title: Melanomas of unknown primary have a mutation profile consistent with cutaneous sun-exposed melanoma.
abstract: Melanoma of unknown primary (MUP) is an uncommon phenomenon whereby patients present with metastatic disease without an evident primary site. To determine their likely site of origin, we combined exome sequencing from 33 MUPs to assess the total rate of somatic mutations and degree of UV mutagenesis. An independent cohort of 91 archival MUPs was also screened for 46 hot spot mutations highly prevalent in melanoma including BRAF, NRAS, KIT, GNAQ, and GNA11. Results showed that the majority of MUPs exhibited high somatic mutation rates, high ratios of C>T/G>A transitions, and a high rate of BRAF (45 of 101, 45%) and NRAS (32 of 101, 32%) mutations, collectively indicating a mutation profile consistent with cutaneous sun-exposed melanomas. These data suggest that a significant proportion of MUPs arise from regressed or unrecognized primary cutaneous melanomas or arise de novo in lymph nodes from nevus cells that have migrated from the skin.
authors.affiliation: Oncogenomics Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Ken
authors.initials: K
authors.lastname: Dutton-Regester
authors.forename: Hojabr
authors.initials: H
authors.lastname: Kakavand
authors.forename: Lauren G
authors.initials: LG
authors.lastname: Aoude
authors.forename: Mitchell S
authors.initials: MS
authors.lastname: Stark
authors.forename: Michael G
authors.initials: MG
authors.lastname: Gartside
authors.forename: Peter
authors.initials: P
authors.lastname: Johansson
authors.forename: Linda
authors.initials: L
authors.lastname: O'Connor
authors.forename: Cathy
authors.initials: C
authors.lastname: Lanagan
authors.forename: Varsha
authors.initials: V
authors.lastname: Tembe
authors.forename: Gulietta M
authors.initials: GM
authors.lastname: Pupo
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Haydu
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Schmidt
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Mann
authors.forename: John F
authors.initials: JF
authors.lastname: Thompson
authors.forename: Richard A
authors.initials: RA
authors.lastname: Scolyer
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Hayward
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D059472:Exome / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000473:pathology*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009382:Neoplasms, Unknown Primary / Q000235:genetics* / Q000473:pathology*; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D013472:Sunlight; D000096142:Cutaneous Malignant Melanoma
keywords: melanoma of unknown primary; mutation profile; sequencing