Norway. Mod. Pathol. 2008 21 46 53.
12. Schmieder M, Wolf S, Danner B et al. p16 expression differentiates high-risk gastrointestinal stromal tumor and predicts poor outcome. Neoplasia 2008 10 1154 1162.
13. Arifin MT, Hama S, Kajiwara Y et al. Cytoplasmic, but not nuclear, p16 expression may signal poor prognosis in high-grade astrocytomas. J. Neurooncol. 2006 77 273 277.
14. Emig R, Magener A, Ehemann V et al. Aberrant cytoplasmic expression of the p16 protein in breast cancer is associated with accelerated tumour proliferation. Br. J. Cancer 1998 78 1661 1668.
15. Milde-Langosch K, Bamberger AM, Rieck G, Kelp B, Loning T. Overexpression of the p16 cell cycle inhibitor in breast cancer is associated with a more malignant phenotype. Breast Cancer Res. Treat. 2001 67 61 70.
16. Atkins KA, Arronte N, Darus CJ, Rice LW. The use of p16 in enhancing the histologic classification of uterine smooth muscle tumours. Am. J. Surg. Pathol. 2008 32 98 102.
17. Evangelou K, Bramis J, Peros I et al. Electron microscopy evidence that cytoplasmic localization of the p16(INK4A) "nuclear" cyclin-dependent kinase inhibitor (CKI) in tumour cells is specific and not an artifact. A study in non-small cell lung carcinomas. Biotech. Histochem. 2004 79 5 10.
18. Nilsson K, Landberg G. Subcellular localization, modification and protein complex formation of the cdk-inhibitor p16 in Rb-functional and Rb-inactivated tumour cells. Int. J. Cancer 2006 118 1120 1125.
19. Agaimy A, Haller F, Gunawan B, Wünsch PH, Füzesi L. Distinct biphasic histomorphologic pattern in gastrointestinal stromal tumours (GIST) with common primary mutations but divergent molecular cytogenetic progression. Histopathology 2009 54 295 302.
20. Redman R, Rufforny I, Liu C, Wilkinson EJ, Masoll NA. The utility of p16(Ink4a) in discriminating between cervical intraepithelial neoplasia 1 and nonneoplastic equivocal lesions of the cervix. Arch. Pathol. Lab. Med. 2008 132 798 799.
21. Klaes R, Friedrich T, Spitkovsky D et al. Overexpression of p16(INK4A) as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri. Int. J. Cancer 2001 92 276 284.
22. Haller F, Gunawan B, von Heydebreck A et al. Prognostic role of E2F1 and members of the CDKN2A network in gastrointestinal stromal tumours. Clin. Cancer Res. 2005 11 6589 6597.
23. Miettinen M, Lasota J. Gastrointestinal stromal tumours: review on morphology, molecular pathology, prognosis, and differential diagnosis. Arch. Pathol. Lab. Med. 2006 130 1466 1478.
24. Cameron S, Haller F, Dudas J et al. Immune cells in primary gastrointestinal stromal tumours. Eur. J. Gastroenterol. Hepatol. 2008 20 327 334.
25. Ihaka R, Gentleman RR. A language for data analysis and graphics. J. Comput. Graph. Stat. 1996 5 299 314.
26. Hothorn T, Lausen B. On the exact distribution of maximally selected rank statistics. Comput. Stat. Data Anal. 2003 43 121 137.
27. Lin YC, Dicianni MB, Kim Y. Human p16c, a novel transcriptional variant of p16INK4A, coexpresses with p16INK4A in cancer cells and inhibits cell-cycle progression. Oncogene 2007 26 7017 7027.
28. Huang HY, Huang WW, Lin CN et al. Immunohistochemical expression of p16INK4A, Ki-67, and Mcm2 proteins in gastrointestinal stromal tumours: prognostic implications and correlations with risk stratification of NIH consensus criteria. Ann. Surg. Oncol. 2006 13 1633 1644.
29. Nemoto Y, Mikami T, Hana K et al. Correlation of enhanced cell turnover with prognosis of gastrointestinal stromal tumours of the stomach: relevance of cellularity and p27kip1. Pathol. Int. 2006 56 724 731.
30. Nakamura N, Yamamoto H, Yao T et al. Prognostic significance of expressions of cell-cycle regulatory proteins in gastrointestinal stromal tumour and the relevance of the risk grade. Hum. Pathol. 2005 36 828 837.
31. Zur Hausen H. Papillomaviruses in anogenital cancer as a model to understand the role of viruses in human cancers. Cancer Res. 1989 49 4677 4681.
32. Tornillo L, Duchini G, Carafa V et al. Patterns of gene amplification in gastrointestinal stromal tumours (GIST). Lab. Invest. 2005 85 921 931.