SF3B1 and BAP1 mutations in blue nevus-like melanoma

Abstract

Blue nevi are melanocytic tumors originating in the cutaneous dermis. Malignant tumors may arise in association with or resembling blue nevi, so called ‘blue nevus-like melanoma’, which can metastasize and result in patient death. Identifying which tumors will behave in a clinically aggressive manner can be challenging. Identifying genetic alterations in such tumors may assist in their diagnosis and prognostication. Blue nevi are known to be genetically related to uveal melanomas (eg, both harboring GNAQ and GNA11 mutations). In this study, we analyzed a large cohort (n=301) of various morphologic variants of blue nevi and related tumors including tumors diagnosed as atypical blue nevi (n=21), and blue nevus-like melanoma (n=12), screening for all gene mutations known to occur in uveal melanoma. Similar to published reports, we found the majority of blue nevi harbored activating mutations in GNAQ (53%) or GNA11 (15%). In addition, rare CYSLTR2 (1%) and PLCB4 (1%) mutations were identified. EIF1AX, SF3B1, and BAP1 mutations were also detected, with BAP1 and SF3B1 R625 mutations being present only in clearly malignant tumors (17% (n=2) and 25% (n =3) of blue nevus-like melanoma, respectively). In sequencing data from a larger cohort of cutaneous melanomas, this genetic profile was also identified in tumors not originally diagnosed as blue nevus-like melanoma. Our findings suggest that the genetic profile of coexistent GNAQ or GNA11 mutations with BAP1 or SF3B1 mutations can aid the histopathological diagnosis of blue nevus-like melanoma and distinguish blue nevus-like melanoma from conventional epidermal-derived melanomas. Future studies will need to further elucidate the prognostic implications and appropriate clinical management for patients with tumors harboring these mutation profiles.

BRCA1‐associated protein (BAP1)‐inactivated melanocytic tumors

“…This highlights that an understanding of BAP1 tumor suppressor gene is not only important in the context of familial BAP1 tumor predisposition syndrome but also important in a nonfamilial context regarding the association of molecular genetic alterations with specific morphologic change. Just as combined BAP1 and BRAF V600E mutations are characteristic of cutaneous BIMT, concurrent BAP1/SF3B1 and GNAQ/GNA11 mutations correspond with blue‐nevus‐like melanoma . Similarly, simultaneous β‐catenin ( APC/CTNNB1 ) and MAPK pathway mutations correspond with deep penetrating nevus, and spitzoid melanocytic tumors may bear ALK, NTRK , and ROS fusions .…”

“…By comparison, BAP1 loss contributes to 3% to 4% of OM, according to a study of 66 OM cases in New South Wales, Australia . It should be noted that BAP1 mutations are seen in other cutaneous tumors, including melanoma and blue‐nevus‐like melanoma; as such, the diagnosis of cutaneous BIMT is one of the clinicopathologic entities, not simply the presence or absence of a marker or molecular abnormality …”

“…As is the case in UMs, which also have a high frequency of these G‐protein mutations, loss of BAP1 in the blue nevus spectrum of tumors is associated with more malignant behavior. A study by Griewank et al analyzed gene mutations associated with UM across 301 cases of blue nevi, atypical blue nevi, and blue‐nevus‐like melanoma. The majority of these tumors harbored GNAQ or GNA11 mutations, and, interestingly, BAP1 and SF3B1 mutations were detected only in histopathologically malignant tumors …”

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.…”

“…Most GNAQ mutations occur at codon 209, which is essential for GTP hydrolysis, and lead to constitutional activation of the G protein . Mutations in genes in the same signaling pathway as GNAQ and GNA11 such as CYSLTR2 and PLCB4 have also been infrequently found . Mutations in BRAF and NRAS have been rarely reported .…”