Dataset Information

Beyond RAS and BRAF: a target rich disease that is ripe for picking.

ABSTRACT: Despite numerous breakthroughs in the understanding of colorectal cancer and identification of many oncogenic mutations, the treatment of metastatic colorectal cancer remains relatively more empiric than targeted. Testing for mutations in rat sarcoma virus (RAS) and rapidly growing fibrosarcoma (RAF) are routinely performed, though identification of these mutations currently offers little more than a negative predictive marker for response to EGFR inhibitor treatment and, in the case of RAF mutation, a poor prognostic indicator. Next-generation sequencing has identified both common and rare mutations in colorectal cancer that offer options for more advanced, targeted therapy. With so much research invested in these targets, the treatment of metastatic colorectal cancer stands to become much more personalized in the near future. This review describes several of the more promising targets that are currently being investigated in advanced colorectal cancer.

SUBMITTER: Friedrich T

PROVIDER: S-EPMC5056247 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Beyond RAS and BRAF: a target rich disease that is ripe for picking.

Friedrich Tyler T Leong Stephen S Lieu Christopher H CH

Journal of gastrointestinal oncology 20161001 5

Despite numerous breakthroughs in the understanding of colorectal cancer and identification of many oncogenic mutations, the treatment of metastatic colorectal cancer remains relatively more empiric than targeted. Testing for mutations in rat sarcoma virus (RAS) and rapidly growing fibrosarcoma (RAF) are routinely performed, though identification of these mutations currently offers little more than a negative predictive marker for response to EGFR inhibitor treatment and, in the case of RAF muta ...[more]

PMID: 27747084

Similar Datasets

Project description:ImportanceUnderstanding RAS dependency and mechanisms of RAS activation in non-V600 BRAF variant cancers has important clinical implications. This is the first study to date to systematically assess RAS dependency of BRAF alterations with real-world cancer genomic databases.ObjectiveTo evaluate RAS dependency of individual BRAF alterations through alteration coexistence analysis using cancer genomic databases.Design and settingA cross-sectional data analysis of 119 538 nonredundant cancer samples using cancer genomics databases including GENIE (Genomics Evidence Neoplasia Information Exchange) and databases in cBioPortal including TCGA (The Cancer Genome Atlas) (accessed March 24, 2020), in addition to 2745 cancer samples from Mayo Clinic Genomics Laboratory (January 1, 2015, to July 1, 2020). Frequencies and odds ratios of coexisting alterations of RAS (KRAS, NRAS and HRAS) and RAS regulatory genes (NF1, PTPN11 and CBL) were calculated for individual BRAF alterations, and compared according to the current BRAF alteration classification; cancer type specificity of coexisting alterations of RAS or RAS regulatory genes was also evaluated.Main outcomes and measuresPrimary outcome measurement is enrichment of RAS (KRAS, NRAS and HRAS) alterations in BRAF variant cancers. Secondary outcome measurement is enrichment of RAS regulatory gene (NF1, PTPN11, and CBL) in BRAF variant cancers.ResultsA total of 2745 cancer samples from 2708 patients (female/male ratio: 1.0) tested by Mayo Clinic Genomics Laboratory and 119 538 patients (female/male ratio: 1.1) from GENIE and cBioPortal database were included in the study. In 119 538 nonredundant cancer samples, class 1 BRAF alterations and BRAF fusions were found to be mutually exclusive to alterations of RAS or RAS regulatory genes (odds ratio range 0.03-0.13 and 0.03-0.73 respectively), confirming their RAS independency. Both class 2 and class 3 BRAF alterations show variable and overlapping levels of enriched RAS alterations (odds ratio range: 0.03-5.9 and 0.63-2.52 respectively), suggesting heterogeneity in RAS dependency and a need to revisit BRAF alteration classification. For RAS-dependent BRAF alterations, the coexisting alterations also involve RAS regulatory genes by enrichment analysis (for example, S467L shows an odds ratio of 8.26 for NF1, 9.87 for PTPN11, and 15.23 for CBL) and occur in a variety of cancer types with some coalterations showing cancer type specificity (for example, HRAS variations account for 46.7% of all coexisting RAS alterations in BRAF variant bladder cancers, but 0% in non-small cell lung cancers). Variant-level assessment shows that BRAF alterations involving the same codon may differ in RAS dependency. In addition, RAS dependency of previously unclassified BRAF alterations could be assessed.Conclusions and relevanceCurrent BRAF alteration classification based on in vitro assays does not accurately predict RAS dependency in vivo for non-V600 BRAF alterations. RAS-dependent BRAF variant cancers with different mechanisms of RAS activation suggest the need for different treatment strategies.

Dataset Information

Beyond RAS and BRAF: a target rich disease that is ripe for picking.

Publications

Beyond RAS and BRAF: a target rich disease that is ripe for picking.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets