Systematic Functional Annotation of Somatic Mutations in Cancer

Abstract

The functional impact of the vast majority of cancer somatic mutations remains unknown, representing a critical knowledge gap for implementing precision oncology. Here, we report the development of a moderate-throughput functional genomic platform consisting of efficient mutant generation, sensitive viability assays using two growth factor-dependent cell models, and functional proteomic profiling of signaling effects for select aberrations. We apply the platform to annotate >1,000 genomic aberrations, including gene amplifications, point mutations, indels, and gene fusions, potentially doubling the number of driver mutations characterized in clinically actionable genes. Further, the platform is sufficiently sensitive to identify weak drivers. Our data are accessible through a user-friendly, public data portal. Our study will facilitate biomarker discovery, prediction algorithm improvement, and drug development.

The identification of patient‐specific mutations reveals dual pathway activation in most patients with melanoma and activated receptor tyrosine kinases in BRAF/NRAS wild‐type melanomas

“…To identify SNVs with a high probability of protumorigenic function in tumor development or maintenance, we focused on known activating/oncogenic alterations as well as deleterious mutations. The interpretation of the oncogenic and deleterious character of the SNV mutations was based on publicly available databases (eg, OncoKB, ClinVar [National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD]) and on published research results, as detailed in Table 1 . Activating mutations were identified in 14 genes, most of which were oncogenes.…”

“… Interpretation of the activating/oncogenic mutations is based on information from OncoKB, ClinVar, or www.cancerhotspots.org (as of 09/18), with the exception of BRAF‐K499N, for which this information was derived from Ng et al All alterations are predicted to be oncogenic or likely oncogenic. …”

“…The interpretation of the oncogenic and deleterious character of the SNV mutations was based on publicly available databases (eg, OncoKB, 15 ClinVar [National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD]) and on published research results, as detailed in Table 1. [16][17][18] Activating mutations were identified in 14 genes, most of which were oncogenes. Next to BRAF and neuroblastoma RAS viral oncogene homolog (NRAS) mutations, we identified oncogenic mutations in mast/stem cell growth factor receptor Kit (KIT ), MAP2K2 and MAP2K1, cyclin-dependent kinase 4 (CDK4), isocitrate dehydrogenase 1 (IDH1), Erb-b2 receptor tyrosine kinase 4 (ERBB4), Ras-related C3 botulinum toxin substrate 1 (RAC1), and splicing factor 3b subunit 1 (SF3B1), as expected for melanoma, but also in kinase insert domain receptor (KDR), Kirsten rat sarcoma viral proto-oncogene (KRAS), RAF protooncogene serine/threonine-protein kinase (CRAF), and fibroblast growth factor receptor 3 (FGFR3), which either rarely are mutated in melanoma (KDR, KRAS, CRAF) or, to our knowledge, have not been described previously for this tumor entity (FGFR3) ( Table 1, Activating/ Oncogenic Mutations).…”

Biomarkers to diagnose metastatic breast carcinoma to the pancreas: A case report and update

“…Two studies identified I767M as a gain‐of‐function mutation with transformative potential, resulting in increased HER2 kinase activity and sustained AKT phosphorylation . However, another study demonstrated no difference in cell proliferation or viability of HER2 I767M compared to wild‐type HER2 . HER2 mutations have been well studied in breast cancer, including HER2 nonamplified breast cancer .…”

“…19,20 However, another study demonstrated no difference in cell proliferation or viability of HER2 I767M compared to wild-type HER2. 21 HER2 mutations have been well studied in breast cancer, including HER2 nonamplified breast cancer. 22,23 However, the diagnostic utility of uncovering a kinase mutation in HER2 is unknown.…”