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Caronia D.,Human Genotyping Unit CeGen | Martin M.,Hospital Universitario Gregorio Maranon | Sastre J.,Hospital Universitario San Carlos | De La Torre J.,Hospital Universitario San Carlos | And 8 more authors.
Clinical Cancer Research | Year: 2011

Purpose: Hand-foot syndrome (HFS) is one of the most relevant dose-limiting adverse effects of capecitabine, an oral prodrug of 5-fluorouracil used in the standard treatment of breast and colorectal cancer. We investigated the association between grade 3 HFS and genetic variations in genes involved in capecitabine metabolism. Experimental Design: We genotyped a total of 13 polymorphisms in the carboxylesterase 2 (CES2) gene, the cytidine deaminase (CDD) gene, the thymidine phosphorylase (TP) gene, the thymidylate synthase (TS) gene, and the dihydropyrimidine dehydrogenase (DPD) gene in 130 patients treated with capecitabine. We correlated these polymorphisms with susceptibility to HFS. Results: We found an association of HFS appearance with rs532545 located in the promoter region of CDD (OR=2.02, 95% CI=1.02-3.99, P=0.039). Because we found no association between the rs532545 genotype and CDD mRNA expression in Epstein-Barr virus lymphoblastoid cells, we explored additional genetic variations across the CDD promoter. We found an insertion, rs3215400, in linkage disequilibrium with rs532545 (D′ = 0.92), which was more clearly associated with HFS (OR = 0.51, 95% CI = 0.27-0.95, P = 0.028) in patients and with total CDD gene expression (P = 0.004) in lymphoblastoid cells. In silico analysis suggested that this insertion might create a binding site for the transcriptional regulator E2F. Using a SNaPshot assay in lymphoblastoid cells, we observed a 5.7-fold increased allele-specific mRNA expression from the deleted allele. Conclusions: The deleted allele of rs3215400 shows an increased allele-specific expression and is significantly associated with an increased risk of capecitabine-induced HFS. ©2011 AACR.

Bogliolo M.,Autonomous University of Barcelona | Bogliolo M.,Institute Salud Carlos III | Schuster B.,University of Wurzburg | Stoepker C.,VU University Amsterdam | And 23 more authors.
American Journal of Human Genetics | Year: 2013

Fanconi anemia (FA) is a rare genomic instability disorder characterized by progressive bone marrow failure and predisposition to cancer. FA-associated gene products are involved in the repair of DNA interstrand crosslinks (ICLs). Fifteen FA-associated genes have been identified, but the genetic basis in some individuals still remains unresolved. Here, we used whole-exome and Sanger sequencing on DNA of unclassified FA individuals and discovered biallelic germline mutations in ERCC4 (XPF), a structure-specific nuclease-encoding gene previously connected to xeroderma pigmentosum and segmental XFE progeroid syndrome. Genetic reversion and wild-type ERCC4 cDNA complemented the phenotype of the FA cell lines, providing genetic evidence that mutations in ERCC4 cause this FA subtype. Further biochemical and functional analysis demonstrated that the identified FA-causing ERCC4 mutations strongly disrupt the function of XPF in DNA ICL repair without severely compromising nucleotide excision repair. Our data show that depending on the type of ERCC4 mutation and the resulting balance between both DNA repair activities, individuals present with one of the three clinically distinct disorders, highlighting the multifunctional nature of the XPF endonuclease in genome stability and human disease. © 2013 The American Society of Human Genetics.

Melchor L.,Human Genetics Group | Melchor L.,Institute of Cancer Research | Benitez J.,Human Genetics Group | Benitez J.,A+ Network
Human Genetics | Year: 2013

Familial breast cancer represents a minor percentage of all human breast cancers. Mutations in two high susceptibility genes BRCA1 and BRCA2 explain around 25 % of familial breast cancers, while other high, moderate and low susceptibility genes explain up to 20 % more of breast cancer families. Thus, it is important to decipher the genetic architecture of families that show no mutations to improve genetic counselling. The comprehensive description of familial breast cancer using different techniques and platforms has shown to be very valuable for better patient diagnosis, tumour surveillance, and ultimately patient treatment. This review focuses on the complex landscape of pathological, protein, genetic and genomic features associated with BRCA1-, BRCA2-, and non-BRCA1/BRCA2-related cancers described up to date. Special emphasis deserves the coexistence of distinct molecular breast cancer subtypes, the development of tumour classifiers to predict BRCA1/2 mutations, and the last insights from recent whole genome sequencing studies and miRNA profiling. © 2013 Springer-Verlag Berlin Heidelberg.

Comino-Mendez I.,Hereditary Endocrine Cancer Group | Comino-Mendez I.,Research Center Biomedica En Red Of Enfermedades Raras Ciberer | Gracia-Aznarez F.J.,Research Center Biomedica En Red Of Enfermedades Raras Ciberer | Gracia-Aznarez F.J.,Human Genetics Group | And 33 more authors.
Nature Genetics | Year: 2011

Hereditary pheochromocytoma (PCC) is often caused by germline mutations in one of nine susceptibility genes described to date, but there are familial cases without mutations in these known genes. We sequenced the exomes of three unrelated individuals with hereditary PCC (cases) and identified mutations in MAX, the MYC associated factor X gene. Absence of MAX protein in the tumors and loss of heterozygosity caused by uniparental disomy supported the involvement of MAX alterations in the disease. A follow-up study of a selected series of 59 cases with PCC identified five additional MAX mutations and suggested an association with malignant outcome and preferential paternal transmission of MAX mutations. The involvement of the MYC-MAX-MXD1 network in the development and progression of neural crest cell tumors is further supported by the lack of functional MAX in rat PCC (PC12) cells and by the amplification of MYCN in neuroblastoma and suggests that loss of MAX function is correlated with metastatic potential. © 2011 Nature America, Inc. All rights reserved.

Zajac M.,Human Genetics Group | Gomez G.,Bioinformatics Unit | Benitez J.,Human Genetics Group | Benitez J.,Center for Biomedical Networking Research on Rare Diseases | And 2 more authors.
BMC Medical Genomics | Year: 2010

Background: HSP90 may be a favorable target for investigational therapy in breast cancer. In fact, the HSP90 inhibitor, 17AAG, currently has entered in phase II clinical trials as an anticancer agent in breast and other tumors. Since HSP90 inhibition leads to global depletion of oncogenic proteins involved in multiple pathways we applied global analysis using gene array technology to study new genes and pathways involved in the drug response in breast cancer. Methods: Gene expression profiling using Whole Human Genome Agilent array technology was applied to a total of six sensitive and two resistant breast cancer cell lines pre-treatment and treated with the 17AAG for 24 and 48 hours. Results: We have identified a common molecular signature of response to 17AAG composed of 35 genes which include novel pharmacodynamic markers of this drug. In addition, different patterns of HSP90 client transcriptional changes after 17AAG were identified associated to the sensitive cell lines, which could be useful to evaluate drug effectiveness. Finally, we have found differentially expressed pathways associated to resistance to 17AAG. We observed significant activation of NF-κB and MAPK pathways in resistant cells upon treatment, indicating that these pathways could be potentially targeted to overcome resistance. Conclusions: Our study shows that global mRNA expression analysis is a useful strategy to examine molecular effects of drugs, which allowed us the discovery of new biomarkers of 17AAG activity and provided more insights into the complex mechanism of 17AAG resistance. © 2010 Zajac et al; licensee BioMed Central Ltd.

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