0000000000066505
AUTHOR
Deborah N. Farlow
The Genetic Landscape of Clinical Resistance to RAF Inhibition in Metastatic Melanoma.
Abstract Most patients with BRAFV600-mutant metastatic melanoma develop resistance to selective RAF kinase inhibitors. The spectrum of clinical genetic resistance mechanisms to RAF inhibitors and options for salvage therapy are incompletely understood. We performed whole-exome sequencing on formalin-fixed, paraffin-embedded tumors from 45 patients with BRAFV600-mutant metastatic melanoma who received vemurafenib or dabrafenib monotherapy. Genetic alterations in known or putative RAF inhibitor resistance genes were observed in 23 of 45 patients (51%). Besides previously characterized alterations, we discovered a “long tail” of new mitogen-activated protein kinase (MAPK) pathway alterations (…
The genetic landscape of clinical resistance to RAF inhibition in melanoma.
11009 Background: Although single-agent RAF inhibition has proved effective in metastatic BRAFV600-mutant melanoma, most patients relapse and some are intrinsically resistant. While several genetic resistance effectors have been identified, a comprehensive assessment of the genetic resistance spectrum in a large patient cohort may further inform resistance patterns and treatment strategies. Methods: Pre-treatment and post-relapse biopsies were obtained from BRAFV600melanoma patients treated with vemurafenib or dabrafenib. Whole exome sequencing of tumor and normal samples was performed to identify exome-wide mutations, insertion/deletions, and chromosomal copy number alterations. Since som…
Large-Scale Candidate Gene Analysis in Whites and African Americans Identifies IL6R Polymorphism in Relation to Atrial Fibrillation The National Heart, Lung, and Blood Institute's Candidate Gene Association Resource (CARe) Project
Background— The genetic background of atrial fibrillation (AF) in whites and African Americans is largely unknown. Genes in cardiovascular pathways have not been systematically investigated. Methods and Results— We examined a panel of approximately 50 000 common single-nucleotide polymorphisms (SNPs) in 2095 cardiovascular candidate genes and AF in 3 cohorts with participants of European (n=18 524; 2260 cases) or African American descent (n=3662; 263 cases) in the National Heart, Lung, and Blood Institute's Candidate Gene Association Resource. Results in whites were followed up in the German Competence Network for AF (n=906, 468 cases). The top result was assessed in relation to incident i…
Exome sequencing in suspected monogenic dyslipidemias.
Background— Exome sequencing is a promising tool for gene mapping in Mendelian disorders. We used this technique in an attempt to identify novel genes underlying monogenic dyslipidemias. Methods and Results— We performed exome sequencing on 213 selected family members from 41 kindreds with suspected Mendelian inheritance of extreme levels of low-density lipoprotein cholesterol (after candidate gene sequencing excluded known genetic causes for high low-density lipoprotein cholesterol families) or high-density lipoprotein cholesterol. We used standard analytic approaches to identify candidate variants and also assigned a polygenic score to each individual to account for their burden of commo…