High frequency of chromosome 9p allelic loss and CDKN2 tumor suppressor gene alterations in squamous cell carcinoma of the bladder

Mirella Gonzalez-zulueta, Atsuko Shibata, Petra F. Ohneseit, Charles H. Spruck, Christer Busch, Mustafa Shamaa, Mustafa Elbaz, Peter W. Nichols, Mark L Gonzalgo, Per Uno Malmström, Peter A. Jones

Research output: Contribution to journalArticle

69 Citations (Scopus)

Abstract

Background: In the Western Hemisphere, 90% of bladder cancers are transitional cell carcinomas, while only 7% are classified as squamous cell carcinomas. In contrast, in Egypt and regions of the Middle East and Africa, where infection by the trematode Schistosoma haematobium is endemic, squamous cell carcinoma is the most common bladder cancer as well as the most common cancer in men. Purpose: We planned experiments to understand the genetic defects underlying the development of squamous cell carcinoma and to determine if the morphologically and clinically distinct squamous cell carcinoma and transitional cell carcinoma of the bladder evolve following different genetic alterations. Methods: Squamous cell carcinoma specimens from high-risk (Egypt, n = 19) and low-risk (Sweden, n = 12) populations were examined for genetic defects known to be involved in transitional cell carcinoma tumorigenesis. Homozygous deletions of the CDKN2 tumor suppressor gene were detected by comparative multiplex polymerase chain reaction. Mutations in the CDKN2 and p53 (also known as TP53) genes were analyzed by single-strand conformation polymorphism and DNA sequencing. Immunohistochemical staining of p53 protein was also performed. Allelic losses in chromosome arms 9p, 9q, and 17p were determined by microsatellite analysis. Results: Homozygous deletions and sequence mutations in the CDKN2 gene were found in 67% (eight of 12) of squamous cell carcinoma specimens, a frequency three times higher than that reported for uncultured transitional cell carcinomas (P = .009). Hemizygous and homozygous deletions in 9p, where CDKN2 resides, were found in 92% (11 of 12) of uncultured squamous cell carcinomas, while only about 39% (35 of 90) of transitional cell carcinomas showed these losses (P = .001). Deletions in 9p with no change in 9q were found in 92% (10 of 11) of squamous cell carcinomas compared with only 10% (11 of 110) of transitional cell carcinomas (P<.001) reported in the literature. The frequency of p53 mutations in squamous cell carcinomas was similar to that reported for invasive transitional cell carcinomas (60%), but the type and position of mutations differed between the two tumor types. Allelic losses in chromosome arm 17p, where the p53 gene resides, were found to be less frequent in squamous cell carcinomas (38%) than in invasive transitional cell carcinomas (60%). Conclusions: Our results suggest that a putative tumor suppressor gene on 9p, possibly CDKN2, may contribute to squamous cell carcinoma tumorigenesis. Our data on squamous cell carcinoma and previously reported data on transitional cell carcinoma indicate that these two bladder carcinomas differ in their genetic alterations, suggesting that distinct underlying genetic defects may explain, at least in part, the pathological differences between the two tumors of the bladder epithelium. Implications: Development of diagnostic and therapeutic strategies for squamous cell carcinoma of the bladder based on its distinct genetic alterations is warranted. [J Natl Cancer Inst 1995;87:1383-93]

Original languageEnglish (US)
Pages (from-to)1383-1393
Number of pages11
JournalJournal of the National Cancer Institute
Volume87
Issue number18
DOIs
StatePublished - Sep 20 1995
Externally publishedYes

Fingerprint

Loss of Heterozygosity
Chromosomes
Tumor Suppressor Genes
Chromosome
Tumors
Squamous Cell Carcinoma
Tumor
Urinary Bladder
Transitional Cell Carcinoma
Genes
Gene
Cell
Cells
Urinary Bladder Neoplasms
Egypt
p53 Genes
Deletion
Mutation
Epithelial Cells
Defects

ASJC Scopus subject areas

  • Statistics, Probability and Uncertainty
  • Applied Mathematics
  • Physiology (medical)
  • Radiology Nuclear Medicine and imaging
  • Oncology
  • Cancer Research

Cite this

High frequency of chromosome 9p allelic loss and CDKN2 tumor suppressor gene alterations in squamous cell carcinoma of the bladder. / Gonzalez-zulueta, Mirella; Shibata, Atsuko; Ohneseit, Petra F.; Spruck, Charles H.; Busch, Christer; Shamaa, Mustafa; Elbaz, Mustafa; Nichols, Peter W.; Gonzalgo, Mark L; Malmström, Per Uno; Jones, Peter A.

In: Journal of the National Cancer Institute, Vol. 87, No. 18, 20.09.1995, p. 1383-1393.

Research output: Contribution to journalArticle

Gonzalez-zulueta, M, Shibata, A, Ohneseit, PF, Spruck, CH, Busch, C, Shamaa, M, Elbaz, M, Nichols, PW, Gonzalgo, ML, Malmström, PU & Jones, PA 1995, 'High frequency of chromosome 9p allelic loss and CDKN2 tumor suppressor gene alterations in squamous cell carcinoma of the bladder', Journal of the National Cancer Institute, vol. 87, no. 18, pp. 1383-1393. https://doi.org/10.1093/jnci/87.18.1383
Gonzalez-zulueta, Mirella ; Shibata, Atsuko ; Ohneseit, Petra F. ; Spruck, Charles H. ; Busch, Christer ; Shamaa, Mustafa ; Elbaz, Mustafa ; Nichols, Peter W. ; Gonzalgo, Mark L ; Malmström, Per Uno ; Jones, Peter A. / High frequency of chromosome 9p allelic loss and CDKN2 tumor suppressor gene alterations in squamous cell carcinoma of the bladder. In: Journal of the National Cancer Institute. 1995 ; Vol. 87, No. 18. pp. 1383-1393.
@article{a7af543ca9ea4fe2af4f9c67aa69ad1b,
title = "High frequency of chromosome 9p allelic loss and CDKN2 tumor suppressor gene alterations in squamous cell carcinoma of the bladder",
abstract = "Background: In the Western Hemisphere, 90{\%} of bladder cancers are transitional cell carcinomas, while only 7{\%} are classified as squamous cell carcinomas. In contrast, in Egypt and regions of the Middle East and Africa, where infection by the trematode Schistosoma haematobium is endemic, squamous cell carcinoma is the most common bladder cancer as well as the most common cancer in men. Purpose: We planned experiments to understand the genetic defects underlying the development of squamous cell carcinoma and to determine if the morphologically and clinically distinct squamous cell carcinoma and transitional cell carcinoma of the bladder evolve following different genetic alterations. Methods: Squamous cell carcinoma specimens from high-risk (Egypt, n = 19) and low-risk (Sweden, n = 12) populations were examined for genetic defects known to be involved in transitional cell carcinoma tumorigenesis. Homozygous deletions of the CDKN2 tumor suppressor gene were detected by comparative multiplex polymerase chain reaction. Mutations in the CDKN2 and p53 (also known as TP53) genes were analyzed by single-strand conformation polymorphism and DNA sequencing. Immunohistochemical staining of p53 protein was also performed. Allelic losses in chromosome arms 9p, 9q, and 17p were determined by microsatellite analysis. Results: Homozygous deletions and sequence mutations in the CDKN2 gene were found in 67{\%} (eight of 12) of squamous cell carcinoma specimens, a frequency three times higher than that reported for uncultured transitional cell carcinomas (P = .009). Hemizygous and homozygous deletions in 9p, where CDKN2 resides, were found in 92{\%} (11 of 12) of uncultured squamous cell carcinomas, while only about 39{\%} (35 of 90) of transitional cell carcinomas showed these losses (P = .001). Deletions in 9p with no change in 9q were found in 92{\%} (10 of 11) of squamous cell carcinomas compared with only 10{\%} (11 of 110) of transitional cell carcinomas (P<.001) reported in the literature. The frequency of p53 mutations in squamous cell carcinomas was similar to that reported for invasive transitional cell carcinomas (60{\%}), but the type and position of mutations differed between the two tumor types. Allelic losses in chromosome arm 17p, where the p53 gene resides, were found to be less frequent in squamous cell carcinomas (38{\%}) than in invasive transitional cell carcinomas (60{\%}). Conclusions: Our results suggest that a putative tumor suppressor gene on 9p, possibly CDKN2, may contribute to squamous cell carcinoma tumorigenesis. Our data on squamous cell carcinoma and previously reported data on transitional cell carcinoma indicate that these two bladder carcinomas differ in their genetic alterations, suggesting that distinct underlying genetic defects may explain, at least in part, the pathological differences between the two tumors of the bladder epithelium. Implications: Development of diagnostic and therapeutic strategies for squamous cell carcinoma of the bladder based on its distinct genetic alterations is warranted. [J Natl Cancer Inst 1995;87:1383-93]",
author = "Mirella Gonzalez-zulueta and Atsuko Shibata and Ohneseit, {Petra F.} and Spruck, {Charles H.} and Christer Busch and Mustafa Shamaa and Mustafa Elbaz and Nichols, {Peter W.} and Gonzalgo, {Mark L} and Malmstr{\"o}m, {Per Uno} and Jones, {Peter A.}",
year = "1995",
month = "9",
day = "20",
doi = "10.1093/jnci/87.18.1383",
language = "English (US)",
volume = "87",
pages = "1383--1393",
journal = "Journal of the National Cancer Institute",
issn = "0027-8874",
publisher = "Oxford University Press",
number = "18",

}

TY - JOUR

T1 - High frequency of chromosome 9p allelic loss and CDKN2 tumor suppressor gene alterations in squamous cell carcinoma of the bladder

AU - Gonzalez-zulueta, Mirella

AU - Shibata, Atsuko

AU - Ohneseit, Petra F.

AU - Spruck, Charles H.

AU - Busch, Christer

AU - Shamaa, Mustafa

AU - Elbaz, Mustafa

AU - Nichols, Peter W.

AU - Gonzalgo, Mark L

AU - Malmström, Per Uno

AU - Jones, Peter A.

PY - 1995/9/20

Y1 - 1995/9/20

N2 - Background: In the Western Hemisphere, 90% of bladder cancers are transitional cell carcinomas, while only 7% are classified as squamous cell carcinomas. In contrast, in Egypt and regions of the Middle East and Africa, where infection by the trematode Schistosoma haematobium is endemic, squamous cell carcinoma is the most common bladder cancer as well as the most common cancer in men. Purpose: We planned experiments to understand the genetic defects underlying the development of squamous cell carcinoma and to determine if the morphologically and clinically distinct squamous cell carcinoma and transitional cell carcinoma of the bladder evolve following different genetic alterations. Methods: Squamous cell carcinoma specimens from high-risk (Egypt, n = 19) and low-risk (Sweden, n = 12) populations were examined for genetic defects known to be involved in transitional cell carcinoma tumorigenesis. Homozygous deletions of the CDKN2 tumor suppressor gene were detected by comparative multiplex polymerase chain reaction. Mutations in the CDKN2 and p53 (also known as TP53) genes were analyzed by single-strand conformation polymorphism and DNA sequencing. Immunohistochemical staining of p53 protein was also performed. Allelic losses in chromosome arms 9p, 9q, and 17p were determined by microsatellite analysis. Results: Homozygous deletions and sequence mutations in the CDKN2 gene were found in 67% (eight of 12) of squamous cell carcinoma specimens, a frequency three times higher than that reported for uncultured transitional cell carcinomas (P = .009). Hemizygous and homozygous deletions in 9p, where CDKN2 resides, were found in 92% (11 of 12) of uncultured squamous cell carcinomas, while only about 39% (35 of 90) of transitional cell carcinomas showed these losses (P = .001). Deletions in 9p with no change in 9q were found in 92% (10 of 11) of squamous cell carcinomas compared with only 10% (11 of 110) of transitional cell carcinomas (P<.001) reported in the literature. The frequency of p53 mutations in squamous cell carcinomas was similar to that reported for invasive transitional cell carcinomas (60%), but the type and position of mutations differed between the two tumor types. Allelic losses in chromosome arm 17p, where the p53 gene resides, were found to be less frequent in squamous cell carcinomas (38%) than in invasive transitional cell carcinomas (60%). Conclusions: Our results suggest that a putative tumor suppressor gene on 9p, possibly CDKN2, may contribute to squamous cell carcinoma tumorigenesis. Our data on squamous cell carcinoma and previously reported data on transitional cell carcinoma indicate that these two bladder carcinomas differ in their genetic alterations, suggesting that distinct underlying genetic defects may explain, at least in part, the pathological differences between the two tumors of the bladder epithelium. Implications: Development of diagnostic and therapeutic strategies for squamous cell carcinoma of the bladder based on its distinct genetic alterations is warranted. [J Natl Cancer Inst 1995;87:1383-93]

AB - Background: In the Western Hemisphere, 90% of bladder cancers are transitional cell carcinomas, while only 7% are classified as squamous cell carcinomas. In contrast, in Egypt and regions of the Middle East and Africa, where infection by the trematode Schistosoma haematobium is endemic, squamous cell carcinoma is the most common bladder cancer as well as the most common cancer in men. Purpose: We planned experiments to understand the genetic defects underlying the development of squamous cell carcinoma and to determine if the morphologically and clinically distinct squamous cell carcinoma and transitional cell carcinoma of the bladder evolve following different genetic alterations. Methods: Squamous cell carcinoma specimens from high-risk (Egypt, n = 19) and low-risk (Sweden, n = 12) populations were examined for genetic defects known to be involved in transitional cell carcinoma tumorigenesis. Homozygous deletions of the CDKN2 tumor suppressor gene were detected by comparative multiplex polymerase chain reaction. Mutations in the CDKN2 and p53 (also known as TP53) genes were analyzed by single-strand conformation polymorphism and DNA sequencing. Immunohistochemical staining of p53 protein was also performed. Allelic losses in chromosome arms 9p, 9q, and 17p were determined by microsatellite analysis. Results: Homozygous deletions and sequence mutations in the CDKN2 gene were found in 67% (eight of 12) of squamous cell carcinoma specimens, a frequency three times higher than that reported for uncultured transitional cell carcinomas (P = .009). Hemizygous and homozygous deletions in 9p, where CDKN2 resides, were found in 92% (11 of 12) of uncultured squamous cell carcinomas, while only about 39% (35 of 90) of transitional cell carcinomas showed these losses (P = .001). Deletions in 9p with no change in 9q were found in 92% (10 of 11) of squamous cell carcinomas compared with only 10% (11 of 110) of transitional cell carcinomas (P<.001) reported in the literature. The frequency of p53 mutations in squamous cell carcinomas was similar to that reported for invasive transitional cell carcinomas (60%), but the type and position of mutations differed between the two tumor types. Allelic losses in chromosome arm 17p, where the p53 gene resides, were found to be less frequent in squamous cell carcinomas (38%) than in invasive transitional cell carcinomas (60%). Conclusions: Our results suggest that a putative tumor suppressor gene on 9p, possibly CDKN2, may contribute to squamous cell carcinoma tumorigenesis. Our data on squamous cell carcinoma and previously reported data on transitional cell carcinoma indicate that these two bladder carcinomas differ in their genetic alterations, suggesting that distinct underlying genetic defects may explain, at least in part, the pathological differences between the two tumors of the bladder epithelium. Implications: Development of diagnostic and therapeutic strategies for squamous cell carcinoma of the bladder based on its distinct genetic alterations is warranted. [J Natl Cancer Inst 1995;87:1383-93]

UR - http://www.scopus.com/inward/record.url?scp=0029124089&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0029124089&partnerID=8YFLogxK

U2 - 10.1093/jnci/87.18.1383

DO - 10.1093/jnci/87.18.1383

M3 - Article

C2 - 7658499

AN - SCOPUS:0029124089

VL - 87

SP - 1383

EP - 1393

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

SN - 0027-8874

IS - 18

ER -