Oncogenic BRAF-positive dysplastic nevi and the tumor suppressor IGFBP7—challenging the concept of dysplastic nevi as precursor lesions?

DeCarlo, Kristen; Yang, Shi; Emley, Andrew; Wajapeyee, Narendra; Green, Michael; Mahalingam, Meera

doi:10.1016/j.humpath.2009.12.002

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Volume 41, Issue 6 , Pages 886-894, June 2010

Oncogenic BRAF-positive dysplastic nevi and the tumor suppressor IGFBP7—challenging the concept of dysplastic nevi as precursor lesions?

Kristen DeCarlo, MA
- Boston University School of Medicine, Boston University School of Medicine, Boston, MA 02118, USA
Shi Yang, MD
- Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA 02118, USA
Andrew Emley, MA
- Division of Graduate Medical Sciences, Boston University School of Medicine, Boston, MA 02118, USA
Narendra Wajapeyee, PhD
- Program in Gene Function and Expression, Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA 01655, USA
Michael Green, MD, PhD
- Program in Gene Function and Expression, Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA 01655, USA
Meera Mahalingam, MD, PhD, FRCPath
- Dermatopathology section, Department of Dermatology, Boston University School of Medicine, Boston, MA 02118, USA
- Corresponding author.

Received 23 October 2009; received in revised form 8 December 2009; accepted 16 December 2009. published online 17 March 2010.

Summary

Oncogenic BRAF as an early and fundamental feature of melanocytic neoplasia has been confirmed with its identification in both melanoma and nevi. Oncogenic BRAF has been shown to induce senescence/apoptosis by up-regulating the tumor suppressor IGFBP7, which acts through autocrine/paracrine pathways to inhibit BRAF-MEK-ERK signaling. Given the putative neoplastic potential of dysplastic nevi, our aim was to ascertain in dysplastic nevi from intermittently sun-exposed skin and of varying severity the frequency of oncogenic BRAF and NRAS and to assess expression of IGFBP7 in the same. BRAF and NRAS genotyping was performed on genomic DNA (isolated using laser capture microdissection) from dysplastic nevi ranging in severity from mild (12), to moderate (11), and to severe (11). Immunohistochemical staining for IGFBP7 was performed on all. Overall, 9 (26%) of 34 cases (2 severely atypical dysplastic nevi, 2 moderately atypical dysplastic nevi, and 5 mildly atypical dysplastic nevi) exhibited the BRAFV600E mutation (P = .22), with lack of IGFBP7 expression in 4 (44.4%) of 9 cases (1 severely atypical, 1 moderately atypical, and 2 mildly atypical); and 25 (73.5%) of 34 cases (9 severely atypical, 9 moderately atypical, and 7 mildly atypical) were BRAFWT, with enhanced IGFBP7 expression in 12 (48%) of 25 cases (6 severely atypical, 3 moderately atypical, and 3 mildly atypical). All cases were NRASWT. The disparate expression of IGFBP7 in BRAFV600E-positive dysplastic nevi (enhanced in 56% and diminished/absent in 44%) indicates that the behavior of oncogenic BRAF in dysplastic nevi, unlike that in malignant melanoma, does not appear to consistently induce senescence/apoptosis through pathways mediated by IGFBP7.