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- Allelic expression imbalance of PIK3CA mutations is frequent in breast cancer and prognostically significantPublication . Correia, Lizelle; Magno, Ramiro; Xavier, JM; Almeida, Bernardo; Duarte, Isabel; Esteves, Filipa; Ghezzo, Marinella; Eldridge, Matthew; Sun, Chong; Bosma, Astrid; Mittempergher, Lorenza; Marreiros, Ana; Bernards, Rene; Caldas, Carlos; Chin, Suet-Feung; Maia, Ana-TeresaPIK3CA 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 a frequent allelic expression imbalance between the missense mutant and wild-type PIK3CA alleles in breast tumors from the METABRIC (70.2%) and the TCGA (60.1%) projects. When considering the mechanisms controlling allelic expression, 27.7% and 11.8% of tumors showed imbalance due to regulatory variants in cis, in the two studies respectively. Furthermore, preferential expression of the mutant allele due to cis-regulatory variation is associated with poor prognosis in the METABRIC tumors (P = 0.031). Interestingly, ER-, PR-, and HER2+ tumors showed significant preferential expression of the mutated allele in both datasets. Our work provides compelling evidence to support the clinical utility of PIK3CA allelic expression in breast cancer in identifying patients of poorer prognosis, and those with low expression of the mutated allele, who will unlikely benefit from PI3K inhibitors. Furthermore, our work proposes a model of differential regulation of a critical cancer-promoting gene in breast cancer.
- Effects of BRCA2 cis-regulation in normal breast and cancer risk amongst BRCA2 mutation carriersPublication . Maia, Ana-Teresa; Antoniou, Antonis C.; O'Reilly, Martin; Samarajiwa, Shamith; Dunning, Mark; Kartsonaki, Christiana; Chin, Suet-Feung; Curtis, Christina; McGuffog, Lesley; Domchek, Susan M.; Easton, Douglas F.; Peock, Susan; Frost, Debra; Evans, D. Gareth; Eeles, Ros; Izatt, Louise; Adlard, Julian; Eccles, Diana; Sinilnikova, Olga M.; Mazoyer, Sylvie; Stoppa-Lyonnet, Dominique; Gauthier-Villars, Marion; Faivre, Laurence; Venat-Bouvet, Laurence; Delnatte, Capucine; Nevanlinna, Heli; Couch, Fergus J.; Godwin, Andrew K.; Caligo, Maria Adelaide; Barkardottir, Rosa B.; Chen, Xiaoqing; Beesley, Jonathan; Healey, Sue; Caldas, Carlos; Chenevix-Trench, Georgia; Ponder, Bruce A. J.Introduction: Cis-acting regulatory single nucleotide polymorphisms (SNPs) at specific loci may modulate penetrance of germline mutations at the same loci by introducing different levels of expression of the wild-type allele. We have previously reported that BRCA2 shows differential allelic expression and we hypothesize that the known variable penetrance of BRCA2 mutations might be associated with this mechanism. Methods: We combined haplotype analysis and differential allelic expression of BRCA2 in breast tissue to identify expression haplotypes and candidate cis-regulatory variants. These candidate variants underwent selection based on in silico predictions for regulatory potential and disruption of transcription factor binding, and were functionally analyzed in vitro and in vivo in normal and breast cancer cell lines. SNPs tagging the expression haplotypes were correlated with the total expression of several genes in breast tissue measured by Taqman and microarray technologies. The effect of the expression haplotypes on breast cancer risk in BRCA2 mutation carriers was investigated in 2,754 carriers. Results: We identified common haplotypes associated with differences in the levels of BRCA2 expression in human breast cells. We characterized three cis-regulatory SNPs located at the promoter and two intronic regulatory elements which affect the binding of the transcription factors C/EBP alpha, HMGA1, D-binding protein (DBP) and ZF5. We showed that the expression haplotypes also correlated with changes in the expression of other genes in normal breast. Furthermore, there was suggestive evidence that the minor allele of SNP rs4942440, which is associated with higher BRCA2 expression, is also associated with a reduced risk of breast cancer (per-allele hazard ratio (HR) = 0.85, 95% confidence interval (CI) = 0.72 to 1.00, P-trend = 0.048). Conclusions: Our work provides further insights into the role of cis-regulatory variation in the penetrance of disease-causing mutations. We identified small-effect genetic variants associated with allelic expression differences in BRCA2 which could possibly affect the risk in mutation carriers through altering expression levels of the wild-type allele.
- Epigenetic therapy in urologic cancers: an update on clinical trialsPublication . Faleiro, Inês; Leão, Ricardo; Binnie, Alexandra; De Mello, Ramon Andrade; Maia, Ana Teresa; Castelo-Branco, PedroEpigenetic dysregulation is one of many factors that contribute to cancer development and progression. Numerous epigenetic alterations have been identified in urologic cancers including histone modifications, DNA methylation changes, and microRNA expression. Since these changes are reversible, efforts are being made to develop epigenetic drugs that restore the normal epigenetic patterns of cells, and many clinical trials are already underway to test their clinical potential. In this review we analyze multiple clinical trials (n=51) that test the efficacy of these drugs in patients with urologic cancers. The most frequently used epigenetic drugs were histone deacetylase inhibitors followed by antisense oligonucleotides, DNA methyltransferase inhibitors and histone demethylase inhibitors, the last of which are only being tested in prostate cancer. In more than 50% of the clinical trials considered, epigenetic drugs were used as part of combination therapy, which achieved the best results. The epigenetic regulation of some cancers is still matter of research but will undoubtedly open a window to new therapeutic approaches in the era of personalized medicine. The future of therapy for urological malignancies is likely to include multidrug regimens in which epigenetic modifying drugs will play an important role.
- TOX3 mutations in breast cancerPublication . Jones, James Owain; Chin, Suet-Feung; Wong-Taylor, Li-An; Leaford, Donna; Ponder, Bruce A. J.; Caldas, Carlos; Maia, Ana TeresaTOX3 maps to 16q12, a region commonly lost in breast cancers and recently implicated in the risk of developing breast cancer. However, not much is known of the role of TOX3 itself in breast cancer biology. This is the first study to determine the importance of TOX3 mutations in breast cancers. We screened TOX3 for mutations in 133 breast tumours and identified four mutations (three missense, one in-frame deletion of 30 base pairs) in six primary tumours, corresponding to an overall mutation frequency of 4.5%. One potentially deleterious missense mutation in exon 3 (Leu129Phe) was identified in one tumour (genomic DNA and cDNA). Whilst copy number changes of 16q12 are common in breast cancer, our data show that mutations of TOX3 are present at low frequency in tumours. Our results support that TOX3 should be further investigated to elucidate its role in breast cancer biology.
- THOR is a targetable epigenetic biomarker with clinical implications in breast cancerPublication . Apolónio, Joana; Dias, João S.; Fernandes, Mónica T.; Komosa, Martin; Lipman, Tatiana; Zhang, Cindy H.; Leão, Ricardo; Lee, Donghyun; Nunes, Nuno M.; Maia, Ana-Teresa; Morera, José L.; Vicioso, Luis; Tabori, Uri; Castelo-Branco, PedroBreast cancer (BC) is the most frequently diagnosed cancer and a leading cause of death among women worldwide. Early BC is potentially curable, but the mortality rates still observed among BC patients demon‑ strate the urgent need of novel and more efective diagnostic and therapeutic options. Limitless self-renewal is a hallmark of cancer, governed by telomere maintenance. In around 95% of BC cases, this process is achieved by telom‑ erase reactivation through upregulation of the human telomerase reverse transcriptase (hTERT). The hypermethylation of a specifc region within the hTERT promoter, termed TERT hypermethylated oncological region (THOR) has been associated with increased hTERT expression in cancer. However, its biological role and clinical potential in BC have never been studied to the best of our knowledge. Therefore, we aimed to investigate the role of THOR as a biomarker and explore the functional impact of THOR methylation status in hTERT upregulation in BC.
- Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriersPublication . Peterlongo, Paolo; Chang-Claude, Jenny; Moysich, Kirsten B.; Rudolph, Anja; Schmutzler, Rita K.; Simard, Jacques; Soucy, Penny; Eeles, Rosalind A.; Easton, Douglas F.; Hamann, Ute; Wilkening, Stefan; Nevanlinna, Heli; Aittomaeki, Kristiina; van Os, Theo A. M.; Jensen, Uffe Birk; Meijers-Heijboer, Hanne E. J.; van der Hout, Annemarie H.; Vreeswijk, Maaike P. G.; Rappaport, Christine; Hoogerbrugge, Nicoline; Arason, Adalgeir; Jonson, Lars; Ausems, Margreet G. E. M.; van der Baan, Frederieke H.; van Doorn, Helena C.; Collee, J. Margriet; Olah, Edith; Diez, Orland; Laitman, Yael; Blanco, Ignacio; Lazaro, Conxi; Lose, Felicity; Osorio, Ana; Kaulich, Daphne Geschwantler; Brunet, Joan; Giannini, Giuseppe; Chiquette, Jocelyne; Teixeira, Manuel R.; Olswold, Curtis; Couch, Fergus J.; Lindor, Noralane M.; Wang, Xianshu; Walker, Logan C.; Martinez-Bouzas, Cristina; Szabo, Csilla I.; Offit, Kenneth; von Wachenfeldt, Anna; Papi, Laura; Ehrencrona, Hans; Corines, Marina; Barwell, Julian; Pfeiler, Georg; Tea, Muy-Kheng M.; Phelan, Catherine M.; Rhiem, Kerstin; Greene, Mark H.; Mai, Phuong L.; Rennert, Gad; Mulligan, Anna Marie; Martayan, Aline; Glendon, Gord; Tchatchou, Sandrine; Maia, Ana-Teresa; Walker, Lisa; Montagna, Marco; Benitez, Javier; Andrulis, Irene L.; Niederacher, Dieter; Askmalm, Marie Stenmark; Borg, Ake; Kuchenbaecker, Karoline B.; Tibiletti, Maria Grazia; McGuffog, Lesley; Barrowdale, Daniel; Healey, Sue; Lee, Andrew; Conway, Edye E.; Izatt, Louise; Pharoah, Paul D. P.; Chenevix-Trench, Georgia; Antoniou, Antonis C.; Steinemann, Doris; Matricardi, Laura; Radice, Paolo; Friedman, Eitan; Lubinski, Jan; Jakubowska, Anna; Blazer, Kathleen R.; Garcia, Encarna B. Gomez; Olopade, Olufunmilayo I.; Side, Lucy E.; Nussbaum, Robert L.; Nathanson, Katherine L.; Domchek, Susan M.; Rebbeck, Timothy R.; Vratimos, Athanassios; Plendl, Hansjoerg; Arun, Banu K.; Porteous, Mary E.; Karlan, Beth Y.; Orsulic, Sandra; Lester, Jenny; Chung, Wendy K.; Kennedy, M. John; Miron, Alex; Southey, Melissa C.; Goldgar, David E.; Fostira, Florentia; Buys, Saundra S.; Weitzel, Jeffrey N.; Janavicius, Ramunas; Kast, Karin; Dorfling, Cecilia M.; van Rensburg, Elizabeth J.; Ding, Yuan Chun; Neuhausen, Susan L.; Rogers, Mark T.; Hansen, Thomas V. O.; Gerdes, Anne-Marie; Arnold, Norbert; Garber, Judy E.; Ejlertsen, Bent; Feliubadalo, Lidia; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Scuvera, Giulietta; Barile, Monica; Ficarazzi, Filomena; Ditsch, Nina; Mariette, Frederique; Fortuzzi, Stefano; Morrison, Patrick J.; Cybulski, Cezary; Platte, Radka; Viel, Alessandra; Jacobs, Lauren; Donaldson, Alan; Brewer, Carole; Foo, Claire; Evans, D. Gareth R.; Frost, Debra; Eccles, Diana; Brady, Angela; Gronwald, Jacek; Cook, Jackie; Tischkowitz, Marc; Varon-Mateeva, Raymonda; Robson, Mark E.; Wappenschmidt, Barbara; Adlard, Julian; Toland, Amanda Ewart; Davidson, Rosemarie; Hodgson, Shirley V.; Ellis, Steve; Spurdle, Amanda B.; Cole, Trevor; Godwin, Andrew K.; Claes, Kathleen; Van Maerken, Tom; Zhang, Liying; Meindl, Alfons; Gehrig, Andrea; Sutter, Christian; Bojesen, Anders; Wang-Gohrke, Shan; Durda, Katarzyna; Engel, Christoph; Chen, Bowang; Bressac-de Paillerets, Brigitte; Buecher, Bruno; Delnatte, Capucine; Joseph, Vijai; Houdayer, Claude; Stoppa-Lyonnet, Dominique; Damiola, Francesca; Coupier, Isabelle; Jaworska-Bieniek, Katarzyna; Pedersen, Inge Sokilde; Barjhoux, Laure; Venat-Bouvet, Laurence; Golmard, Lisa; Rookus, Matti A.; Boutry-Kryza, Nadia; Berger, Andreas; Sinilnikova, Olga M.; Caron, Olivier; Pujol, Pascal; Sukiennicki, Grzegorz; Mazoyer, Sylvie; Belotti, Muriel; Thomassen, Mads; Piedmonte, Marion; Friedlander, Michael L.; Rodriguez, Gustavo C.; Copeland, Larry J.; Singer, Christian F.; Schmidt, MarjankaK.; de la Hoya, Miguel; Rantala, Johanna; Perez Segura, PedroBackground: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes. Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. Results: The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies. (C)2014 AACR.
- Matrix Gla protein expression: a complex process involving the use of alternative promoters, multiple splicing events and microRNAsPublication . Cancela, Leonor; Laizé, Vincent; Conceição, N.; Tiago, Daniel; Maia, Ana-Teresa; Bensimon-Brito, A.; Gavaia, Paulo J.Matrix Gla protein (MGP) is a secreted vitamin K-dependent protein (VKD) located in the extracellular matrix and capable of binding calcium through its -carboxyglutamate residues. Although identified in 1983, transcriptional and post-transcriptional mechanisms regulating its expression remain unclear.
- Quincunx: an R package to query, download and wrangle PGS catalog dataPublication . Magno, Ramiro; Duarte, Isabel; Maia, Ana-TeresaFor two decades, GWAS identified individual variants associated with risk for complex diseases. These associations can be combined into polygenic scores (PGS) aiming at quantifying an individual’s risk to disease, inform on prognosis and even treatment response (Lambert et al., 2019). Broadly, PGS use summary statistics produced by GWAS to calculate a weighted sum of trait-associated alleles carried by each individual, in which the weights correspond to the per-allele size effects. Initially used to validate associations with disease and uncover interactions between variants, PGS have been more challenging to implement in the clinic. In 2020, over 1400 publications on PGS appeared in PubMed, raising the need for a standardized distribution of studies’ key data, assuring their wide evaluation and accurate use. The Polygenic Score (PGS) Catalog, created in 2019, is a publicly available, manually curated database of PGS and relevant metadata, that responds to this need (Lambert et al., 2020). Its current release [date 2021-02-03] includes data from 133 publications and 721 PGS associated with 194 traits. Currently, data is accessed via three ways: (i) the web graphical user interface (GUI); (ii) by downloading database dumps; and (iii) the recent PGS Catalog representational state transfer (REST) application programming interface (API), the preferred method for batch analyses.
- Gwasrapidd: an R package to query, download and wrangle GWAS catalog dataPublication . Magno, Ramiro; Maia, Ana-TeresaThe National Human Genome Research Institute Catalog of Published Genome-Wide Association Studies (GWAS) Catalog has collected, curated and made available data from over 7100 studies. The recently developed GWAS Catalog representational state transfer (REST) application programming interface (API) is the only method allowing programmatic access to this resource.
- Allele-specific miRNA-binding analysis identifies candidate target genes for breast cancer riskPublication . Jacinta-Fernandes, Ana; Xavier, Joana M.; Magno, Ramiro; Lage, Joel; Maia, Ana-TeresaMost breast cancer (BC) risk-associated single-nucleotide polymorphisms (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 microRNA (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≤5×10-8 ) 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 3'-untranslated regions of putative miRNA target genes were predicted to alter miRNA::mRNA (messenger RNA) 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 reinforce 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.