title: Intratumoral molecular heterogeneity in a BRAF-mutant, BRAF inhibitor-resistant melanoma: a case illustrating the challenges for personalized medicine.
abstract: Targeted therapies are increasingly being used to treat a variety of cancers. Their efficacy depends upon the accurate detection and targeting of a specific mutation or aberration in the tumor. All cancers, such as melanoma, are molecularly heterogeneous, with drug-resistant subclones present before the treatment or emerging as a result of targeted therapies. Here, we show intralesional molecular heterogeneity in a progressing V600E BRAF-mutant melanoma metastasis from a patient treated for 7 months with the BRAF inhibitor vemurafenib. In the single metastasis, two distinct subclones were observed, both V600E BRAF-mutant and only one with an additional G13R NRAS mutation. Molecular heterogeneity even at the intralesional level shows that personalizing or adjusting therapies based on genotyping of a portion of a single lesion may not accurately depict the molecular profile or drivers of oncogenesis across the entire patient's melanoma.
authors.affiliation: Melanoma Institute Australia, Australia.
authors.forename: James S
authors.initials: JS
authors.lastname: Wilmott
authors.forename: Varsha
authors.initials: V
authors.lastname: Tembe
authors.forename: Julie R
authors.initials: JR
authors.lastname: Howle
authors.forename: Raghwa
authors.initials: R
authors.lastname: Sharma
authors.forename: John F
authors.initials: JF
authors.lastname: Thompson
authors.forename: Helen
authors.initials: H
authors.lastname: Rizos
authors.forename: Roger S
authors.initials: RS
authors.lastname: Lo
authors.forename: Richard F
authors.initials: RF
authors.lastname: Kefford
authors.forename: Richard A
authors.initials: RA
authors.lastname: Scolyer
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Long
mesh_terms: D000368:Aged; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D009362:Neoplasm Metastasis; D057285:Precision Medicine; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics*
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf