Genetic alterations in gastrinomas and nonfunctioning pancreatic neuroendocrine tumors: an analysis of p16/MTS1 tumor suppressor gene inactivation.

Neoplasms of the endocrine pancreas are extremely rare, and molecular mechanisms influencing their development are poorly understood. Nevertheless, gastrinomas have become a paradigm for the study of hormonally active tumors. In the present study, 12 gastrinoma and nonfunctioning pancreatic neuroendocrine tumor specimens were evaluated for genetic alterations of the p16/MTS1 tumor suppressor gene. DNA extracted from microdissected portions of paraffin-embedded tumor sections were examined for mutations and homozygous deletions using "Cold" single-strand conformation polymorphism and semiquantitative PCR-based analyses, respectively. Samples were also analyzed for the presence of 5' CpG island hypermethylation using methylation-specific PCR. The p16/MTS1 gene was found to be homozygously deleted in 41.7% of tumors and methylated in 58.3%, but no mutations were identified by single-strand conformation polymorphism analyses. Overall, 91.7% of the specimens demonstrated inactivating alterations in p16/MTS1. These data suggest that transcriptional silencing of p16/MTS1 is a frequent event in these rare and poorly understood tumors.

[1]  C. Moskaluk,et al.  Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas. , 1997, Cancer research.

[2]  Y Wang,et al.  Positional cloning of the gene for multiple endocrine neoplasia-type 1. , 1997, Science.

[3]  J. Herman,et al.  Frequent aberrant methylation of p16INK4a in primary rat lung tumors , 1997, Molecular and cellular biology.

[4]  D. Bostwick,et al.  Absence of p16/MTS1 gene mutations in human prostate cancer. , 1996, Carcinogenesis.

[5]  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.

[6]  J. Bartek,et al.  High frequency of p16 (CDKN2/MTS-1/INK4A) inactivation in head and neck squamous cell carcinoma. , 1996, Cancer research.

[7]  W. Schmiegel,et al.  Frequent codeletion of p16/MTS1 and p15/MTS2 and genetic alterations in p16/MTS1 in pancreatic tumors. , 1996, Gastroenterology.

[8]  T. Goodrow,et al.  Deletion and mutation analyses of the P16/MTS-1 tumor suppressor gene in human ductal pancreatic cancer reveals a higher frequency of abnormalities in tumor-derived cell lines than in primary ductal adenocarcinomas. , 1996, Cancer research.

[9]  J. Herman,et al.  Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers. , 1995, Cancer research.

[10]  R. Beart,et al.  Methylation of the 5' CpG island of the p16/CDKN2 tumor suppressor gene in normal and transformed human tissues correlates with gene silencing. , 1995, Cancer research.

[11]  S. Baylin,et al.  p53 activates expression of HIC-1, a new candidate tumour suppressor gene on 17p13.3 , 1995, Nature Genetics.

[12]  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.

[13]  R. Hruban,et al.  Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma , 1994, Nature Genetics.

[14]  W. Nealon,et al.  Gastrinomas Demonstrate Amplification of the HER‐2/neu Proto‐oncogene , 1994, Annals of surgery.

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

[16]  E. Kaplan,et al.  Comparison of mutations of ras oncogene in human pancreatic exocrine and endocrine tumors. , 1993, Surgery.

[17]  T. Hongyo,et al.  'Cold SSCP': a simple, rapid and non-radioactive method for optimized single-strand conformation polymorphism analyses. , 1993, Nucleic acids research.

[18]  Y. Nakamura,et al.  Putative tumor-suppressor gene on chromosome 11 is important in sporadic endocrine tumor formation. , 1993, American journal of surgery.

[19]  T. Sano,et al.  ras Mutations in Endocrine Tumors: Mutation Detection by Polymerase Chain Reaction‐Single Strand Conformation Polymorphism , 1992, Japanese journal of cancer research : Gann.

[20]  L. Frankel.  Contributions of the Zollinger-Ellison syndrome. , 1992, American journal of surgery.

[21]  J. Norton,et al.  Allelic loss on chromosome 11 in hereditary and sporadic tumors related to familial multiple endocrine neoplasia type 1. , 1991, Cancer research.

[22]  E. Saint,et al.  Primary peptic ulceration of the jejunum. , 1955, Lancet.