Multiple Primary Tumors as an Indicator for p16INK4a Germline Mutations in Pancreatic Cancer Patients?
- 1 November 2000
- journal article
- Published by Wolters Kluwer Health in Pancreas
- Vol. 21 (4) , 369-375
- https://doi.org/10.1097/00006676-200011000-00007
Abstract
Multiple primary tumors in pancreatic cancer patients might indicate a genetic predisposition to the development of malignancies. In this study we evaluated whether the mutation rate of the TP53 and p16INK4a genes of pancreatic cancers differs in pancreatic cancer patients with and without multiple primaries. Furthermore, we investigated whether pancreatic cancer patients with multiple primaries carry germline mutations in either p16INK4a, TP53, or BRCA2 tumor suppressor genes to detect a genetic alteration that predisposes to the development of different primaries. Fourteen (23%) of 60 pancreatic cancer patients developed histologically verified additional primaries during their lifetimes. Normal constitutional and tumor DNA of the 14 patients with a positive cancer history, but negative family history, were analyzed for p16INK4a, TP53, and BRCA2 mutations by single-strand conformational variant (SSCV) analysis and direct sequencing. Hypermethylation of the p16INK4a promoter region in pancreatic cancers was identified by methylation-specific polymerase chain reaction (PCR; MSP). Four of 14 pancreatic carcinomas carried somatic intragenic p16INK4a mutations, and another four tumors revealed hypermethylation of the p16INK4a promoter region. Somatic intragenic TP53 mutations were identified in six of 14 tumors. None of the pancreatic cancer patients carried TP53 or BRCA2 germline mutations. In contrast, one of 14 pancreatic cancer patients with multiple primaries carried the p16INK4a mutation A68V in his germline. This mutation was localized in the conserved second ankyrin repeat of p16INK4a and did not occur in 100 control patients. The frequency of somatic TP53 and p16INK4a mutations in pancreatic cancer is similar in patients with and without multiple primaries. TP53 and BRCA2 germline mutations seem not to be significantly associated with the occurrence of multiple primaries in pancreatic cancer patients. However, p16INK4a germline mutations might be causative for tumor development in some pancreatic cancer patients with multiple primaries. The genetic investigation of patients with accumulation of different cancers even without a positive family history may be a new approach for the understanding of the relation of different cancers.Keywords
This publication has 22 references indexed in Scilit:
- Analysis of β-Catenin Gene Mutations in Pancreatic TumorsDigestion, 1999
- Genetics of Pancreatic CancerSurgical Oncology Clinics of North America, 1998
- Positional Cloning of the Gene for Multiple Endocrine Neoplasia-Type 1Science, 1997
- Mutation analysis of the BRCA2 gene in 49 site–specific breast cancer familiesNature Genetics, 1996
- Compilation of somatic mutations of theCDKN2 gene in human cancers: Non-random distribution of base substitutionsGenes, Chromosomes and Cancer, 1996
- Frequent mutations of CDKN2 in primary pancreatic adenocarcinomasGenes, Chromosomes and Cancer, 1995
- Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinomaNature Genetics, 1994
- Germline p16 mutations in familial melanomaNature Genetics, 1994
- Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2ANature, 1993
- Germline Mutations of the p53 Tumor-Suppressor Gene in Children and Young Adults with Second Malignant NeoplasmsNew England Journal of Medicine, 1992