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Genetic alterations of the transforming growth factor beta receptor genes in pancreatic and biliary adenocarcinomas

M Goggins1, M Shekher, K Turnacioglu

  • 1Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA.

Cancer Research
|December 16, 1998
PubMed

Insights

Transforming growth factor beta (TGF-beta) pathway defects are common in pancreatic cancer. This study found genetic inactivation of TGF-beta type I (ALK-5) and type II (TGFBR2) receptors in these cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Transforming growth factor beta (TGF-beta) signaling regulates cell growth, differentiation, and apoptosis.
  • Many cancers, including pancreatic cancer, exhibit resistance to TGF-beta-mediated growth suppression due to pathway defects.
  • Genetic alterations in DPC4 are frequent in pancreatic and biliary carcinomas, indicating a role for TGF-beta pathway dysfunction.

Purpose of the Study:

  • To investigate further mutations in the TGF-beta signaling pathway in pancreatic and biliary cancers.
  • To identify specific genetic alterations in TGF-beta receptors, ALK-5 and TGFBR2, within these cancer types.

Main Methods:

  • Screening of pancreatic and biliary adenocarcinomas for alterations in the TGF-beta type I receptor gene (ALK-5).
  • Analysis of TGF-beta type II receptor gene (TGFBR2) for somatic alterations, including deletions and frameshift mutations.
  • Sequencing of other related type I receptors (ALK-1, ALK-2, ALK-3, ALK-6) in cancer cell lines and xenografts.
  • Determination of the overall rate of genetic inactivation of key TGF-beta pathway members in pancreatic cancers.

Main Results:

  • Homozygous deletions of ALK-5 were found in 1 pancreatic and 1 biliary adenocarcinoma.
  • Somatic alterations in TGFBR2, including deletions and frameshift mutations, were identified in 4.1% of pancreatic cancers.
  • Genetic inactivation of DPC4, p15, ALK-5, or TGFBR2 was observed in 82% of the analyzed pancreatic cancers.

Conclusions:

  • The TGF-beta type I (ALK-5) and type II (TGFBR2) receptor genes are identified as selective targets of genetic inactivation in pancreatic and biliary cancers.
  • These findings highlight the significant role of TGF-beta receptor mutations in the pathogenesis of these cancers.
  • The high frequency of genetic inactivation across multiple TGF-beta pathway members underscores its importance in cancer development.

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