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De La Paz M.P.,Instituto Of Investigacion En Enfermedades Raras Iier
Advances in Experimental Medicine and Biology

Rare Diseases Epidemiology is a novel action field still largely unexplored. However, Rare Diseases is a topic of growing interest at world level. The aims of this chapter are to revise useful epidemiological tools and define areas where epidemiology can help improve the rare disease knowledge, and facilitate policy decisions taking into account the real burden of rare diseases in society. This chapter also seeks to describe: the problems of coding and classification of diseases, measuring disease frequency, the study designs and association studies, the causality, the evolution from descriptive to epigenetic epidemiology and the natural history of disease. One of the major challenges facing analytical epidemiology and clinical epidemiological research into rare diseases is that genes can be involved in both aetiology and prognosis. Despite the many similarities between genetic association studies and classic observational epidemiological studies, the former pose several specific limitations, including an unprecedented volume of new data and the likelihood of very small individual effects, as well other limitations. Selecting the appropriate pathway from among all those available, i.e. the one that best relates genes from the various known regions and disease mechanisms, is crucial for the success of this type of studies. © Springer Science+Business Media B.V. 2010. Source

Tanic M.,Human Genetics Group | Tanic M.,Serbian Institute for Oncology and Radiology of Serbia | Yanowski K.,Human Genetics Group | Andres E.,Bioinformatics Unit | And 7 more authors.
Genomics Data

Hereditary breast cancer constitutes only 5-10% of all breast cancer cases and is characterized by strong family history of breast and/or other associated cancer types. Only ~. 25% of hereditary breast cancer cases carry a mutation in BRCA1 or BRCA2 gene, while mutations in other rare high and moderate-risk genes and common low penetrance variants may account for additional 20% of the cases. Thus the majority of cases are still unaccounted for and designated as BRCAX tumors. MicroRNAs are small non-coding RNAs that play important roles as regulators of gene expression and are deregulated in cancer. To characterize hereditary breast tumors based on their miRNA expression profiles we performed global microarray miRNA expression profiling on a retrospective cohort of 80 FFPE breast tissues, including 66 hereditary breast tumors (13 BRCA1, 10 BRCA2 and 43 BRCAX), 10 sporadic breast carcinomas and 4 normal breast tissues, using Exiqon miRCURY LNA™ microRNA Array v.11.0. Here we describe in detail the miRNA microarray expression data and tumor samples used for the study of BRCAX tumor heterogeneity (Tanic et al., 2013) and biomarkers associated with positive BRCA1/2 mutation status (Tanic et al., 2014). Additionally, we provide the R code for data preprocessing and quality control. © 2014 The Authors. Source

Lara B.,Hospital Universitario Arnau Of Vilanova | Martinez M.T.,Hospital Universitario Doce Of Octubre | Blanco I.,Board of Directors of the Alpha 1 Antitrypsin Deficiency Spanish Registry | Hernandez-Moro C.,Institute Biologia y Genetica Molecular CSIC UVa | And 8 more authors.
Respiratory Research

Background: Severe Alpha-1 Antitrypsin (AAT) deficiency is a hereditary condition caused by mutations in the SERPINA1 gene, which predisposes to lung emphysema and liver disease. It is usually related to PI*Z alleles, and less frequent to rare and null (QO) alleles. Null-AAT alleles represent the end of a continuum of variants associated with profound AAT deficiency and extremely increased risk of emphysema.Methods: A family with severe AAT deficiency was analyzed to achieve genetic diagnosis. The complete exons and introns of the SERPINA1 gene were sequenced and transcriptional analysis by RT-PCR was performed to characterize the effect of splicing variants found in the patients. In addition, a minigene MGserpa1_ex1b-1c was cloned into the pSAD vector to in vitro investigate the independent impact of variants on splicing process.Results: We report a new identified null allele (PI*QOMadrid) in two adult siblings with practically no detectable serum AAT. The PI*QOMadrid allele consist of a duplication of the thymine (T) in position +2 of the donor splice site of exon 1C (+2dupT). In these two subjects, PI*QOMadrid occurred in compound heterozygote combination with the previously described variant PI*QOPorto. Both QOMadrid and QOPorto variants are located very close together in a regulatory region of the SERPINA1 gene. Analysis of transcripts revealed that QOMadrid variant prevented the expression of transcripts from exon 1C, and then normally spliced RNA products are not expected in the liver of these patients. In addition, aberrant splicing patterns of both variants were clearly distinguished and quantified by functional in vitro assays lending further support to their pathogenicity.Conclusion: Finding pathogenic mutations in non-coding regions of the SERPINA1 highlight the importance that regulatory regions might have in the disease. Regulatory regions should be seriously considered in discordant cases with severe AAT deficiency where no coding mutations were found. © 2014 Lara et al.; licensee BioMed Central Ltd. Source

Tanic M.,Human Genetics Group | Tanic M.,Serbian Institute for Oncology and Radiology of Serbia | Andres E.,Bioinfo Unit | M Rodriguez-Pinilla S.,Fundacion Jimenez Diaz | And 7 more authors.
British Journal of Cancer

Background:Hereditary breast cancer comprises 5-10% of all breast cancers. Mutations in two high-risk susceptibility genes, BRCA1 and BRCA2, along with rare intermediate-risk genes and common low-penetrance alleles identified, altogether explain no more than 45% of the high-risk breast cancer families, although the majority of cases are unaccounted for and are designated as BRCAX tumours. Micro RNAs have called great attention for classification of different cancer types and have been implicated in a range of important biological processes and are deregulated in cancer pathogenesis.Methods:Here we have performed an exploratory hypothesis-generating study of miRNA expression profiles in a large series of 66 primary hereditary breast tumours by microarray analysis.Results:Unsupervised clustering analysis of miRNA molecular profiles revealed distinct subgroups of BRCAX tumours, 'normal-like' BRCAX-A, 'proliferative' BRCAX-B, 'BRCA1/2-like' BRCAX-C and 'undefined' BRCAX-D subgroup. These findings introduce a new insight in the biology of hereditary breast cancer, defining specific BRCAX subgroups, which could help in the search for novel susceptibility pathways in hereditary breast cancer.Conclusion:Our data demonstrate that BRCAX hereditary breast tumours can be sub-classified into four previously unknown homogenous groups characterised by specific miRNA expression signatures and histopathological features. © 2013 Cancer Research UK. All rights reserved. Source

Martinez-Delgado B.,Human Genetics Group | Martinez-Delgado B.,Instituto Of Investigacion En Enfermedades Raras Iier | Gallardo M.,Telomeres and Telomerase Group | Tanic M.,Human Genetics Group | And 7 more authors.
Breast Cancer Research and Treatment

Telomere shortening is a common event involved in malignant transformation. Critically short telomeres may trigger chromosomal aberrations and produce genomic instability leading to cancer development. Therefore, telomere shortening is a frequent molecular alteration in early stages of many epithelial tumors and in breast cancer correlates with stage and prognosis. A better understanding of the involvement of short telomeres in tumors may have a significant impact on patient management and the design of more specific treatments. To understand the role of telomere length (TL) in breast cancer etiology we measured the length of individual telomere signals in single cells by using quantitative telomere in situ hybridization in paraffin-embedded tissue from hereditary and sporadic breast cancers. A total of 104 tumor tissue samples from 75 familial breast tumors (BRCA1, n = 14; BRCA2, n = 13; non-BRCA1/2, n = 48) and 29 sporadic tumors were analyzed. Assessment of telomere signal intensity allowed estimation of the mean TL and related variables, such as percentage of critically short telomeres and percentage of cells with short telomeres. These data were correlated with the immunohistochemical expression of molecular breast cancer markers. Hereditary BRCA1, BRCA2, and non-BRCA1/2 tumors were characterized by shorter TL comparing to sporadic tumors. Considering all tumors, tumor grade was a strong risk factor determining the proportion of short telomeres or short telomere cells. Moreover, some histopathological features appeared to be differentially associated to hereditary or sporadic subgroups. Short telomeres correlated with ER-negative tumors in sporadic cases but not in familial cases, whereas a high level of apoptosis was associated with shorter telomeres in hereditary BRCA1 and BRCA2 tumors. In addition, TL helped to define a subset of non-BRCA1/2 tumors with short telomeres associated with increased expression of antiapoptotic proteins. These findings highlight the potential interest of TL measurements as markers of aggressiveness in breast cancer. © 2013 Springer Science+Business Media New York. Source

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