High P rognostic V alue o f p16 INK4 Alterations i n Gastrointestinal S tromal T umors

Purpose: Gastrointestinal stromal tumors (GISTs) represent a distinctive (but histologically heterogeneous) group of neoplasms, the malignant potential of which is often uncertain. To determine the prognostic relevance of p16 INK4 alterations in GISTs, we investigated a larger group of GISTs and correlated the genetic findings with clinicopathological factors and patient survival. Material and Methods: We evaluated the methylation status of the promotor by methylation-specific polymerase chain reaction (PCR), the presence of mutations by PCRSSCP-sequencing, the loss of heterozygosity at the p16 INK4 locus (using the c5.1 marker), and the immunohistochemical expression of p16 INK4 protein in 43 GISTs in 39 patients. Results: p16 INK4 alterations were found in 25 of 43 GISTs (58.1%), with benign, borderline, or malignant GISTs showing no differences in the type and frequency of alteration.

[1]  L. Sobin,et al.  Diagnosis of gastrointestinal stromal tumors: A consensus approach. , 2002, Human pathology.

[2]  M. Heinrich,et al.  KIT mutations are common in incidental gastrointestinal stromal tumors one centimeter or less in size. , 2002, The American journal of pathology.

[3]  W. El-Rifai,et al.  Evaluation of malignancy and prognosis of gastrointestinal stromal tumors: a review. , 2002, Human pathology.

[4]  B. Gunawan,et al.  Biological and clinical significance of cytogenetic abnormalities in low-risk and high-risk gastrointestinal stromal tumors. , 2002, Human pathology.

[5]  John D Minna,et al.  Aberrant promoter methylation profile of prostate cancers and its relationship to clinicopathological features. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[6]  J. Herman,et al.  Cancer as an epigenetic disease: DNA methylation and chromatin alterations in human tumours , 2002, The Journal of pathology.

[7]  C. J. Chen,et al.  KIT activation is a ubiquitous feature of gastrointestinal stromal tumors. , 2001, Cancer research.

[8]  Charles J. Sherr,et al.  The INK4a/ARF network in tumour suppression , 2001, Nature Reviews Molecular Cell Biology.

[9]  M. Debiec‐Rychter,et al.  Chromosomal aberrations in malignant gastrointestinal stromal tumors: correlation with c-KIT gene mutation. , 2001, Cancer genetics and cytogenetics.

[10]  J. Herman,et al.  A gene hypermethylation profile of human cancer. , 2001, Cancer research.

[11]  R. E. Cunningham,et al.  Apoptosis, bcl-2 Expression, and p53 Expression in Gastrointestinal Stromal/Smooth Muscle Tumors , 2001, Applied immunohistochemistry & molecular morphology : AIMM.

[12]  F. Bosman,et al.  Methylation Silencing and Mutations of the p14ARF and p16INK4a Genes in Colon Cancer , 2001, Laboratory Investigation.

[13]  J. Herman,et al.  K-ras and p16 aberrations confer poor prognosis in human colorectal cancer. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  A. Gemma,et al.  Increase in the frequency of p16INK4 gene inactivation by hypermethylation in lung cancer during the process of metastasis and its relation to the status of p53. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[15]  R. Jensen,et al.  Alterations in the p16INK4a/CDKN2A tumor suppressor gene in gastrinomas. , 2000, The Journal of clinical endocrinology and metabolism.

[16]  L. Sobin,et al.  Mutations in exons 9 and 13 of KIT gene are rare events in gastrointestinal stromal tumors. A study of 200 cases. , 2000, The American journal of pathology.

[17]  L. Sobin,et al.  Immunohistochemical Spectrum of GISTs at Different Sites and Their Differential Diagnosis with a Reference to CD117 (KIT) , 2000, Modern Pathology.

[18]  S. Knuutila,et al.  DNA sequence copy number changes in gastrointestinal stromal tumors: tumor progression and prognostic significance. , 2000, Cancer research.

[19]  R. Schneider-Stock,et al.  Telomerase activity and expression of hTRT and hTR in gastrointestinal stromal tumors in comparison with extragastrointestinal sarcomas. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[20]  E. de Álava,et al.  Predicting Metastatic Risk of Gastrointestinal Stromal Tumors: Role of Cell Proliferation and Cell Cycle Regulatory Proteins , 2000, International journal of surgical pathology.

[21]  J. Fletcher,et al.  KIT extracellular and kinase domain mutations in gastrointestinal stromal tumors. , 2000, The American journal of pathology.

[22]  Hoguen Kim,et al.  Putative chromosomal deletions on 9p, 9q and 22q occur preferentially in malignant gastrointestinal stromal tumors , 2000, International journal of cancer.

[23]  S. Hirota,et al.  Effect of c-kit mutation on prognosis of gastrointestinal stromal tumors. , 1999, Cancer research.

[24]  Peter A. Jones,et al.  Early acquisition of homozygous deletions of p16/p19 during squamous cell carcinogenesis and genetic mosaicism in bladder cancer , 1998, Oncogene.

[25]  L. Sobin,et al.  KIT mutation portends poor prognosis in gastrointestinal stromal/smooth muscle tumors. , 1998, Laboratory investigation; a journal of technical methods and pathology.

[26]  M. Fukayama,et al.  Telomerase activity in gastrointestinal stromal tumors , 1998 .

[27]  L. Kindblom,et al.  Gastrointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal. , 1998, The American journal of pathology.

[28]  S. Hirota,et al.  Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. , 1998, Science.

[29]  R. Schneider-Stock,et al.  Loss of heterozygosity on chromosome 9q21 (p16 gene) uncommon in soft‐tissue sarcomas , 1997, Molecular carcinogenesis.

[30]  G. Landberg,et al.  Telomerase activity is associated with cell cycle deregulation in human breast cancer. , 1997, Cancer research.

[31]  J. Herman,et al.  Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[32]  J. Herman,et al.  5′ CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers , 1995, Nature Medicine.

[33]  A. Okamoto,et al.  IS-12 Mutation and altered expression of P16^ in human cancer. , 1995 .

[34]  A. Rustgi,et al.  MTS-1 (CDKN2) tumor suppressor gene deletions are a frequent event in esophagus squamous cancer and pancreatic adenocarcinoma cell lines. , 1995, Oncogene.

[35]  M. Skolnick,et al.  A cell cycle regulator potentially involved in genesis of many tumor types. , 1994, Science.

[36]  C. Merril,et al.  Silver staining of DNA in polyacrylamide gels: Linearity and effect of fragment size , 1982 .

[37]  J. Lasota,et al.  Gastrointestinal stromal tumors – definition, clinical, histological, immunohistochemical, and molecular genetic features and differential diagnosis , 2000, Virchows Archiv.

[38]  J. Lasota,et al.  Mutations in exon 11 of c-Kit occur preferentially in malignant versus benign gastrointestinal stromal tumors and do not occur in leiomyomas or leiomyosarcomas. , 1999, The American journal of pathology.