Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients

Abstract

Tumor molecular profiling is a fundamental component of precision oncology, enabling the identification of genomic alterations in genes and pathways that can be targeted therapeutically. The existence of recurrent targetable alterations across distinct histologically-defined tumor types, coupled with an expanding portfolio of molecularly-targeted therapies, demands flexible and comprehensive approaches to profile clinically significant genes across the full spectrum of cancers. We established a large-scale, prospective clinical sequencing initiative utilizing a comprehensive assay, MSK-IMPACT, through which we have compiled matched tumor and normal sequence data from a unique cohort of more than 10,000 patients with advanced cancer and available pathological and clinical annotations. Using these data, we identified clinically relevant somatic mutations, novel non-coding alterations, and mutational signatures that were shared among common and rare tumor types. Patients were enrolled on genomically matched clinical trials at a rate of 11%. To enable discovery of novel biomarkers and deeper investigation into rare alterations and tumor types, all results are publicly accessible.

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

“…In Fig. 9, we show the results from a dataset of 10,000 cancer patients (Zehir et al, 2017). In most cases, these mutations alter the interaction of the DLG and ETGE motifs of NRF2 with KEAP1, hence inducing hyperactivation of NRF2 in several solid tumors, including esophagus, skin, lung, and larynx carcinomas (Kim et al, 2010b;Taguchi and Yamamoto, 2017).…”

Genomic analysis of hairy cell leukemia identifies novel recurrent genetic alterations

“…Sequencing and analysis were performed as previously described. [16][17][18] The FACETS algorithm was used to estimate tumor purity, ploidy, and allele-specific CN from sequencing data of tumor-normal pairs as previously described. 18,19 Additional experimental details are described in the supplemental Methods.…”

Plasma DNA-Based Molecular Diagnosis, Prognostication, and Monitoring of Patients With EWSR1 Fusion-Positive Sarcomas

“…Droplet digital PCR has been established as an attractive platform for circulating nucleic acids based on the ease of quantitation of mutant fragments as compared to Real-time PCR. 38 Furthermore, broad, hybrid-capture NGS platforms are becoming increasingly utilized for clinical use, as exemplified by the MSK-IMPACT sequencing platform with well over 10,000 patient tumor samples studied to date 39 and even greater numbers studied by similar NGS-based assays at commercial reference laboratories.…”