Loss of heterozygosity on chromosome 9 andp16 (MTS1, CDKN2) gene mutations in esophageal cancers

Abstract

Loss of heterozygosity on chromosome 9 has been reported in a variety of human cancers. The cyclin-dependent kinase inhibitor p16 gene, mapped on chromosome 9p21, is presumed to be the tumor-suppressor gene localized in this chromosome. The aim of our study was to determine, in 26 Barrett's adenocarcinomas and 20 squamous-cell carcinomas of the esophagus, the prevalence of loss of heterozygosity on chromosome 9 by typing of microsatellite loci and mutation of p16 by direct sequencing of exons 1 and 2. Allelic losses were found in 69% of adenocarcinomas, but only a microdeletion in exon 1 of p16 occurred in 1 tumor. Among squamouscell carcinomas, 65% had allelic losses and 5 tumors were mutated on the p16 gene (1 deletion, 3 nucleotide substitutions and 1 insertion). The relatively low rate of p16 mutation observed here coupled with the high frequency of loss of heterozygosity on chromosome 9 suggests that one or several tumor-suppressor gene(s) distinct from p16 may be the target(s) of allelic deletion in most esophageal cancers or that p16 is inactivated in another way. Int. J. Cancer 72:27-30, 1997.r 1997 Wiley-Liss, Inc.Cancer of the esophagus is among the most common and severe malignant neoplasms worldwide and occurs primarily in 2 forms: squamous-cell carcinoma (SCC) and adenocarcinoma arising in the context of Barrett's esophagus. The mechanisms underlying pathogenesis of the disease are unclear, though both environmental and genetic factors are suspected to play roles. Previously, no tumorsuppressor gene other than p53 (Gleeson et al., 1995;Muzeau et al., 1996) has been reported to play an important role during esophageal tumorigenesis.A high frequency of loss of heterozygosity (LOH) and/or homozygous deletion affecting chromosome 9p21-22 has been reported in a variety of primary tumors and cell lines (Holland et al., 1994;Cairns et al., 1994). Chromosome 9, therefore, is presumed to contain a tumor-suppressor gene(s) involved in the genesis of different human tumors.A new tumor-suppressor gene, p16 (also known as CDKN2A, INK4A or MTS1), has been identified and mapped on chromosome 9p21. It contains 3 coding exons (Serrano et al., 1993) and encodes a 156-amino-acid protein, previously identified as a cyclindependent kinase (CDK) inhibitor that has capacities to bind CDK4 and CDK6 and to inhibit cellular proliferation by preventing entry into the S phase of the cell cycle (Serrano et al., 1993;Lukas et al., 1995). This gene is homozygously deleted or mutated in a variety of cell lines derived from tumors and has been proposed to constitute a potential target of point mutations and deletions in primary human tumors (Pollock et al., 1996).There is a controversy regarding the implication of p16 gene alterations in the development of esophageal cancers (Mori et al., 1994;Okamoto et al., 1994;Zhou et al., 1994;Igaki et al., 1995;Liu et al., 1995;Suzuki et al., 1995; Esteve et al., 1996;Maesawa et al., 1996). The present study was thus undertaken to determine the prevalence of LOH on chromosome 9 and p16 mutati...

Qualitative analysis of Adenomatous Polyposis Coli promoter: Hypermethylation, engagement and effects on survival of patients with esophageal cancer in a high risk region of the world, a potential molecular marker

“…The present report is an extension to our former studies [4,10] on the molecular etiology of SCCE in this region, aiming to identify potential molecular markers. It is well known that tumor suppressor genes are mostly affected in SCCE [9,11,13-17,34,53-57]. As part of a long-term study we have started analysis of APC promoter methylation among tumor suppressor genes such as p15 INKb (data not shown) as well as cell cycle inhibitors such as p14 , p15 , p16 and p21 .…”

Genetic Insights in Barrett’s Esophagus and Esophageal Adenocarcinoma

“…In the early days of BE genetic research, mutation studies focused on known genes, such as TP53 and CDKN2A because DNA sequencing technology was limited 97–99 . In a study evaluating a panel of tumor suppressor genes and DNA content abnormalities (tetraploidy, aneuploidy), only the chromosome instability markers, loss of heterozygosity (LOH), tetraploidy and aneuploidy, provided independent cancer risk assessment in multivariate analysis 100 .…”

Functional implications of a cancer associated p16INK4A mutation insilico

“…Loss of P16 function, rendering the protein unable to bind or inhibit CDKs, can result in uncontrolled cell proliferation leading to tumorogenesis (18)(19)(20)(21)(22)(23)(24)(25)(26)(27). A variable spectrum of p16 INK4A mutations has been observed in esophageal squamous cell carcinoma among different populations of the world (28).…”