title: Identification of recurrent mutational events in anorectal melanoma.
abstract: Anorectal melanoma is a rare disease that carries a poor prognosis. To date, limited genetic analyses confirmed KIT mutations as a recurrent genetic event similar to other mucosal melanomas, occurring in up to 30% of anorectal melanomas. Importantly, a subset of tumors harboring activating KIT mutations have been found to respond to c-Kit inhibitor-based therapy, with improved patient survival at advanced tumor stages. We performed comprehensive targeted exon sequencing analysis of 467 cancer-related genes in a larger series of 15 anorectal melanomas, focusing on potentially actionable variants based on gain- and loss-of-function mutations. We report the identification of oncogenic driver events in the majority (93%) of anorectal melanomas. These included variants in canonical MAPK pathway effectors rarely observed in cutaneous melanomas (including an HRAS mutation, as well as a BRAF mutation resulting in duplication of threonine 599), and recurrent mutations in the tumor suppressor NF1 in 20% of cases, which represented the second-most frequently mutated gene after KIT in our series. Furthermore, we identify SF3B1 mutations as a recurrent genetic event in mucosal melanomas. Our findings provide an insight into the genetic diversity of anorectal melanomas, and suggest significant potential for alternative targeted therapeutics in addition to c-Kit inhibitors for this melanoma subtype.
authors.affiliation: Department of Pathology & Cell Biology, Columbia University Medical Center, New York, NY, USA.|Department of Pathology & Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Hui Min
authors.initials: HM
authors.lastname: Yang
authors.affiliation: Department of Pathology & Cell Biology, Columbia University Medical Center, New York, NY, USA.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Hsiao
authors.affiliation: Department of Pathology & Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: David F
authors.initials: DF
authors.lastname: Schaeffer
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Chi
authors.initials: C
authors.lastname: Lai
authors.affiliation: Department of Pathology & Cell Biology, Columbia University Medical Center, New York, NY, USA.
authors.forename: Helen E
authors.initials: HE
authors.lastname: Remotti
authors.affiliation: Pathologisches Institut, Ludwig-Maximilians-Universitaet, Muenchen, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Horst
authors.affiliation: Department of Pathology & Cell Biology, Columbia University Medical Center, New York, NY, USA.
authors.forename: Mahesh M
authors.initials: MM
authors.lastname: Mansukhani
authors.affiliation: Department of Pathology & Cell Biology, Columbia University Medical Center, New York, NY, USA.|Department of Dermatology, Columbia University Medical Center, New York, NY, USA.
authors.forename: Basil A
authors.initials: BA
authors.lastname: Horst
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001005:Anus Neoplasms / Q000235:genetics* / Q000473:pathology; D005091:Exons; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D025542:Neurofibromin 1 / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D000072260:RNA Splicing Factors / Q000235:genetics*; D012004:Rectal Neoplasms / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics
chemical_list: D025542:Neurofibromin 1; D010750:Phosphoproteins; D000072260:RNA Splicing Factors; C112491:SF3B1 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf