High BRAF mutation frequency does not characterize all melanocytic tumor types

Abstract

Cutaneous melanoma (CM) is the most lethal form of skin cancer. Along with some benign melanocytic tumors, the majority shows BRAF or NRAS mutation, but it is not known whether these are essential to all forms of melanocytic neoplasia. We screened 79 melanocytic tumors of different types for BRAF and NRAS mutations and looked at MAPK pathway activity using immunohistochemistry in a subset. Significant differences in BRAF exon 15 mutation frequency were found: 14/16 (87.5%) in common acquired naevi (CANs), 9/12 (75%) in CMs, 0/26 in Spitz naevi and 3/25 (12%) in blue naevi (p < 0.01). We looked at whether Spitz and blue naevi showed a compensatory increase in BRAF exon 11 and/or NRAS exons 1 and 2 mutations to account for the low BRAF exon 15 mutation frequency. NRAS mutations were found in only 1/16 (6.3%) Spitz naevi and 0/15 blue naevi. In addition, NRAS mutations were found in 2/11 (18.2%) CANs and 3/12 (25%) CMs. None of the tumors showed BRAF exon 11 mutations. Despite their low combined BRAF and NRAS mutation frequency, Spitz naevi showed strong MAPK pathway activation as measured by cytoplasmic expression of dually phosphorylated ERK1/2, while blue naevi had weak pathway activation. We conclude that BRAF and NRAS mutations are not necessary for melanocytic tumor development and that some types of tumor must arise by alternative mechanisms. Cutaneous melanoma (CM) is the most lethal form of skin cancer and incidence in the Western world is rising. Recently, it was found that 66% of CMs and 82% of benign melanocytic tumors (comprising congenital, common acquired and dysplastic naevi) showed BRAF mutations, 1,2 while NRAS mutations are common in the remainder. 2 Both genes encode proteins of the MAPK pathway, which is therefore deregulated in the vast majority of melanocytic tumors. Congenital, common acquired and dysplastic naevi appear to be melanoma precursors based on histologic similarities and apparent development of melanomas from contiguous naevi. 3,4 This suggests that BRAF and NRAS mutations may be early events in melanoma progression, although this issue remains uncertain. A key question now is whether the very high combined frequency of these mutations is common to all melanocytic neoplasia. The answer is important because the relationship of Spitz and blue naevi to melanoma is poorly documented. This may be partly because these tumors occur less frequently than common acquired naevi (CANs) and would therefore be expected to have a less frequent association with melanoma, although large congenital naevi are rarer than Spitz naevi and yet have a significant association with melanoma. In addition, Spitz naevus and melanoma have many histologic similarities, so contiguous Spitz and melanoma would be hard to identify. 5 Malignant blue naevi have been reported, 6 but their relationship to benign blue naevus is unknown. To address whether these mutations are common in all types of melanocytic tumor, we screened for mutation hot-spot alterations in BRAF and examined a subset of mutant and wild-type case...

BRAF and NRAS mutations in spitzoid melanocytic lesions

“…Similar to other investigators, we have previously shown that the highest incidence of BRAF mutations (82%) occurred in a group of congenital, common acquired, and atypical (dysplastic) nevi. 24,27,42,64 In contrast, 27% of primary invasive melanomas and 39% of metastatic melanomas had BRAF mutations in our series, which is similar to previously published data by other groups. 25,35,39 The high incidence of BRAF mutations in nevi suggests that this is an early event in melanocytic neoplasia.…”

“…25,[40][41][42][43][44][45][46] With the exception of the study by van Dijk et al, 40 which included an atypical Spitz nevus group, all other studies evaluated typical or classic Spitz nevi and/or spitzoid melanoma. The classic or typical Spitz nevus is usually readily distinguished from melanoma when standard histologic criteria are applied.…”

“…[25][26][27][28][29][30][31][32][33][34][35][36][37][38][39] However, a number of studies have failed to demonstrate BRAF mutations in Spitz nevi. 25,[40][41][42][43][44][45][46][57][58][59][60][61] Most of these studies analyzed only classic Spitz nevi. Only one study included atypical Spitz nevi and histologically borderline spitzoid lesions in their BRAF analysis.…”

Malignant melanoma: genetics and therapeutics in the genomic era

“…B-RAF mutations are also common in benign and dysplastic nevi (Pollock et al 2003;Yazdi et al 2003;Kumar et al 2004;Saldanha et al 2004), suggesting a role in the earliest stages of neoplasia. It is notable that nevi are considered growth-arrested and only rarely progress into melanoma, raising the possibility of BRAF V600E -induced checkpoint mechanisms operating to constrain malignant transformation.…”

Oncogenic GNAQ mutations are not correlated with disease-free survival in uveal melanoma

“…In contrast, melanocytic tumours such as uveal melanomas rarely show BRAF and NRAS mutations (Kilic et al, 2004;Saldanha et al, 2004;Janssen et al, 2008;Maat et al, 2008). Recently, somatic mutations in the heterotrimeric G protein alpha subunit q (GNAQ) have been found to be associated with dominant dark skin in a large-scale mutagenesis screen of inbred C3HeB/FeJ mice (Van Raamsdonk et al, 2004).…”