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Pattern of TGFbeta receptor 1 expression differs between kras-mutated keratoacanthomas and squamous cell carcinomas

Franziska Berger1, Helene Geddert1, Gerhard Faller1

  • 1Institute of Pathology, St. Vincentius Hospital Karlsruhe, Germany.

Pathology, Research and Practice
|June 24, 2014
PubMed
Abstract

Insights

TGFbeta-signaling and KRAS mutations are implicated in skin tumors. Keratoacanthoma (KA) shows distinct TGFbetaR1 expression, aiding differentiation from squamous cell carcinoma (SCC).

Area of Science:

  • Dermatopathology
  • Molecular Oncology
  • Cancer Signaling Pathways

Background:

  • Transforming growth factor-beta (TGFbeta) and epidermal growth factor receptor (EGFR) signaling pathways are increasingly recognized for their roles in the pathogenesis of keratoacanthoma (KA) and cutaneous squamous cell carcinoma (SCC).
  • Understanding the molecular underpinnings of these skin cancers is crucial for accurate diagnosis and potential therapeutic strategies.

Purpose of the Study:

  • To analyze the expression patterns of TGFbeta-signaling components in KA and SCC.
  • To screen for mutations in key signaling genes, including tgfbetaR1, egfr, kras, and braf, within these skin tumors.

Main Methods:

  • Immunohistochemical analysis was conducted on tissue samples from 29 KAs, 30 well-differentiated SCCs, and 31 moderately differentiated SCCs to assess the expression of TGFbeta1, TGFbetaR1, TGFbetaR2, and phospho-SMAD2/3.
  • Mutation screening in hotspot regions of tgfbetaR1, egfr, kras, and braf was performed using pyrosequencing of tumor DNA.

Main Results:

  • Elevated expression of TGFbeta1, TGFbetaR1, and phospho-SMAD2/3 was observed in tumors compared to adjacent normal skin.
  • Keratoacanthomas exhibited a characteristic strong, discontinuous membranous expression of TGFbetaR1, frequently associated with KRAS mutations.
  • Squamous cell carcinomas displayed continuous TGFbetaR1 expression, heightened phospho-SMAD2/3 levels, and less frequent KRAS mutations. Tumors at sun-exposed sites showed stronger TGFbetaR1 expression. One SCC had a TGFbetaR1 mutation, but no other mutations were detected.

Conclusions:

  • Despite germline TGFbetaR1 mutations causing inherited KAs and observed strong discontinuous membranous expression suggesting functionally altered protein accumulation, no TGFbetaR1 mutations were found in this study cohort, nor a direct influence on TGFbeta-signaling.
  • Frequent KRAS mutations were identified in a subgroup of KAs.
  • The distinct TGFbetaR1 expression pattern in KA can serve as a valuable feature for histopathological differentiation from SCC.
Keywords:
EGFRKeratoacanthomaSkin carcinogenesisSquamous cell carcinomaTGFbeta

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