The CDKN2A and MAP Kinase Pathways: Molecular Roads to Primary Oral Mucosal Melanoma

Author(s)

Hsieh, Ricardo ^{[1, 2]} ; Nico, Marcello M. S. ^{[1, 2]} ; Coutinho-Camillo, Claudia M. ^[3] ; Buim, Marcilei E. ^[3] ; Sangueza, Martin ^[4] ; Lourenco, Silvia V. ^{[1, 5, 2]}

Affiliation

^[1] Univ Sao Paulo, Inst Trop Med, Immunopathol Lab, BR-05508000 Sao Paulo - Brazil

^[2] Univ Sao Paulo, Dept Dermatol, Sch Med, BR-05508000 Sao Paulo - Brazil

^[3] Hosp AC Camargo Fund Antonio Prudente, Dept Surg Pathol, Sao Paulo - Brazil

^[4] Hosp Obrero, Dept Pathol, La Paz - Bolivia

^[5] Univ Sao Paulo, Gen Pathol Dept, Sch Dent, BR-05508000 Sao Paulo - Brazil

• Document type: Journal article
• Source: AMERICAN JOURNAL OF DERMATOPATHOLOGY; v. 35, n. 2, p. 167-175, APR 2013.
• Web of Science Citations: 12

Abstract

The etiology and pathogenesis of oral mucosal melanomas are poorly understood, and no intraoral risk factors have been identified. Recent studies have postulated that DNA repair mechanisms and cell growth pathways are involved in the development of melanoma-particularly changes in the CDKN2A (p16-cyclinD-Cdk-pRb) and MAPK pathways (RAS, BRAF, MEK 1/2, and ERK 1/2 proteins). We examined the central components of the CDKN2A and RAS-RAF-MEK-ERK cascades by immunohistochemistry in a series of 35 primary oral melanomas by tissue microarray (TMA). We noted altered expression of the CDKN2A cascade proteins, although these modulations did not correlate significantly with clinical and pathological parameters. The expression of MAP kinase cascade proteins changed in most cases. We observed that 28.57% of cases were RAS-positive and that 82.85% and 74.28% of cases were positive for BRAF and ERK2, respectively; MEK2 and ERK1 were not expressed in 48.57% and 80% of cases, and all cases were negative for MEK1. The absence of RAS and ERK1 and positivity for BRAF and ERK2 were associated with higher histological grade, vascular invasion, and metastasis. Expression of MEK2 was significantly linked to vascular invasion (P = 0.043). The CDKN2A and MAPK pathways require further study in mucosal melanomas, but our results highlight the significance of important alterations, particularly with regard to histological indicators of poor prognosis in primary oral mucosal melanomas, independent of UV exposure. (AU)