Molecular alterations in malignant blue nevi and related blue lesions

Abstract

Malignant blue nevi (MBN) are extremely rare dermal melanocytic tumors that arise in association with atypical cellular blue nevi (ACBN), cellular blue nevi (CBN), common blue nevi (BN), or de novo. The frequency of BRAF, NRAS, and KIT mutations in malignant melanoma varies according to histological subtype and localization. These mutations are rarely observed in blue nevi, which have recently been shown to carry activating mutations in GNAQ/GNA11 genes. Only few small molecular studies of MBN have been published. The aim of the present study was to analyze in MBN and related blue lesions such as ACBN, CBN, and BN the prevalence of BRAF, NRAS, KIT, GNAQ, and GNA11 gene mutations and their association with clinicopathological features. We included in our study 12 MBN, 6 ACBN, 29 CBN, and 35 common BN diagnosed between 1996 and 2014. Sanger sequencing method was used for mutation analysis. Overall, GNAQ exon 5 mutation was the most frequent alteration (46 %), in 2 of 12 (17 %) MBN, 1 of 6 (17 %) ACBN, 22 of 29 (76 %) CBN, and 13 of 35 (37 %) common BN. BRAF V600E and GNA11 exon 5 mutations were respectively detected in 3 of 12 (25 %) and in 2 of 12 (17 %) MBN while none in ACBN, CBN, and common BN. None of the cases harbored NRAS exon 2/3, KIT exon 9/11/13/17/18, or GNAQ/GNA11 exon 4 mutations. GNAQ gene exon 5 mutations are rare in MBN and ACBN but frequent in CBN and common BN. Remarkably, BRAF V600E and GNA11 exon 5 mutations were only detected in MBN, whereas none were found in ACBN, CBN, or common BN. Our data contribute new elements to the limited data on molecular alterations in MBN.

Generalized congenital epithelioid blue nevi (pigmented epithelioid melanocytomas) in an infant: Report of case and review of the literature

“…The clinical workup for our patient revealed absence of pathogenic variants in the PRKAR1A gene and also no candidates identified on trio whole exome sequencing. It should be noted that germline PRKAR1A testing was not performed in the prior published reports . Our case demonstrated a slightly elevated proliferative index at 10% to 20% of the MART‐1 positive cells, despite a lack of identifiable dermal mitotic figures.…”

“…Molecular abnormalities can also help distinguish EBN from common blue nevi and other entities. Several studies have shown that a large proportion of blue nevi, up to 87%, have a mutation in GNAQ , a gene encoding the α‐subunit of heterotrimeric q‐class G protein, or less commonly its paralogue GNA11 . Most GNAQ mutations occur at codon 209, which is essential for GTP hydrolysis, and lead to constitutional activation of the G protein .…”

“…Several studies have shown that a large proportion of blue nevi, up to 87%, have a mutation in GNAQ, a gene encoding the α-subunit of heterotrimeric q-class G protein, or less commonly its paralogue GNA11. [24][25][26][27][30][31][32] Most GNAQ mutations occur at codon 209, which is essential for GTP hydrolysis, and lead to constitutional activation of the G protein. 26,32 Mutations in genes in the same signaling pathway as GNAQ and GNA11 such as CYSLTR2…”

BRAF mutation, TERT promoter mutation, and HER2 amplification in sporadic or neurofibromatosis‐related neurofibromas and malignant peripheral nerve sheath tumors: do these molecules have a signature in malignant transformation?

“…: 56404) (QIAGEN, Hilden, Germany). Mutations in the promoter region of the TERT gene (chr5, 1,295,228 C>T and 1,295,250 C>T) and exon 15 of BRAF gene were analyzed by using our previously described PCR-based direct-sequencing (analytical sensitivity 25%) method (18,19).…”

GNA11-mutated and BAP1-negative Melanomas Ex Blue Naevi: A Particularly Aggressive Entity

“…The molecular mechanisms involved in the development and progression of various subtypes of melanoma have been studied widely. In melanomas that lack BRAF-, NRAS-or c-KIT-activating mutations, found in common subtypes of skin melanoma, driver mutations were identified in GNAQ and GNA11 genes coding G proteins in uveal melanomas and in the rare skin melanomas associated with blue naevi or mimicking cellular blue naevi, so-called "melanoma ex blue naevi" (MEBN) (1)(2)(3)(4)(5)(6). Whereas the loss of p16 protein (coded by the CDKN2A gene) tumour suppressor function is a major molecular event in the progression of most skin melanomas, the loss of function of another tumour suppressor BAP1 protein is a key molecular event in the progression of uveal melanomas and in their metastatic evolution (3,7).…”