KRAS Alleles: The Devil Is in the Detail

Haigis, Kevin M.

doi:10.1016/j.trecan.2017.08.006

Cited by 276 publications

(270 citation statements)

References 80 publications

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“…In these cases, a high fraction of cells across the samples had concurrent DNMT3A and IDH mutations, whereas few clones were identified with co-mutated signaling genes ( p ≤ 0.00326), with the exception of a sample with co-mutated NRAS G13R and KRAS G60V within the same clone. While NRAS G13R has been previously identified as an oncogenic mutation, mutations in KRAS G60V have not been characterized as being truly oncogenic and may represent a hypomorphic or non-functional allele which does not contribute to transformation and clonal dominance 11 .…”

Section: Resultsmentioning

confidence: 99%

Single cell mutational profiling delineates clonal trajectories in myeloid malignancies

Miles

Bowman

Merlinsky

et al. 2020

Preprint

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1Myeloid malignancies, including acute myeloid leukemia (AML), arise from the proliferation and 2 expansion of hematopoietic stem and progenitor cells which acquire somatic mutations. Bulk 3 molecular profiling studies on patient samples have suggested that somatic mutations are obtained 4 in a step-wise fashion, where mutant genes with high variant allele frequencies (VAFs) are 5 proposed to occur early in disease development and mutations with lower VAFs are thought to be 6 acquired later in disease progression 1-3 . Although bulk sequencing informs leukemia biology and 7 prognostication, it cannot distinguish which mutations occur in the same clone(s), accurately 8 measure clonal complexity and clone size, or offer definitive evidence of mutational order. To 9 elucidate the clonal framework of myeloid malignancies, we performed single cell mutational 10 profiling on 146 samples from 123 patients. We found AML is most commonly comprised of a 11 small number of dominant clones, which in many cases harbor co-occurring mutations in 12 epigenetic regulators. Conversely, mutations in signaling genes often occur more than once in 13 distinct subclones consistent with increasing clonal diversity. We also used these data to map the 14 clonal trajectory of each patient and found that specific mutation combinations (FLT3-ITD + 15 NPM1 c ) synergize to promote clonal expansion and dominance. We combined cell surface protein 16 expression with single cell mutational analysis to map somatic genotype and clonal architecture 17 with immunophenotype. Our studies of clonal architecture at a single cell level provide novel 18 insights into the pathogenesis of myeloid transformation and how clonal complexity contributes 19 to disease progression. 20 21 22 23 2 Results 24The genomic landscape of myeloid malignancies has been well described, with a near complete 25 catalogue of putative mutant driver genes [3][4][5][6][7] . While combinations of mutations have been 26 functionally investigated in mouse models of disease, there remains uncertainty about the co-27 occurrence of somatic mutations within the same clone. The composition and combinatorial 28 distribution of mutations across cell types and states continues to be poorly understood. To analyze 29 the clonal architecture in clinical isolates from patients with myeloid malignancies, we performed 30 single cell DNA sequencing on the Tapestri platform using a custom 109 amplicon panel covering 31 31 of the most frequently mutated genes in myeloid malignancies (Extended Table 1) 8 . We 32 sequenced 740,529 cells from 146 samples from 123 patients with myeloid malignancies, 33 including clonal hematopoiesis (CH), myeloproliferative neoplasms (MPN), and AML (Figure 341A). Samples from patients at diagnosis and at relapse were queried, with the majority of samples 35 being from patients with relapsed/refractory disease (Figure 1B; Extended Table 2). The most 36 common mutations identified in single cell profiling were found in DNMT3A (n=62 patients), 37 TET2 (n=58 patients), NPM1 (...

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Section: Resultsmentioning

confidence: 99%

Single cell mutational profiling delineates clonal trajectories in myeloid malignancies

Miles

Bowman

Merlinsky

et al. 2020

Preprint

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“…Briefly, KRAS proteins are small GTPases that function as signal transducers of extracellular stimuli from several different cell surface receptors (e.g., EGFR) to the interior of the cell. Mutations in this oncogene, either by inhibiting its ability to hydrolyze GTP or by promoting the rapid exchange of GDP for GTP, render the protein constitutively active [2]. This impacts several signaling pathways, such as RAF-MEK-ERK, PI3K-AKT-mTOR, and RALGDS-RAL, that control a myriad Strategies to target mutant KRAS cells.…”

Section: Introductionmentioning

confidence: 99%

Targeting the Tumor Microenvironment: An Unexplored Strategy for Mutant KRAS Tumors

Carvalho

Machado

Martins

et al. 2019

Cancers

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Current evidence strongly suggests that cancer cells depend on the microenvironment in order to thrive. In fact, signals from the surrounding tumor microenvironment are crucial for cancer cells´aggressiveness, altering their expression profile and favoring their metastatic potential. As such, targeting the tumor microenvironment to impair cancer progression became an attractive therapeutic option. Interestingly, it has been shown that oncogenic KRAS signaling promotes a pro-tumorigenic microenvironment, and the associated crosstalk alters the expression profile of cancer cells. These findings award KRAS a key role in controlling the interactions between cancer cells and the microenvironment, granting cancer a poor prognosis. Given the lack of effective approaches to target KRAS itself or its downstream effectors in the clinic, exploring such interactions may open new perspectives on possible therapeutic strategies to hinder mutant KRAS tumors. This review highlights those communications and their implications for the development of effective therapies or to provide insights regarding response to existing regimens.

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“…KRAS mutations, on the other hand, were detected in approximately half (8/15) of the IA‐PGCG evaluated cases. KRAS oncogenic mutations are frequent in pancreatic, colorectal, and lung cancers, with codon 12 mutations corresponding to approximately 90% of these mutations (Haigis, ). In our cohort, we detected codon 12 mutations in 2/15 cases, corresponding to 2 out of the 8 KRAS mutations detected in these lesions.…”

Section: Discussionmentioning

confidence: 99%

KRAS mutations in implant‐associated peripheral giant cell granuloma

et al. 2019

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Objectives To investigate the molecular pathogenesis of implant‐associated peripheral giant cell granuloma (IA‐PGCG). Methods A convenience sample of 15 IA‐PGCG cases was selected. Hotspot mutations of KRAS, FGFR1, and TRPV4 genes, previously reported in conventional giant cell lesions of the jaws, were investigated by Sanger sequencing. As these mutations could activate MAPK/ERK pathway, the expression of phospho‐ERK1/2 was also evaluated by immunohistochemistry. Results KRAS mutations were detected in 8/15 (53.4%) samples. Similar to conventional peripheral giant cell granuloma, the KRAS mutations most frequently occurred in codon 146 (p.A146V, n = 3), followed by codon 12 (p.G12A and p.G12D, n = 1 each) and codon 14 (p.V14L, n = 1). Variants of unknown significance (VUS) were also detected in two cases, affecting codons 37 (p.E37K) and 127 (p.T127I). All samples showed wild‐type (WT) sequences for FGFR1 and TRPV4 genes. Consistent with MAPK/ERK pathway activation, all mononuclear cells of the lesion showed strong staining for phospho‐ERK1/2 protein in the immunohistochemical analysis. Conclusions KRAS mutations and activation of the MAPK‐ERK signaling pathway occur in IA‐PGCG. This is the first study to demonstrate cancer‐associated gene mutations in a non‐neoplastic reactive condition associated with dental implants.

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KRAS Alleles: The Devil Is in the Detail

Cited by 276 publications

References 80 publications

Single cell mutational profiling delineates clonal trajectories in myeloid malignancies

Single cell mutational profiling delineates clonal trajectories in myeloid malignancies

Targeting the Tumor Microenvironment: An Unexplored Strategy for Mutant KRAS Tumors

KRAS mutations in implant‐associated peripheral giant cell granuloma

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