Computational modelling of cancerous mutations in the EGFR/ERK signalling pathway

This article has been made available through the Brunel Open Access Publishing Fund - Copyright @ 2009 Orton et al.BACKGROUND: The Epidermal Growth Factor Receptor (EGFR) activated Extracellular-signal Regulated Kinase (ERK) pathway is a critical cell signalling pathway that relays the signal for a cell to proliferate from the plasma membrane to the nucleus. Deregulation of the EGFR/ERK pathway due to alterations affecting the expression or function of a number of pathway components has long been associated with numerous forms of cancer. Under normal conditions, Epidermal Growth Factor (EGF) stimulates a rapid but transient activation of ERK as the signal is rapidly shutdown. Whereas, under cancerous mutation conditions the ERK signal cannot be shutdown and is sustained resulting in the constitutive activation of ERK and continual cell proliferation. In this study, we have used computational modelling techniques to investigate what effects various cancerous alterations have on the signalling flow through the ERK pathway. RESULTS: We have generated a new model of the EGFR activated ERK pathway, which was verified by our own experimental data. We then altered our model to represent various cancerous situations such as Ras, B-Raf and EGFR mutations, as well as EGFR overexpression. Analysis of the models showed that different cancerous situations resulted in different signalling patterns through the ERK pathway, especially when compared to the normal EGF signal pattern. Our model predicts that cancerous EGFR mutation and overexpression signals almost exclusively via the Rap1 pathway, predicting that this pathway is the best target for drugs. Furthermore, our model also highlights the importance of receptor degradation in normal and cancerous EGFR signalling, and suggests that receptor degradation is a key difference between the signalling from the EGF and Nerve Growth Factor (NGF) receptors. CONCLUSION: Our results suggest that different routes to ERK activation are being utilised in different cancerous situations which therefore has interesting implications for drug selection strategies. We also conducted a comparison of the critical differences between signalling from different growth factor receptors (namely EGFR, mutated EGFR, NGF, and Insulin) with our results suggesting the difference between the systems are large scale and can be attributed to the presence/absence of entire pathways rather than subtle difference in individual rate constants between the systems.This work was funded by the Department of Trade and Industry (DTI), under their Bioscience Beacon project programme. AG was funded by an industrial PhD studentship from Scottish Enterprise and Cyclacel

A Genome-Wide Association Study of Upper Aerodigestive Tract Cancers Conducted within the INHANCE Consortium

Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p≤5×10−7). Two novel variants were identified, a 4q21 variant (rs1494961, p = 1×10−8) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p = 2×10−8) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5×10−8; rs1229984-ADH1B, p = 7×10−9; and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility

A Sex-Specific Association between a 15q25 Variant and Upper Aerodigestive Tract Cancers

Sequence variants located at 15q25 have been associated with lung cancer and propensity to smoke. We recently reported an association between rs16969968 and risk of upper aerodigestive tract (UADT) cancers (oral cavity, oropharynx, hypopharynx, larynx and esophagus) in women (odds ratio (OR) =1.24, P=0.003) with little effect in men (OR=1.04, P=0.35)

Reversing Reactivity: Stereoselective Desulfurative β-O-Glycosylation of Anomeric Thiosugars with Carboxylic Acids Under Copper or Cobalt Catalysis

We have discovered a new mode of reactivity of 1-thiosugars in the presence of Cu(II) or Co(II) for a stereoselective O-glycosylation reaction. The process involves the use of a catalytic amount of Cu(acac)2 or Co(acac)2 and Ag2CO3 as an oxidant in α,α,α-trifluorotoluene (TFT). Moreover, this protocol turned out to have a broad scope, allowing to prepare a wide range of com-plex substituted O-glycoside esters in good to excellent yields with an exclusive β-selectivity. The late-stage modification of phar-maceuticals by this method was also demonstrated

Genetic susceptibility factors in familial nasopharyngeal carcinoma

Nasopharyngeal carcinoma is common in Southern China, Hong Kong, Taiwan and Southeast Asian countries. The current study was performed on an exceptionally large multiplex NPC family from Sarawak, Malaysia (denoted as JAQBAB family). We aimed to explore the segregation of deleterious mutation(s) or NPC risk- associated allele within the genomic segment shared identical by descent (IBD) between the affected individuals. Genome-wide SNP-array covering all somatic chromosomes were performed on 11 of the NPC patients and their first-degree family members. The kinship was assessed and pairwise IBD estimation between target individuals were performed. Haplotype phasing was also performed on certain region of interests. Whole-exome sequencing was performed to identify deleterious mutations. The highest IBD score was detected within chromosome 10. Analysis of the exome sequencing data, however, did not find any deleterious mutation within this region that was shared between individuals in the JAQBAB family. Highest IBD score at chromosome 6 was found within the major histocompatibility complex (MHC) region, supporting strong HLA-EBV-NPC association that has been reported in an earlier study. HLA deep sequence-based typing (SBT) and gene sequencing on the 11 NPC patient samples revealed that the segregation of HLA-A*27:07 allele was consistent with the haplotype phasing pattern. Our results suggest that HLA-A*24:07 may harbour the risk allele for NPC among the subjects. However, further analysis is required before any definitive conclusion can be made. Further studies on the HLA-A*24:07 sequence may reveal more specific variation within this gene that can be associated with NPC risk in this family. In addition, further studies on HLA-A and risk of NPC other Southeast-Asian populations may shed more understanding about the association between HLA-A*24:07 and sporadic NPC in this region of the world

Total energy expenditure during arduous wildfire suppression

BACKGROUND: A proportion of the genetic variants involved in susceptibility to Hodgkin lymphoma differ by the tumor's Epstein-Barr virus (EBV) status, particularly within the MHC region. METHODS: We have conducted an SNP imputation study of the MHC region, considering tumor EBV status in 1,200 classical Hodgkin lymphoma (cHL) cases and 5,726 control subjects of European origin. Notable findings were genotyped in an independent study population of 468 cHL cases and 551 controls. RESULTS: We identified and subsequently replicated a novel association between a common genetic variant rs6457715 and cHL. Although strongly associated with EBV-positive cHL [OR, 2.33; 95% confidence interval (CI), 1.83-2.97; P = 7 × 10(-12)], there was little evidence for association between rs6457715 and the EBV-negative subgroup of cHL (OR, 1.06; 95% CI, 0.92-1.21), indicating that this association was specific to the EBV-positive subgroup (Phet < P = 10(-8)). Furthermore, the association was limited to EBV-positive cHL subgroups within mixed cell (MCHL) and nodular sclerosis subtypes (NSHL), suggesting that the association is independent of histologic subtype of cHL. CONCLUSIONS rs6457715, located near the HLA-DPB1 gene, is associated with EBV-positive cHL and suggests this region as a novel susceptibility locus for cHL. IMPACT This expands the number of genetic variants that are associated with cHL and provides additional evidence for a critical and specific role of EBV in the etiology of this disease