EIF1AX Research Articles

Metastatic Disease in Polyploid Uveal Melanoma Patients Is Associated With BAP1 Mutations.

Most of the uvea melanoma (UM) display a near-diploid (normal, -2N) karyotype with only a few chromosomal changes. In contrast to these simple aberrations 18% of the UM samples show a polyploid character (>2N) and this was associated with an unfavorable prognosis. This study attempts to gain insight in the prognostic value of polyploidy in UM. In 202 patients the ploidy status of the UM was determined using cytogenetic analysis, fluorescence-in-situ-hybridization (FISH), multiplex ligation dependent probe amplification (MLPA), and/or single nucleotide polymorphism (SNP) array analysis. Immunohistochemistry was used to determine the BAP1 expression and mutation analyses of BAP1 (coding regions) and the mutation hotspots for the SF3B1, EIF1AX, GNAQ, and GNA11 genes was carried out using Sanger sequencing or whole-exome sequencing. Twenty-three patients had a polyploid UM karyotype (11.4%). Patients with a polyploid tumor had larger tumors (15.61 vs. 13.13 mm, P = 0.004), and more often loss of heterozygosity of chromosome 3 (P = 0.003). No difference in occurrence of mutations between polyploid and diploid tumors was observed for BAP1, SF3B1, EIF1AX, GNAQ, and GNA11. Polyploidy did not affect survival (P = 0.143). BAP1 deficiency was the only significant independent prognostic predictor for patients with polyploid tumors, with a 16-fold increased hazard ratio (HR 15.90, P = 0.009). The prevalence of mutations in the UM related genes is not different in polyploid UM compared with diploid UM. Moreover, similar to patients with diploid UM, BAP1 mutation is the most significant prognostic predictor of metastasis in patients with polyploid UM.

BAP1 correlates with metastasis in polyploid uveal melanoma

PurposeMost of the Uvea melanoma (UM) display a near‐diploid karyotype with only a few chromosomal changes. In contrast to these simple aberrations 10% of the UM samples show a polyploid character (> 58 chromosomes) and were associated with unfavorable prognosis. This study attempts to gain insight in polyploidy in UM and supplement the old data with the current knowledge on mutations in UM specific genes.MethodsFluorescence‐In‐Situ‐Hybridization (FISH) and/or Single‐Nucleotide‐Polymorphism (SNP) array was used to determine the ploidy status. Tumors showing signs of polyploidy (range tri‐ tetraploidy) were further investigated. Immune‐histochemistry was used to determine the BAP1 expression and mutation analyses of BAP1 (coding regions) or the hotspots for the GNAQ, GNA11, SF3B1 and EIF1AX genes was carried out using Sanger Sequencing .ResultsPolyploidy was seen in 23 tumor samples. Fourteen of the UM patients developed metastases with a median follow‐up of 35 months. Thirteen tumors showed loss of BAP1 expression and all genetically tested polyploid tumors harbored a GNAQ or GNA11 mutation. SF3B1 mutations were found in three UM specimens and one of the tumors harbored an EIF1AX mutation. Univariate analyses showed a significant association with decreased survival for chromosome 1, 3 and 8 aberrations, SF3B1 wild type and a loss of BAP1 expression. In the multivariate analyses, BAP1 expression was the only independent prognostic marker within the polyploid tumors (HR 10.1; p = 0.008).ConclusionsAlso for the tumors displaying polyploidy loss of BAP1 expression is associated with an increased risk of metastatic disease.

Integrated Genomic Characterization of Papillary Thyroid Carcinoma

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Here, we describe the genomic landscape of 496 PTCs. We observed a low frequency of somatic alterations (relative to other carcinomas) and extended the set of known PTC driver alterations to include EIF1AX, PPM1D, and CHEK2 and diverse gene fusions. These discoveries reduced the fraction of PTC cases with unknown oncogenic driver from 25% to 3.5%. Combined analyses of genomic variants, gene expression, and methylation demonstrated that different driver groups lead to different pathologies with distinct signaling and differentiation characteristics. Similarly, we identified distinct molecular subgroups ofBRAF-mutant tumors, and multidimensional analyses highlighted a potential involvement of oncomiRs in less-differentiated subgroups. Our results propose a reclassification of thyroid cancers into molecular subtypes that better reflect their underlying signaling and differentiation properties, which has the potential to improve their pathological classification and better inform the management of the disease.

SF3B1 and EIF1AX mutations in uveal melanoma: a protective factor, or not?

AbstractPurpose The recent identification of mutations in the splicing factor SF3B1 and translation initiation factor EIF1AX prompted us to investigate the occurrence of these mutations in our uveal melanoma (UM) cohort.Methods Nineteen tumours were subjected to whole exome sequencing. In addition, the SF3B1 (exon 14) and EIF1AX (exon 1 and 2) mutation status was determined in 95 UM by Sanger sequencing.Results Mutations in SF3B1 were identified in 26% of UM and 19% harboured a mutation in either exon 1 or 2 of the EIF1AX gene. SF3B1 and EIF1AX mutations correlated significantly with good prognostic features such as spindle cell type, absence of closed vascular loops, positive BAP1 immunohistochemistry staining and disomy 3. Univariate analyses of EIF1AX mutated cases compared to those without EIF1AX mutations showed a significantly increase in disease‐free survival (DFS). Overall, the SF3B1 mutated cases did not show a significant difference in DFS compared to SF3B1 wild types. After stratifying for chromosome 3 status, patients with a disomy 3 UM and a SF3B1 mutation had a worse DFS compared to those with a disomy 3 UM and a wild type SF3B1 (P < 0.01).Conclusion SF3B1 and EIF1AX mutations occur in approximately a quarter of UM. Mutations in these genes associate with favourable prognostic features. In our study, we also reveal that patients with a normal chromosome 3 UM and a SF3B1 mutation have a higher risk of developing late metastasis.

Protein Synthesis Initiation Factor eIF-1A Is a Moderately Abundant RNA-binding Protein

Eukaryotic initiation factor (eIF) 1A (formerly called eIF-4C) is a small protein that promotes dissociation of 80 S ribosomes into subunits, stabilizes methionyl-tRNA binding to 40 S ribosomal subunits, and is required for the binding of mRNA to ribosomes. The sequence of eIF-1A derived from its cloned cDNA possesses a high frequency of basic residues and acidic residues at its N and C termini, respectively. Northwestern blotting with a fragment of mRNA indicates that eIF-1A binds RNA. Overexpression of the human eIF-1A cDNA in Escherichia coli and subsequent purification enabled us to prepare large quantities of active factor. The level of eIF-1A in HeLa cells determined by Western immunoblotting is 0.01% of total protein, which corresponds to 0.2 molecules of eIF-1A/ribosome. The moderate abundance means that eIF-1A is equal to or in excess of native 40 S subunits and suggests that the factor may not be limiting for protein synthesis, a conclusion reinforced by the failure of overproduced eIF-1A to stimulate translation rates in transiently transfected COS-1 cells. S1 nuclease protection and primer extension analyses show that eIF-1A mRNA possesses an unusually long 5'-untranslated leader that is very G/C-rich (72%). Unexpectedly, the mRNA is efficiently translated in HeLa cells as judged by polysome profile analyses.