SMAD7 is a novel independent predictor of survival in patients with cutaneous melanoma

Overexpression of SMAD7-a hallmark inhibitor of transforming growth factor β (TGFβ) signaling-has been documented and related with adverse prognosis in a number of epithelial malignancies, suggesting that it may be responsible for resistance to TGFβ-induced growth arrest of cancer cells. The involvement of SMAD7 in development and progression of malignant melanoma is unclear, and its expression has not been characterized so far at the protein level in clinical melanoma tissue samples. We evaluated SMAD7 expression in 205 skin melanoma primary tumors by immunohistochemistry and correlated the findings with clinicopathological profiles of patients. Melanocytic SMAD7 was evidenced in 204 cases, and the expression pattern was predominantly nuclear. High expression of SMAD7 was positively associated with several features of tumor aggressiveness, for example, presence of ulceration (P < 0.001), higher tumor thickness (P < 0.001), and mitotic rate (P < 0.001), but not presence of regional or distant metastases. Moreover, high SMAD7 expression independently predicted unfavorable outcome: melanoma-specific survival (hazard ratio = 3.16, P < 0.001) and recurrence-free survival (hazard ratio = 2.88, P < 0.001). Taken together, our results underline the importance of TGFβ signaling in cancer and define SMAD7 as a marker of aggressive tumor behavior and adverse clinical outcomes in melanoma patients.