Dataset Information

A novel, somatic, transforming mutation in the extracellular domain of Epidermal Growth Factor Receptor identified in myeloproliferative neoplasm.

ABSTRACT: We describe a novel ERBB1/EGFR somatic mutation (p. C329R; c.985?T?>?C) identified in a patient with JAK2^V617F Polycythaemia Vera (PV). This substitution affects a conserved cysteine residue in EGFR domain 2 and leads to the formation of a ligand-independent covalent receptor dimer, associated with increased transforming potential. Aberrant signalling from the EGFR^C329R receptor is cell type-dependent and in the TF1.8 erythroid cell line expression of this mutant suppresses EPO-induced differentiation. Clonal analysis shows that the dominant JAK2^V617F-positive clone in this PV patient harbors EGFR^C329R, thus this mutation may contribute to clonal expansion. Somatic mutations affecting other ERBB and related receptor tyrosine kinases are observed in myeloproliferative neoplasms (MPN), and we show elevated EGFR levels in MPN samples, consistent with previous reports. Thus activation of this group of receptors, via multiple mechanisms, may contribute to clonal growth and survival of the JAK2^V617F disease clone in MPN.

SUBMITTER: Casolari DA

PROVIDER: S-EPMC5446393 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A novel, somatic, transforming mutation in the extracellular domain of Epidermal Growth Factor Receptor identified in myeloproliferative neoplasm.

Casolari D A DA Nguyen T T Butcher C M CM Iarossi D G DG Hahn C N CN Bray S C SC Neufing P P Parker W T WT Feng J J Maung K Z Y KZY Wee A A Vidovic L L Kok C H CH Bardy P G PG Branford S S Lewis I D ID Lane S W SW Scott H S HS Ross D M DM D'Andrea R J RJ

Scientific reports 20170526 1

We describe a novel ERBB1/EGFR somatic mutation (p. C329R; c.985 T > C) identified in a patient with JAK2<sup>V617F</sup> Polycythaemia Vera (PV). This substitution affects a conserved cysteine residue in EGFR domain 2 and leads to the formation of a ligand-independent covalent receptor dimer, associated with increased transforming potential. Aberrant signalling from the EGFR<sup>C329R</sup> receptor is cell type-dependent and in the TF1.8 erythroid cell line expression of this mutant suppresses ...[more]

PMID: 28550306

Similar Datasets

Project description:BackgroundWhether inflammation is independently associated with development of JAK2V617F mutation and myeloproliferative neoplasm is not clear. We tested the hypothesis that a loss-of-function polymorphism in IL6R (marked by rs4537545) reduces risk of JAK2V617F mutation and myeloproliferative neoplasm in a Mendelian randomization study.MethodsWe genotyped 107,969 Danes from the Copenhagen General Population Study for the IL6R rs4537545 genotype, where the T-allele is associated with impaired interleukin-6 receptor signaling and reduced inflammation. JAK2V617F was examined in a subset of 49,143 individuals. We investigated the association between IL6R rs4537545 and risk of JAK2V617F using logistic regression and myeloproliferative neoplasm using Cox regression.Findings36,871 were non-carriers, 52,500 heterozygotes, and 18,598 homozygotes for the T-allele of the IL6R rs4537545 genotype. Among 107,969 individuals, 352 were diagnosed with myeloproliferative neoplasm, and among 49,143 individuals, 62 were JAK2V617F-positive (of these 62 individuals, 46 had myeloproliferative neoplasm diagnosed). Compared to non-carriers, age- and sex-adjusted odds ratios for risk of JAK2V617F were 0·55(95%CI:0·32-0·94) in heterozygotes, 0·51(0·24-1·12) in homozygotes, 0·54(0·33-0·89) in carriers, and 0·66(0·45-0·96) per T-allele. Compared to non-carriers, age- and sex-adjusted hazard ratios for risk of myeloproliferative neoplasm were 0·82(95% CI: 0·65-1·02) in heterozygotes, 0·65(0·47-0·91) in homozygotes, 0·77(0·63-0·96) in carriers, and 0·81(0·70-0·94) per T-allele. Associations were primarily observed for polycythaemia vera and myelofibrosis, and for JAK2V617F-positive myeloproliferative neoplasm.InterpretationA loss-of-function polymorphism in IL6R reduces risk of JAK2V617F mutation and myeloproliferative neoplasm. This finding supports inflammation as an independent risk factor for JAK2V617F mutation and myeloproliferative neoplasm and indicates that therapeutics designed to block interleukin-6 receptor signaling might prevent or retard progression of myeloproliferative neoplasm.FundingKaren Elise Jensen Foundation.

Project description:BACKGROUND: Tumour growth in colorectal cancer and other solid cancers is frequently supported by activating mutations in the epidermal growth factor receptor (EGFR) signaling pathway (Patholog Res Int 2011:932932, 2011). Treatment of metastatic colorectal cancer with targeted anti-EGFR therapeutics such as cetuximab extends survival in only 25% of patients who test wild-type for KRAS, while the majority of patients prove resistant (J Clin Oncol 28(7):1254-1261, 2010).Prediction of cetuximab responsiveness for KRAS wild-type colorectal cancers is currently not well defined, and prognostic biomarkers would help tailor treatment to individual patients. Somatic mutation of the EGFR signalling pathway is a prevalent mechanism of resistance to cetuximab (Nature 486(7404):532-536, 2012). If the human genome harbours variants that influence susceptibility of the EGFR pathway to oncogenic mutation, such variants could also be prognostic for cetuximab responsiveness. METHODS: We assessed whether patient genetic variants may associate with somatic mutation of the EGFR signalling pathway. We combined tumour mutation data from the Cancer Genome Atlas with matched patient genetic data, and tested for germline variants that associate with somatic mutation of the EGFR pathway (including EGFR, KRAS, BRAF, PTEN and PIK3CA). RESULTS: Two single nucleotide polymorphisms (SNPs) located 90 kb upstream of the TERT oncogene associated with somatic mutation of the EGFR pathway beyond the threshold of genome-wide significance: rs7736074 (P?=?4.64 × 10-9) and rs4975596 (P?=?5.69 × 10-9). We show that allelic variants of rs7736074 and rs4975596 modulate TERT expression levels in multiple cancer types, and exhibit preliminary prognostic value for response to cetuximab. CONCLUSIONS: We have identified two germline SNPs that associate with somatic mutation of the EGFR pathway, and may be prognostic for cetuximab responsiveness. These variants could potentially contribute to a panel of prognostic biomarkers for assessing whether metastatic colorectal cancer patients are likely to derive benefit from cetuximab treatment. Genotyping of a large cohort of cetuximab-treated colorectal cancer patients is called for to further clarify the association.

Dataset Information

A novel, somatic, transforming mutation in the extracellular domain of Epidermal Growth Factor Receptor identified in myeloproliferative neoplasm.

Publications

A novel, somatic, transforming mutation in the extracellular domain of Epidermal Growth Factor Receptor identified in myeloproliferative neoplasm.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets