Faculty Collaboration Database

Prospective blinded study of BRAFV600E mutation detection in cell-free DNA of patients with systemic histiocytic disorders. Cancer Discov 2015 Jan;5(1):64-71

Date

10/18/2014

Pubmed ID

25324352

Pubmed Central ID

PMC5705028

DOI

10.1158/2159-8290.CD-14-0742

Scopus ID

2-s2.0-84922372527 (requires institutional sign-in at Scopus site)   113 Citations

Abstract

UNLABELLED: Patients with Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) have a high frequency of BRAF(V600E) mutations and respond to RAF inhibitors. However, detection of mutations in tissue biopsies is particularly challenging in histiocytoses due to low tumor content and stromal contamination. We applied a droplet-digital PCR assay for quantitative detection of the BRAF(V600E) mutation in plasma and urine cell-free (cf) DNA and performed a prospective, blinded study in 30 patients with ECD/LCH. There was 100% concordance between tissue and urinary cfDNA genotype in treatment-naïve samples. cfDNA analysis facilitated identification of previously undescribed KRAS(G12S)-mutant ECD and dynamically tracked disease burden in patients treated with a variety of therapies. These results indicate that cfDNA BRAF(V600E) mutational analysis in plasma and urine provides a convenient and reliable method of detecting mutational status and can serve as a noninvasive biomarker to monitor response to therapy in LCH and ECD.

SIGNIFICANCE: Patients with BRAF(V600E)-mutant histiocytic disorders have remarkable responses to RAF inhibition, but mutation detection in tissue in these disorders is challenging. Here, we identify that analysis of plasma and urinary cfDNA provides a reliable method to detect the BRAF(V600E) mutation and monitor response to therapy in these disorders.

Author List

Hyman DM, Diamond EL, Vibat CR, Hassaine L, Poole JC, Patel M, Holley VR, Cabrilo G, Lu TT, Arcila ME, Chung YR, Rampal R, Lacouture ME, Rosen N, Meric-Bernstam F, Baselga J, Kurzrock R, Erlander MG, Janku F, Abdel-Wahab O

Author

Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adolescent
Adult
Aged
Amino Acid Substitution
Biopsy
Child
Codon
Cross-Sectional Studies
DNA Mutational Analysis
Erdheim-Chester Disease
Female
Gene Frequency
Genes, ras
Genotype
Histiocytosis
Histiocytosis, Langerhans-Cell
Humans
Magnetic Resonance Imaging
Male
Middle Aged
Mutation
Positron-Emission Tomography
Proto-Oncogene Proteins B-raf
Young Adult