BRAF and NRAS mutations in melanoma and melanocytic nevi : Melanoma Research (original) (raw)

ORIGINAL ARTICLES

Poynter, Jenny N.a; Elder, James T.b c i; Fullen, Douglas R.d; Nair, Rajan P.b; Soengas, Maria S.b; Johnson, Timothy M.b e f; Redman, Bruceg; Thomas, Nancy E.j; Gruber, Stephen B.a g h

Departments of aEpidemiology

bDermatology

cRadiation Oncology

dPathology

eOtolaryngology

fSurgery

gInternal Medicine

hHuman Genetics, University of Michigan

iAnn Arbor Veterans Affairs Hospital, Ann Arbor, Michigan

jDepartment of Dermatology, University of North Carolina, Chapel Hill, North Carolina, USA

Correspondence and requests for reprints to Dr Stephen B. Gruber, MD, PhD, 1524 BSRB, 109 Zina Pitcher, Ann Arbor, MI, 48109-2200, USA

Tel: +1 734 615 9712; fax: +1 734 647 7950; e-mail: [email protected]

Sponsorship: This work was supported in part by NCI U01 CA83180 (SBG, NET) and NIH T32 HG 00040 (JNP), as well as a generous gift from Lewis and Lillian Becker. J.T.E. and R.N. were supported by the Babcock Memorial Trust. J.T.E. is supported by the Ann Arbor Veterans Affairs Hospital.

Received 8 April 2006 Accepted 19 April 2006

Abstract

In this report, we investigated BRAF/NRAS mutations in samples from a case–control study of melanoma and a series of benign melanocytic nevi. We evaluated potential associations between BRAF mutations and histopathologic and pigmentary characteristics of melanoma. Mutations in BRAF and NRAS were detected by sequencing microdissected/laser-captured DNA from 18 in-situ melanomas, 64 primary melanomas, and 51 nevi. Nevi showed the highest frequency of BRAF mutations (82%). BRAF mutations were identified in 29% of invasive melanomas and in only 5.6% of in-situ melanomas. Mutations in NRAS were found in 5.2% of primary melanomas, 5.9% of nevi and no NRAS mutations were seen in in-situ melanomas. A majority of the BRAF mutations observed in primary invasive melanoma were seen in superficial spreading melanoma (15/17), and melanomas with BRAF mutations were also more likely to be found on a body site that was likely to be exposed to intermittent sun exposure compared with chronic or no sun exposure (_P_=0.02). Tumors with BRAF mutations were also significantly more likely to occur in association with a contiguous nevus (odds ratio 3.49, 95% confidence interval 1.06–11.46), although a contiguous nevus was not found in all melanomas with a BRAF mutation. Our data support the evidence that the mitogen-activated protein kinase pathway is upregulated in a large percentage of melanocytic lesions, but these mutations are not sufficient for malignant transformation. We suggest that BRAF mutations contribute to benign melanocytic hyperplasia, but are likely to contribute to invasive melanoma only in conjunction with other mutations.