Alterations in pancreatic, biliary, and breast carcinomas support MKK4 as a genetically targeted tumor suppressor gene

Gloria H. Su, Werner Hilgers, Manu C. Shekher, David J. Tang, Charles J. Yeo, Ralph H Hruban, Scott E Kern

Research output: Contribution to journalArticle

Abstract

Mitogen-activated protein kinase (MAPK) kinase 4 (MKK4) is a component of a stress and cytokine-induced signal transduction pathway involving MAPK proteins. The MKK4 protein has been implicated in activation of JNK1 and p38 MAPK on phnsphorylation by conserved kinase pathways. A recent report on the deletion and mutation of the MKK4 gene in human pancreatic, lung, breast, testicle, and colorectal cancer cell lines suggests an additional role for MKK4 in tumor suppression. Both the gene function and the infrequency of mutations might be considered atypical for many human tumor suppressor genes, and constitutional DNA was not previously available to determine whether the reported sequence variants had preceded tumor development. Here, we report that homozygous deletions are detected in 2 of 92 pancreatic adenocarcinomas (2%), 1 of 16 biliary adenocarcinomas (6%), and 1 of 22 breast carcinomas (when combined with reported sequence alterations, 3 of 22 or 14%). In addition, in a panel of 45 pancreatic carcinomas prescreened for loss of heterozygosity, one somatic missense mutation of MKK4 is observed and confirmed in the primary tumor (2%). Mapping of the homozygous deletions further indicated MKK4 to lie at the target of deletion. The finding of a somatic missense mutation in the absence of any other nucleotide polymorphisms or silent nucleotide changes continues to favor MKK4 as a mutationally targeted tumor suppressor gene. Coexistent mutations of other tumor suppressor genes in MKK4-deficient tumors suggest that MKK4 may participate in a tumor suppressive signaling pathway distinct from DPC4, p16, p53, and BRCA2.

Original languageEnglish (US)
Pages (from-to)2339-2342
Number of pages4
JournalCancer Research
Volume58
Issue number11
StatePublished - Jun 1 1998

Fingerprint

Mitogen-Activated Protein Kinase Kinases
Tumor Suppressor Genes
Breast Neoplasms
Missense Mutation
Neoplasms
Adenocarcinoma
Nucleotides
MAP Kinase Kinase 4
Mutation
Pancreatic Carcinoma
Sequence Deletion
Loss of Heterozygosity
p38 Mitogen-Activated Protein Kinases
Mitogen-Activated Protein Kinases
Genes
Testis
Colorectal Neoplasms
Signal Transduction
Proteins
Phosphotransferases

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Alterations in pancreatic, biliary, and breast carcinomas support MKK4 as a genetically targeted tumor suppressor gene. / Su, Gloria H.; Hilgers, Werner; Shekher, Manu C.; Tang, David J.; Yeo, Charles J.; Hruban, Ralph H; Kern, Scott E.

In: Cancer Research, Vol. 58, No. 11, 01.06.1998, p. 2339-2342.

Research output: Contribution to journalArticle

Su, Gloria H. ; Hilgers, Werner ; Shekher, Manu C. ; Tang, David J. ; Yeo, Charles J. ; Hruban, Ralph H ; Kern, Scott E. / Alterations in pancreatic, biliary, and breast carcinomas support MKK4 as a genetically targeted tumor suppressor gene. In: Cancer Research. 1998 ; Vol. 58, No. 11. pp. 2339-2342.
@article{3de3715cfce34444b0de4396f7c6abca,
title = "Alterations in pancreatic, biliary, and breast carcinomas support MKK4 as a genetically targeted tumor suppressor gene",
abstract = "Mitogen-activated protein kinase (MAPK) kinase 4 (MKK4) is a component of a stress and cytokine-induced signal transduction pathway involving MAPK proteins. The MKK4 protein has been implicated in activation of JNK1 and p38 MAPK on phnsphorylation by conserved kinase pathways. A recent report on the deletion and mutation of the MKK4 gene in human pancreatic, lung, breast, testicle, and colorectal cancer cell lines suggests an additional role for MKK4 in tumor suppression. Both the gene function and the infrequency of mutations might be considered atypical for many human tumor suppressor genes, and constitutional DNA was not previously available to determine whether the reported sequence variants had preceded tumor development. Here, we report that homozygous deletions are detected in 2 of 92 pancreatic adenocarcinomas (2{\%}), 1 of 16 biliary adenocarcinomas (6{\%}), and 1 of 22 breast carcinomas (when combined with reported sequence alterations, 3 of 22 or 14{\%}). In addition, in a panel of 45 pancreatic carcinomas prescreened for loss of heterozygosity, one somatic missense mutation of MKK4 is observed and confirmed in the primary tumor (2{\%}). Mapping of the homozygous deletions further indicated MKK4 to lie at the target of deletion. The finding of a somatic missense mutation in the absence of any other nucleotide polymorphisms or silent nucleotide changes continues to favor MKK4 as a mutationally targeted tumor suppressor gene. Coexistent mutations of other tumor suppressor genes in MKK4-deficient tumors suggest that MKK4 may participate in a tumor suppressive signaling pathway distinct from DPC4, p16, p53, and BRCA2.",
author = "Su, {Gloria H.} and Werner Hilgers and Shekher, {Manu C.} and Tang, {David J.} and Yeo, {Charles J.} and Hruban, {Ralph H} and Kern, {Scott E}",
year = "1998",
month = "6",
day = "1",
language = "English (US)",
volume = "58",
pages = "2339--2342",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "11",

}

TY - JOUR

T1 - Alterations in pancreatic, biliary, and breast carcinomas support MKK4 as a genetically targeted tumor suppressor gene

AU - Su, Gloria H.

AU - Hilgers, Werner

AU - Shekher, Manu C.

AU - Tang, David J.

AU - Yeo, Charles J.

AU - Hruban, Ralph H

AU - Kern, Scott E

PY - 1998/6/1

Y1 - 1998/6/1

N2 - Mitogen-activated protein kinase (MAPK) kinase 4 (MKK4) is a component of a stress and cytokine-induced signal transduction pathway involving MAPK proteins. The MKK4 protein has been implicated in activation of JNK1 and p38 MAPK on phnsphorylation by conserved kinase pathways. A recent report on the deletion and mutation of the MKK4 gene in human pancreatic, lung, breast, testicle, and colorectal cancer cell lines suggests an additional role for MKK4 in tumor suppression. Both the gene function and the infrequency of mutations might be considered atypical for many human tumor suppressor genes, and constitutional DNA was not previously available to determine whether the reported sequence variants had preceded tumor development. Here, we report that homozygous deletions are detected in 2 of 92 pancreatic adenocarcinomas (2%), 1 of 16 biliary adenocarcinomas (6%), and 1 of 22 breast carcinomas (when combined with reported sequence alterations, 3 of 22 or 14%). In addition, in a panel of 45 pancreatic carcinomas prescreened for loss of heterozygosity, one somatic missense mutation of MKK4 is observed and confirmed in the primary tumor (2%). Mapping of the homozygous deletions further indicated MKK4 to lie at the target of deletion. The finding of a somatic missense mutation in the absence of any other nucleotide polymorphisms or silent nucleotide changes continues to favor MKK4 as a mutationally targeted tumor suppressor gene. Coexistent mutations of other tumor suppressor genes in MKK4-deficient tumors suggest that MKK4 may participate in a tumor suppressive signaling pathway distinct from DPC4, p16, p53, and BRCA2.

AB - Mitogen-activated protein kinase (MAPK) kinase 4 (MKK4) is a component of a stress and cytokine-induced signal transduction pathway involving MAPK proteins. The MKK4 protein has been implicated in activation of JNK1 and p38 MAPK on phnsphorylation by conserved kinase pathways. A recent report on the deletion and mutation of the MKK4 gene in human pancreatic, lung, breast, testicle, and colorectal cancer cell lines suggests an additional role for MKK4 in tumor suppression. Both the gene function and the infrequency of mutations might be considered atypical for many human tumor suppressor genes, and constitutional DNA was not previously available to determine whether the reported sequence variants had preceded tumor development. Here, we report that homozygous deletions are detected in 2 of 92 pancreatic adenocarcinomas (2%), 1 of 16 biliary adenocarcinomas (6%), and 1 of 22 breast carcinomas (when combined with reported sequence alterations, 3 of 22 or 14%). In addition, in a panel of 45 pancreatic carcinomas prescreened for loss of heterozygosity, one somatic missense mutation of MKK4 is observed and confirmed in the primary tumor (2%). Mapping of the homozygous deletions further indicated MKK4 to lie at the target of deletion. The finding of a somatic missense mutation in the absence of any other nucleotide polymorphisms or silent nucleotide changes continues to favor MKK4 as a mutationally targeted tumor suppressor gene. Coexistent mutations of other tumor suppressor genes in MKK4-deficient tumors suggest that MKK4 may participate in a tumor suppressive signaling pathway distinct from DPC4, p16, p53, and BRCA2.

UR - http://www.scopus.com/inward/record.url?scp=0032100617&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032100617&partnerID=8YFLogxK

M3 - Article

C2 - 9622070

AN - SCOPUS:0032100617

VL - 58

SP - 2339

EP - 2342

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 11

ER -