Biology subjects

Maia, A.-T.

Publications and source records attributed to Maia, A.-T..

7 recordsLinked to original sources

bioRxiv2025

Combined expression of FOXO and Tribbles proteins predicts survival of glioma patients

BackgroundGliomas, particularly high-grade variants such as glioblastoma, remain therapeutically challenging with poor survival outcomes. Current biomarkers inadequately stratify patients for therapy selection, monitoring, and early detection of progression. The FOXO transcription factors and Tribbles pseudokinases, key regulators of the PI3K/AKT pathway, have been implicated in cancer progression but their prognostic value in gliomas is unclear. The aim of this study was to determine whether transcriptional profiles of FOXO and Tribbles family members predict survival in glioma patients better than established biomarkers. MethodsUsing RNA-seq data from The Cancer Genome Atlas (TCGA, n = 705) and Chinese Glioma Genome Atlas (CGGA, n = 1018), along with microarray datasets (REMBRANDT, n = 552; Gravendeel, n = 268), we analyzed mRNA levels of FOXO1/3/4/6 and TRIB1/2/3. Survival analysis was performed via Kaplan-Meier curves, log-rank tests, and concordance indices. Gene expression differences across tumor grades and molecular subgroups were assessed using Students t-test. ResultsHigh FOXO1 and low FOXO3/4 mRNA levels, combined with elevated TRIB1/2/3 expression, formed a signature significantly associated with worse survival across all cohorts. This signature stratifies grade 4 gliomas, with a median survival difference of 4.5 months. Grade 4 tumors exhibited elevated FOXO1 and TRIB1/2/3 but reduced FOXO3/4 levels compared to lower-grade gliomas. ConclusionsThe FOXO/Tribbles transcriptional signature robustly predicts survival in glioma patients. These findings highlight its potential as a biomarker for patient stratification and a therapeutic target for high-grade gliomas. Key PointsO_LIFOXO/Tribbles mRNA signature predicts glioma survival status. Our analysis identifies a distinct transcriptional signature - characterized by high FOXO1 and TRIB1/2/3 levels along with low FOXO3 and FOXO4 - that consistently predicts poor prognosis across glioma cohorts. This FOXO/Tribbles signature demonstrates great prognostic power, particularly in grade 4 gliomas, providing an improved tool for risk stratification and clinical decision-making. C_LIO_LIHigh FOXO1 and Tribbles levels mark aggressive glioblastoma tumors. We show that elevated expression of FOXO1 and Tribbles pseudokinases is enriched in glioblastoma (GB) and grade 4 astrocytomas. These tumors, known for their aggressiveness and therapy resistance, are consistently associated with this unfavorable mRNA profile. This suggests a functional role for FOXO1 and Tribbles in glioma progression and highlights them as promising biomarkers and therapeutic targets. C_LIO_LIMulti-cohort validation (TCGA, CGGA) confirms prognostic robustness. The predictive FOXO/Tribbles expression pattern was validated across four large and independent datasets (TCGA, CGGA, REMBRANDT, and Gravendeel), demonstrating consistency despite differences in platform and population. This multi-cohort validation reinforces the robustness and generalizability of this transcriptional signature for predicting survival outcomes in glioma patients. C_LI Importance of the StudyGlioblastoma and high-grade gliomas have dismal prognoses, yet current biomarkers fail to adequately guide therapy. This study identifies a novel transcriptional signature - combining FOXO transcription factors and Tribbles pseudokinases - that robustly predicts survival in glioma patients stratifying aggressive tumors. Using multi-cohort validation (TCGA, CGGA, REMBRANDT), we demonstrate that elevated FOXO1 and Tribbles (TRIB1/2/3) levels, coupled with reduced FOXO3/4, correlate with poor outcomes in grade 4 gliomas. This signature is enriched in glioblastomas, highlighting its link to therapy resistance. Unlike prior studies focusing on individual proteins, our integrated analysis reveals their collective prognostic power, offering a pathway-specific biomarker for patient stratification. These findings provide a translational framework for targeting FOXO/Tribbles in precision oncology, addressing an urgent need for improved therapeutic strategies in neuro-oncology.

cancer biology↗

bioRxiv2021

Preferential allelic expression of PIK3CA mutations is frequent in breast cancer and is prognostically significant

PIK3CA mutations are the most common in breast cancer, particularly in the estrogen receptor positive cohort, but the benefit of PI3K inhibitors has had limited success compared with approaches targeting other less common mutations. We found allelic imbalances in the expression of PIK3CA in normal breast tissue and mapped a germline candidate regulatory variant. An imbalance was also frequently observed in the expression of the missense mutant and wild-type PIK3CA alleles in breast tumors from METABRIC and TCGA projects. Moreover, although 60% of tumors preferentially expressed the mutant allele, 10% did preferentially express the wild-type allele. Mechanistically, we show that these imbalances are more frequently due to regulatory variants in cis than altered copy-number and predict that somatic variants have a more significant role than germline ones. We further found that imbalanced allelic expression between mutant and wild-type alleles due to cis-regulatory variants associated with poor prognosis (p=0.0081). Interestingly, ER+, PR+, and Her2- tumors expressing very low levels of the mutant allele had the poorest prognosis (DSS <7.5yrs for ER+ and PR+ tumors and <5yrs for Her2- tumors). Hence, our work provides compelling evidence to support the clinical utility of PIK3CA allelic expression in breast cancer in identifying this cohort of low mutant allele expressing patients of poorer prognosis, who will unlikely benefit from PI3K inhibitors. Furthermore, our work establishes a new model of differential regulation of critical cancer-promoting genes.

cancer biology↗

bioRxiv2021

quincunx: an R package to query, download and wrangle PGS Catalog data

MotivationThe Polygenic Score (PGS) Catalog is a recently established open database of published polygenic scores that, to date, has collected, curated, and made available 721 polygenic scores from over 133 publications. The PGS Catalog REST API is the only method allowing programmatic access to this resource. ResultsHere, we describe quincunx, an R package that provides the first client interface to the PGS Catalog REST API. quincunx enables users to query and quickly retrieve, filter and integrate metadata associated with polygenic scores, as well as polygenic scoring files in tidy table format. Availabilityquincunx is freely available under an MIT License, and can be accessed from https://github.com/maialab/quincunx.

bioinformatics↗

bioRxiv2020

Differential expression between African-ancestry and White patients diagnosed with Triple-Negative Breast Cancer: EGFR, Myc, Bcl2 and β-Catenin as ancestry-associated markers

PurposeTriple-negative breast cancer (TNBC) has a higher incidence, a younger age of onset, and a more aggressive behavior in African-ancestry women. Biological disparities have been suggested as an important factor influencing the ancestry-associated TNBC discrepancy. In this study, we sought to identify ancestry-associated differential gene and protein expression between African-ancestry and White TNBC patients, controlling for patients menopause status and pathological staging at diagnosis. MethodsDifferential gene expression analyses (DGEA) were performed using RNA-sequencing data from The Cancer Genome Atlas (TCGA). Gene set enrichment analysis (GSEA) and Ingenuity Pathway Analysis (IPA), with focus on network design, were performed to highlight candidate genes for further validation through immunohistochemistry of TNBC samples from patients followed in Portugal. ResultsWith 52 African-American and 90 White TNBC patients included, TCGAs data corroborate that African-American patients have a higher TNBC incidence (28.42% vs 11.89%, p<0.0001). Particularly, premenopausal and stage II disease African-American patients also have significantly lower survival probability, comparing with White patients (log-rank p=0.019 and 0.0038, respectively). DGEA results suggest that expression profile differences are more associated with TNBC staging than with patients menopause status. Hippo pathway and cellular community gene sets are downregulated, while breast cancer gene set is upregulated in African-Americans, comparing with White TNBC patients. Furthermore, MAPK pathway gene set is upregulated when controlling for stage II disease. Due to their central role in highly scored networks resulted from IPAs network design, EGFR, Myc and Bcl2 genes were selected for further validation through immunohistochemistry. We also included {beta}-Catenin in the validation study as it is consensually reported to be required in TNBC tumorigenesis. Although patients used in the DGEA and in the immunohistochemistry experiments are geographically and culturally distinct, both groups of African-ancestry patients are mostly of western-African ancestry and, interesting, differential gene and protein expression matched. ConclusionsWe found ancestry-associated gene expression patterns between African-ancestry and White TNBCs, particularly when controlling for menopause status or staging. EGFR, Myc, Bcl2 and {beta}-catenin gene and protein differential expression matching results in distinct populations suggest these markers as being important indicators of TNBCs ancestry-associated development.

cancer biology↗

bioRxiv2019

Allele-specific miRNA-binding analysis identifies candidate target genes for breast cancer risk

Most breast cancer (BC) risk-associated variants (raSNPs) identified in genome-wide association studies (GWAS) are believed to cis-regulate the expression of genes. We hypothesise that cis-regulatory variants contributing to disease risk may be affecting miRNA genes and/or miRNA-binding. To test this we adapted two miRNA-binding prediction algorithms -- TargetScan and miRanda -- to perform allele-specific queries, and integrated differential allelic expression (DAE) and expression quantitative trait loci (eQTL) data, to query 150 genome-wide significant (P [≤] 5 x 10-8) raSNPs, plus proxies. We found that no raSNP mapped to a miRNA gene, suggesting that altered miRNA targeting is an unlikely mechanism involved in BC risk. Also, 11.5% (6 out of 52) raSNPs located in 3UTRs of putative miRNA target genes were predicted to alter miRNA::mRNA pair binding stability in five candidate target genes. Of these, we propose RNF115, at locus 1q21.1, as a strong novel target gene associated with BC risk, and re-inforce the role of miRNA mediated cis-regulation at locus 19p13.11. We believe that integrating allele-specific querying in miRNA-binding prediction, and data supporting cis-regulation of expression, improves the identification of candidate target genes in BC risk, as well as in other common cancers and complex diseases.

cancer biology↗

bioRxiv2019

Alternative splicing regulation by GWAS risk loci for breast cancer

Recent genome-wide association studies (GWAS) have revealed the association of hundreds of single nucleotide polymorphisms (SNPs) with breast cancer (BC) risk, which mostly locate in non-coding regions, suggesting regulatory roles to the causal variants. Functional characterisation of GWAS loci has been biased towards the effect of regulatory SNPs on transcription factor binding. Here we set out to determine the extent of the contribution of breast cancer risk-associated SNPs to alternative splicing (AS).\n\nWe screened genome-wide significant (P [≤] 5 x 10-8) BC risk SNPs for association with AS, using expression and genotype data from normal breast samples, from the GTEx project. We identified four splicing quantitative trait loci (sQTL). In locus 6p22.1, rs6456883 is a significant cis-sQTL for the expression of ZNF311 gene isoforms. Three SNPs in locus 8p23.3, rs6682326, rs3008282 and rs2906324, were also identified as significant cis-sQTLs/svQTLs for the expression of RPL23AP53 gene isoforms. In-silico functional analysis revealed that these variants can potentially alter enhancer splicing elements within the target genes.\n\nOur work shows that BC risk-associated variants at two loci are associated with AS isoforms in normal breast tissue, thus demonstrating that AS plays an important role in breast cancer susceptibility. Furthermore, it supports that all cis-regulatory mechanisms should be considered in the functional characterisation of risk loci.

cancer biology↗

bioRxiv2019

gwasrapidd: an R package to query, download and wrangle GWAS Catalog data

MotivationThe NHGRI Catalog of Published Genome-Wide Association Studies (GWAS) Catalog has collected, curated, and made available data from over 3 900 studies. The recently developed GWAS Catalog REST API is the only method allowing programmatic access to this resource.\n\nResultsHere, we describe gwasrapidd, an R package that provides a client interface to the GWAS Catalog REST API, representing an important software counterpart to the server-side component. gwasrapidd enables users to quickly retrieve, filter and integrate data with comprehensive bioinformatics analysis tools, which is particularly critical for those looking into functional characterisation of risk loci.\n\nAvailabilitygwasrapidd is freely available under an MIT License, and can be accessed from https://github.com/ramiromagno/gwasrapidd.

bioinformatics↗