title: Neurofibromin protein loss in desmoplastic melanoma subtypes: implicating NF1 allelic loss as a distinct genetic driver?
abstract: Loss of the NF1 allele, coding for the protein neurofibromin, and polymorphism in the proto-oncogene RET (RETp) are purportedly common in desmoplastic melanoma (DM). DM is categorized into pure (PDM) and mixed (MDM) subtypes, which differ in prognosis. Most NF1 mutations result in a truncated/absent protein, making immunohistochemical screening for neurofibromin an ideal surrogate for NF1 allelic loss. Using antineurofibromin, our aims were to ascertain the incidence of neurofibromin loss in DM subtypes and to evaluate the relationship with RET, perineural invasion (PNI) and established histopathologic prognosticators. A total of 78 archival samples of DM met criteria for inclusion (54 cases of non-DM serving as controls). Immunohistochemistry was performed for neurofibromin, whereas direct DNA sequencing was used for RETp and BRAF mutation status. Statistical analyses included χ(2) test as well as Fisher exact test. Neurofibromin loss was more common in DM than non-DM (69% versus 54%; P=.02). In DM, significant differences in neurofibromin loss were noted in the following: non-head and neck versus head and neck biopsy site (88% versus 55%) and PDM versus MDM variants (80% versus 56%). No significant associations were noted with sex, presence of a junctional component, Breslow depth, ulceration, mitoses, host response, RETp, BRAF status, or PNI. RETp was marginally associated with PNI-positive DM versus PNI-negative DM (36 versus 18%; P=.08). Our findings, the largest to date investigating neurofibromin in DM, validate the incidence of NF1 mutations/allelic loss in DM and suggest that the DM subtypes have distinct genetic drivers.
authors.affiliation: Division of Graduate Medical Sciences, Boston University School of Medicine, Boston, MA 02118.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kadokura
authors.affiliation: University of Iowa Carver College of Medicine, Iowa City, IA 52240.
authors.forename: Noah
authors.initials: N
authors.lastname: Frydenlund
authors.affiliation: Boston University School of Public Health, Boston, MA 02118.
authors.forename: Dominick A
authors.initials: DA
authors.lastname: Leone
authors.affiliation: Department of Pathology, Boston University of Medicine, Boston, MA 02118.
authors.forename: Shi
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, MA 02118.
authors.forename: Mai P
authors.initials: MP
authors.lastname: Hoang
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01601.
authors.forename: April
authors.initials: A
authors.lastname: Deng
authors.affiliation: Miraca Life Sciences, Newton Upper Falls, MA 02458.
authors.forename: Marier
authors.initials: M
authors.lastname: Hernandez-Perez
authors.affiliation: Department of Pathology, Western General Hospital, Edinburgh, Scotland EH13 9QW.
authors.forename: Asok
authors.initials: A
authors.lastname: Biswas
authors.affiliation: Department of Pathology and Dermatology, Icahn School of Medicine Mount Sinai, New York, NY 10001.
authors.forename: Rajendra
authors.initials: R
authors.lastname: Singh
authors.affiliation: Aurora Diagnostics GPA Laboratories, Greensboro, NC 27401.
authors.forename: Ron
authors.initials: R
authors.lastname: Yaar
authors.affiliation: Dermatopathology Section, Department of Pathology and Laboratory Medicine, VA Consolidated Laboratories, West Roxbury, MA 02132. Electronic address: me@meeramahalingam.com.
authors.forename: Meera
authors.initials: M
authors.lastname: Mahalingam
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D001706:Biopsy; D016009:Chi-Square Distribution; D002648:Child; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D019656:Loss of Heterozygosity; D008297:Male; D008545:Melanoma / Q000145:classification / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D009361:Neoplasm Invasiveness; D025542:Neurofibromin 1 / Q000235:genetics*; D010641:Phenotype; D011237:Predictive Value of Tests; D000090063:Proto-Oncogene Mas; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics; D012878:Skin Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C000715470:MAS1 protein, human; D025542:Neurofibromin 1; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: Desmoplastic melanoma subtypes; Mixed variant; Neurofibromin; Pure variant; RETp