Upregulated NOTCH2 Expression Is Implicated in the Clinical Aggressiveness of Atypical Fibroxanthoma and Pleomorphic Dermal Sarcoma

TL;DR

This study shows that increased NOTCH2 activity is linked to more aggressive behavior in two skin tumors, suggesting it could be a target for treatment.

Contribution

The study is the first to show that NOTCH2, not NOTCH1, drives disease progression in AFX and PDS through HES1 activation.

Findings

Upregulated NOTCH2 expression correlates with disease progression in AFX and PDS.

HES1 activation is driven by NOTCH2, not NOTCH1, in these tumors.

NOTCH1 appears to be functionally inactive in these tumor types.

Abstract

Atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) represent clinicopathological variants of a spectrum. It is known that AFX and PDS tumors harbor frequent NOTCH1/2 mutations. However, the expression of Notch signaling pathway‐associated proteins in both tumor cells has not been studied before.

We conducted an immunohistochemical study by performing NOTCH1, NOTCH2, NICD, and HES1 staining on the most representative formalin‐fixed paraffin‐embedded (FFPE) tumor tissues out of sixty‐two patients with the first diagnosis of either AFX (n = 33) or PDS (n = 29) in a single tertiary medical center.

Ten patients (PDS, n = 9; AFX, n = 1) had disease progression in terms of locoregional relapse, including local recurrence and regional lymph node metastasis, with a median time‐to‐(first)‐recurrence interval of 8 months after a wide local excision. Among all the Notch expression profiles, only the upregulated NOTCH2 expression has a positive correlation with disease progression [odds ratio (OR): 1.02, 95% confidence interval (CI): 1–1.04, p = 0.029]. Furthermore, HES1 is activated through the NOTCH2 signaling pathway (r (60) = 0.27, p = 0.032) rather than NOTCH1, and NOTCH1 does not appear to be functionally active.

Upregulated NOTCH2 expression plays a significant role in disease progression, in part through the canonical signaling pathway involving the downstream effector HES1. Targeting NOTCH2 signaling might hold therapeutic promise in patients with disease progression.

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