Dataset Information

Overlapping and Distinct Transcriptional Functions of an Extended Repertoire of KRAS Mutations

ABSTRACT: The challenge of interpreting novel genetic variations in genomics is widespread. Previous studies have shown the role of KRAS mutations in heritable and somatic conditions, but more genetic variants have been observed than have been characterized. This study compares a broad genomic landscape of 25 KRAS mutations at three cellular checkpoint levels: ERK and AKT signaling, early cell-intrinsic transcriptional regulation, and secretory inflammatory responses. The results show heterogeneity in KRAS biology, with distinct mutations inducing significantly different levels of phosphorylated ERK, transcriptional profiles, and cytokine protein profiles. This heterogeneity may underlie variation in inter-individual disease patterns and contribute to differences in disease initiation or progression. Transcriptional profiles implicate different extents of feedback from upstream receptor kinases through diverse downstream nuclear targets and immunomodulatory programs. Integrated analysis reveals heterogeneity and potentially actionable outcomes for distinct groups of KRAS mutations in human cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE230860 | GEO | 2026/04/01

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:The small GTPase KRAS transmits signals from cell surface receptors to various downstream signaling pathways, thereby regulating a multitude of cellular processes. Activating KRAS mutations occur in approximately 30% of human cancers and contribute to malignant transformation through constitutive activation of downstream signaling cascades. These mutations cluster in several hotspots, with codons 12 and 13 being most commonly. It has been suggested that the position and type of amino acid exchange influence the transforming capacity of mutant KRAS proteins. To address this hypothesis, we used MCF10A human mammary epithelial cells to establish isogenic cell lines that express eight different cancer-associated KRAS mutations (G12C, G12D, G12V, G13C, G13D, A18D, Q61H, K117N) at physiological levels, and investigated the biochemical and functional consequences of the different KRAS variants in vitro. In addition, selected effects were evaluated in comparison to cells that overexpress mutant KRAS. The overall effects of mutants expressed at normal levels were moderate compared to overexpressed variants, but allowed delineation of biological functions that were related to specific alleles rather than KRAS expression level. None of the mutations induced morphological changes or migratory abilities. KRAS-G12D, -G12V, -G13D, and -K117N were able to mediate EGF-independent proliferation, whereas anchorage-independent growth was primarily induced by the K117N and Q61H variants. Analysis of known RAS effectors showed that none of the mutations led to increased phosphorylation of ERK, PDK1, or AKT. Both codon 13 mutations were associated with increased EGFR expression, which was not seen with other variants. Finally, comparative gene expression analysis of MCF10A-G13D versus MCF10A-G12D revealed distinct transcriptional changes, such as enhanced cytokine and p53 signaling, upon G13D expression. Together, we describe a useful resource for investigating the function of multiple KRAS mutations and provide insights into the differential effects of these variants in MCF10A cells.

Dataset Information

Overlapping and Distinct Transcriptional Functions of an Extended Repertoire of KRAS Mutations

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets