A Mutational Survey of Acral Nevi

Abstract

cral melanoma is a rare melanocytic tumor that arises on the non-hair-bearing skin of the palms, soles, and nail beds. 1 Unlike cutaneous melanoma, acral melanoma is not linked to UV radiation exposure; it exhibits a much lower point mutation burden than cutaneous melanoma but a higher frequency of structural variants and copy number alterations. 2,3 The incidence of acral melanoma is uniform across all populations, making it the most common melanoma subtype in individuals of African, Asian, and Hispanic descent. 1 Acral melanomas differ in their mutational profiles from cutaneous melanomas, with a lower incidence of BRAF mutations (18%) and NF1 mutations (11%) and the presence of mutations in TYRP1 (8%) and NOTCH2 (4%) and amplification/ mutation in the receptor tyrosine kinase c-KIT (approximately 2%-3%). 3 Acral melanomas with BRAF mutations harbor fewer genomic amplifications and are more common in patients with European ancestry, possibly constituting a unique subset. 4 Melanocytic nevi are benign proliferations of melanocytes; melanomas sometimes arise in a small proportion of melanocytic nevi. [5][6][7] Genomic analyses have shown that 100% of nevi on sun-exposed skin harbor mutually exclusive mutations in melanoma driver oncogenes, such as BRAF and NRAS. [8][9][10] Although the development of nevi has been linked to sun exposure, 10,11 they can also arise on skin with low levels of UV radiation exposure, such as the palms and soles. At this time, little is known about the mutational profiles of acral nevi, which arise on skin with little UV radiation exposure. Methods Patient SamplesThis study was approved by the University of South Florida institutional review board (protocol No. PRO00036516). Deidentified archival samples were collected under a waiver of informed consent under the Common Rule (45 CFR 46). After institutional review board approval, the pathology databases at 2 institutions were queried for a diagnosis containing the words melanocytic nevus at any acral location (palm, sole, finger, toe, foot, hand). Slides were reviewed and diagnoses verified by the study pathologist (J.L.M.); 49 of 50 cases with greater than 10% nevus cellularity and 1 case with 5% nevus cellularity were submitted for analysis. DNA SequencingTargeted DNA sequencing was performed on 151 cancerassociated genes (eTable 1 in the Supplement) (Agilent Sure-Select XT ClearSeq Comprehensive Cancer Panel). For each sample, 75-base paired-end sequence reads were generated IMPORTANCE Acral skin may develop nevi, but their mutational status and association with acral melanoma is unclear.OBJECTIVE To perform targeted next-generation sequencing on a cohort of acral nevi to determine their mutational spectrum.DESIGN, SETTING, AND PARTICIPANTS Acral nevi specimens (n = 50) that had been obtained for diagnostic purposes were identified from the pathology archives of a tertiary care academic cancer center and a university dermatology clinic. Next-generation sequencing was performed on DNA extracted from the specimens, and mutations calle...

Integrated genomic analyses of acral and mucosal melanomas nominate novel driver genes

“…This raises the possibility that melanomas on acral are of two different types, with a bona fide and unique acral type with an admixture of cutaneous melanoma of the World health Organization (WHO) low-CSD subtype, i.e., melanomas on the sun-exposed skin with low degree of cumulative sun damage [ 89 ]. A recent study on acral nevi identified BRAF V600E mutation in 86% of samples [ 90 ], which is similar to what was observed in cutaneous nevi that considered the precursors of low-CSD melanomas [ 45 ]. Another study identified transcriptome-level differences between acral and cutaneous melanocytes [ 91 ].…”

Integrative Genomic Profiling Uncovers Therapeutic Targets of Acral Melanoma in Asian Populations

“…In parallel, copy-number variants (CNV) intensively favor potential driver genes in acral melanoma that thus exhibit a heavy CNV mutational burden ( 3, 5 ). However, Smalley and colleagues have analyzed the genome data and demonstrated that acral nevi are not precursors to the majority of prototypical acral melanomas, indicating that acral melanoma has an evolutionary trajectory different from that of cutaneous melanoma ( 7 ).…”

Acral Melanocytic Neoplasms: A Comprehensive Review of Acral Nevus and Acral Melanoma in Asian Perspective

“…They showed that CNVs were much less common in acral melanocytic nevus than acral melanoma. A mutational survey of acral melanocytic nevi was also performed in a U.S. population [ 12 ]. Similarly to the Korean results, BRAF mutation was commonly observed in acral melanocytic nevus.…”

“…The lesions are benign, and progression to melanoma is rare. Most acral melanomas arise de novo, not in association with a preexisting acral nevus [ 12 , 29 ]. Acral melanocytic nevi which do not show typical benign dermoscopic patterns may require clinical and dermoscopic surveillance, and once or twice a year is enough [ 30 ].…”