BRAF Mutation: A Frequent Event in Benign, Atypical, and... : The American Journal of Dermatopathology (original) (raw)
Original Article
A Frequent Event in Benign, Atypical, and Malignant Melanocytic Lesions of the Skin
From the Department of Anatomic Pathology (Drs Wistuba and González) and Medical Sciences Doctorate Program (Dr Uribe), Medical School, P. Universidad Catolica de Chile, Santiago, Chile.
Supported by grants FONDECYT (Fondo Nacional de Desarrollo Cientifico y Tecnologico, Chile) #1020696 (S.G.), and PG–04/02 (P.U.), Escuela de Medicina, Universidad Catolica de Chile.
Reprints: Sergio González, MD, Professor of Pathology, Department of Anatomic Pathology, P. Universidad Catolica de Chile, Lira 85, 4th floor, P.O. Box 114-D, Santiago, Chile. E-mail: [email protected]
Abstract
BRAF mutations have recently been detected with a high frequency (66%) in cutaneous melanoma. All those mutations are activating, with a single substitution (T1796A) at codon 599 (V599E) accounting for over 90%. To investigate the stage in which those mutations occur in the currently proposed sequential malignant transformation of melanocytes, 22 benign melanocytic nevi, 23 melanocytic atypical nevi, and 25 primary cutaneous melanoma from 63 different patients were examined for BRAF mutations using DNA extracted from microdissected formalin-fixed and paraffin-embedded tissues, and a two-round PCR-RFLP–based strategy. A subset of samples was sequenced for mutation confirmation. Sixteen benign (73%) and eleven atypical (52%) melanocytic nevi, and thirteen melanoma (56%) demonstrated BRAF mutations at codon 599, and no statistically significant differences were detected among all three types of lesions. No mutations were demonstrated in microdissected epidermal keratinocytes adjacent to melanocytic lesions having BRAF mutations. No correlation was detected between BRAF mutational status and age, sun exposure, and Clark's level in malignant melanoma. However, comparing only atypical nevi and melanoma lesions the frequency of BRAF mutation is significantly greater in male (78%) than female (35%) patients (P = 0.0194). The previously described T1796A point mutation was detected in 17 of 18 mutated samples, and a novel mutation consisting of a substitution of valine for lysine (GT1795-96AA) was detected in one melanoma case. Our findings of a high frequency of BRAF mutations at codon 599 in benign melanocytic lesions of the skin indicate that this mutation is not sufficient by itself for malignant transformation.
© 2003 Lippincott Williams & Wilkins, Inc.