Cuando el cáncer es una enfermedad rara

When a person inherits a mutation in a cancer susceptibility gene it means that he/she will have a high probability of developing cancer at an early age of onset and will live with several first and second degree familial members in the same situation. There are more than 200 clinical entities with cancer susceptibility and all of them have a familial and personal impact. Although their frequency is low, corresponding to around 5% of cancers, they have a high impact on the population. The identification of people at risk and their clinical follow up are important to provide adequate genetic counseling and help to reduce costs by focusing the different surveillance measures only on people with the highest probability of developing cancer. Determining the genes responsible and conducting a genetic study in families at risk constitute critical steps in this process. New technologies of massive sequencing have facilitated the search for genes associated with familial cancer. We expect to soon have a wide spectrum of the genetic bases of these syndromes and to be able to apply these results to clinical practice.Heredar una alteración en un gen de susceptibilidad al cáncer supone vivir con una probabilidad alta de desarrollar la enfermedad, con frecuencia más de una vez, y por lo general a una edad temprana. Y también convivir con otros familiares, padres, hijos, o hermanos, que pasan por idénticas circunstancias. Existen 200 entidades clínicas diferentes en las que se hereda la susceptibilidad al cáncer y todas ellas tienen un enorme impacto personal y familiar. Aunque en su mayoría son poco frecuentes, en su conjunto representan una parte sustancial, en torno al 5%, del conjunto de cánceres, por lo que también su impacto poblacional resulta importante. La identificación de estas personas o familias y su derivación a unidades especializadas para que reciban un adecuado asesoramiento genético y posterior seguimiento clínico contribuye a aliviar a las familias, a la vez que evita costes sanitarios innecesarios restringiendo las medidas de seguimiento solo a aquellos que las necesitan. En este proceso el conocimiento de los genes responsables y el estudio genético de las familias en riesgo es un paso de importancia crucial. Las nuevas técnicas de secuenciación masiva del exoma han facilitado la búsqueda de nuevos genes responsables del cáncer familiar y de síndromes de susceptibilidad al cáncer que a corto plazo proporcionarán un espectro más correcto y completo de los mismos y a medio plazo permitirán una aplicación masiva en la práctica clínica

Tenencia, acceso y uso de la tierra en el altiplano de Bolivia : informe narrativo final

Incluye el CD-ROM con informes finales y anexo

Marginalización de la agricultura campesina e indígena : dinámicas locales, seguridad y soberanía alimentaria

imaginada como si fuera un entorno sosegado con altos grados de autonomía y capacidad de autoabastecimiento. Sus formas comunitarias incluso han sido fuente de inspiración para quienes buscan respuestas al desarrollismo en crisis o se interesan en alternativas poscapitalistas. Este libro más bien muestra que las dinámicas contemporáneas han permeado con fuerza el mundo rural y afectado sus habilidades para alcanzar –por sí mismos– seguridad y soberanía alimentaria. Muchos sectores del agro podrían ser considerados o auto identificarse como agricultores familiares. El riesgo es que al incluir con poca rigurosidad una amplia gama de sectores podemos perder de vista cuál es nuestra unidad de análisis. Por eso hemos optado por utilizar el término de ‘agricultura campesina e indígena’ para referirnos a aquellas unidades productivas agropecuarias operadas por familias que están débil pero crecientemente conectadas al mercado de productos agrícolas y precariamente al mercado laboral. En términos de Shanin (1990; 5) consiste en pequeños productores del agro que apoyados por equipos de trabajo simples y a base de fuerza de trabajo familiar producen principalmente para su propio consumo y a su vez están subordinados a poderes externos..

Genetic variation in the NEIL2 DNA glycosylase gene is associated with oxidative DNA damage in BRCA2 mutation carriers

In this report, we have tried to gain molecular insight into a single nucleotide polymorphism (SNP) in the NEIL2 gene previously identified as "cancer risk modifier" for BRCA2 mutation carriers. To that end, we studied the role of this SNP (rs804271) on NEIL2 transcriptional regulation, oxidative DNA damage and genome instability in two independent set of samples: The first one was a series of eighty-six BRCA1 and BRCA2 mutation carriers and eighty non-carrier controls in which we evaluated the effect of the SNP on NEIL2 gene expression and oxidative DNA damage accumulation. The second was a set of twenty lymphoblastoid cell lines (LCLs), thirteen BRCA1 mutation carriers and seven non-carriers control, that were used to analyze the correlation between NEIL2 mRNA and/or protein levels, the oxidative and the double stranded break (DSB) DNA damage levels. Our results suggest that an excessive production of NEIL2 enzyme, associated with the SNP, may have a deleterious effect modifying cancer risk susceptibility in BRCA2 mutation carriers. We hypothesize that due to the SNP impact on NEIL2 transcriptional upregulation, a cascade of events may converge in the accumulation of oxidative DNA damage and its posterior conversion into DSBs for this specific group of patients.We thank Alicia Barroso her technical assistance. Also to Dr. Thomas Helleday, (Karolinska Institutet, Stockholm, Sweden) that kindly provided NEIL2 and UNG purified enzymes. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health. Additional funds were provided by the NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. Donors were enrolled at Biospecimen Source Sites funded by NCI/SAIC-Frederick, Inc. (SAIC-F) subcontracts to the National Disease Research Interchange (10XS170),Roswell Park Cancer Institute (10XS171), and Science Care, Inc. (X10S172). The Laboratory, Data Analysis, and Coordinating Center (LDACC) were funded through a contract (HHSN268201000029C) to The Broad Institute, Inc. Biorepository operations were funded through an SAIC-F subcontract to the Van Andel Institute (10ST1035). Additional data repository and project management were provided by SAIC-F (HHSN261200800001E). The Brain Bank was supported by supplements to University of Miami grants DA006227 & DA033684 and to contract N01MH000028. Statistical Methods development grants were made to the University of Geneva (MH090941 & MH101814), the University of Chicago (MH090951, MH090937, MH101820, MH101825), the University of North Carolina - Chapel Hill (MH090936 & MH101819), Harvard University (MH090948), Stanford University (MH101782), Washington University St Louis (MH101810), and the University of Pennsylvania (MH101822). The data used for the analyses described in this manuscript were obtained from: [insert, where appropriate] the GTEx Portal on 01/12/2015 and/or dbGaP accession number phs000424.v7.p2 on 01/10/2017.S

The wide spectrum of POT1 gene mutations correlates with multiple cancer types.

The POT1 protein forms part of the shelterin complex, which binds and protects telomeres. Germline mutations in the POT1 gene have recently been shown to be involved in tumors in different tissues such as familial colorectal, glioma and melanoma tumors, which demonstrate the importance of this gene. Recently, we uncovered a mutation in the POT1 gene (p.R117C) as causative of cardiac angiosarcomas in families with multiple tumors. Our in silico studies predicted that the POT1 p.R117C protein had lost the ability to interact with TPP1 and ssDNA. In vitro studies corroborated this prediction, and showed that this lack of function leads to abnormally long telomeres with increased fragility. In order to better understand the spectrum of mutations in the POT1 gene and its relation with tumorigenesis, we extended the study to families with multiple tumors (with and without angiosarcomas) and sporadic angiosarcomas and cardiac sarcomas. We found four new mutations that were not described previously and another patient carrying the previously described p.R117C mutation. In silico studies predicted that these new mutations were damaging in the same manner as previously described for the POT1 p.R117C mutation. These mutations were present in both, families and sporadic cases with angiosarcomas and sarcomas, although the major part was involved in families with AS and in cardiac tumors. The wide spectrum of mutations in the POT1 gene leading to different tumorigenesis processes demonstrates the general importance of this gene.pre-print252 K

A clinico-pathological and molecular analysis reveals differences between solitary (early and late-onset) and synchronous rectal cancer

Rectal cancer (RC) appears to behave differently compared with colon cancer. We aimed to analyze existence of different subtypes of RC depending on distinct features (age of onset and the presence of synchronous primary malignant neoplasms). We compared the clinicopathological, familial and molecular features of three different populations diagnosed with RC (early-onset RC [EORC], late-onset RC, and synchronous RC [SRC]). Eighty-five RCs were identified and were evaluated according to their microsatellite instability, CpG Island Methylator Phenotype (CIMP) and chromosomal instability, as assessed by Next Generation Sequencing and microarray-based comparative genomic hybridization approaches. The results were subjected to cluster analysis. SRCs displayed the most specific characteristics including a trend for the development of multiple malignant neoplasms, a greater proportion of CIMP-High tumors (75%) and more frequent genomic alterations. These findings were confirmed by a clustering analysis that stratified RCs according to their genomic alterations. We also found that EORCs exhibited their own features including an important familial cancer component and a remarkable rate of mutations in TP53 (53%). Together, heterogeneity in RC characteristics by age of disease-onset and SRC warrants further study to optimize tailored prevention, detection and intervention strategies—particularly among young adults.This work was funded by the Spanish Ministry of Health and Consumer Affairs and FEDER, Grant number PI16/01650 to José Perea, PI16/01920 to Rogelio González-Sarmiento, and PI14/00459 to Miguel Uriost

Comment on 'Distinct clinical outcomes of two CIMP-positive colorectal cancer subtypes based on a revised CIMP classification system'

This work was funded by Projects PI13/01741, PI13/01273, PI16/01920 and PI16/01650 from the Spanish Ministry of Health and Consumer Affairs and FEDER, and Mutua Madrileña Foundation (2012-0036), and was approved by the Ethics Committee of our Institution.Peer Reviewe

Intermediate-onset colorectal cancer: A clinical and familial boundary between both early and late-onset colorectal cancer

Comparative studies of colorectal cancer (CRC) according to the age of onset have found differences between early-onset CRC (EOCRC) and late-onset CRC (LOCRC). Using this as a starting point, we wished to determine whether intermediate-onset CRC (IOCRC) might also be considered as an independent group within CRC. We performed a retrospective comparative study of the clinicopathological and familial features, as well as of the symptoms and their duration, of a total of 272 subjects diagnosed with CRC classified into three groups according to the age-of-onset (98 EOCRC, 83 IOCRC and 91 LOCRC). The results show that from a clinicopathological point of view, IOCRC shared certain features with EOCRC (gender, prognosis), and with LOCRC (multiple primary CRCs), whereas it also had characteristics that were specific for IOCRC (mean number of associated polyps). A gradual progression was observed from EOCRC to LOCRC from a greater family aggregation to sporadic cases, in parallel with a change of Lynch Syndrome cases to the sporadic microsatellite instability pathway, with the IOCRC being a boundary group that is more related to EOCRC. With respect to symptoms, duration and correlation with stages, IOCRC appeared more similar to EOCRC. Clinically, IOCRC behaves as a transitional group between EOCRC and LOCRC, with features in common with both groups, but also with IOCRC-specific features. Excluding cases with familial cancer history, the awareness for EOCRC diagnosis should be extended to IOCRC.Wethank the Tumor Registry of the Pathology Department of the 12 de Octubre University Hospita lfor providing the paraffinembedded tissues,and Ron Hartong for his help with the English revision of this manuscript.S

Scarce evidence of the causal role of germline mutations in UNC5C in hereditary colorectal cancer and polyposis

Germline mutations in UNC5C have been suggested to increase colorectal cancer (CRC) risk, thus causing hereditary CRC. However, the evidence gathered thus far is insufficient to include the study of the UNC5C gene in the routine genetic testing of familial CRC. Here we aim at providing a more conclusive answer about the contribution of germline UNC5C mutations to genetically unexplained hereditary CRC and/or polyposis cases. To achieve this goal we sequenced the coding region and exon-intron boundaries of UNC5C in 544 familial CRC or polyposis patients (529 families), using a technique that combines pooled DNA amplification and massively parallel sequencing. A total of eight novel or rare variants, all missense, were identified in eight families. Co-segregation data in the families and association results in case-control series are not consistent with a causal effect for 7 of the 8 identified variants, including c.1882_1883delinsAA (p.A628K), previously described as a disease-causing mutation. One variant, c.2210G > A (p.S737N), remained unclassified. In conclusion, our results suggest that the contribution of germline mutations in UNC5C to hereditary colorectal cancer and to polyposis cases is negligible

De novo erythroleukemia chromosome features include multiple rearrangements, with special involvement of chromosomes 11 and 19

Erythroid leukemia (ERL or AML-M6) is an uncommon subtype of acute myeloid leukemia, the clinical, morphological, and genetic behavior of which needs further characterization. We analyzed a homogeneous group of 23 de novo AML-M6 patients whose bone marrow cells showed complex karyotypes. We also analyzed eight leukemia cell lines with erythroid phenotype, performing detailed molecular cytogenetic analyses, including spectral karyotyping (SKY) in all samples. The main features are: (1) A majority of patients (56%) had hypodiploidy. Loss of genetic material was the most common genetic change, especially monosomies of chromosome 7 or 18, and deletions of chromosome arm 5q. Taken together, 87% of the cases displayed aberrations involving chromosome 5 or 8. (2) We describe a novel, cryptic, and recurrent translocation, t(11;19)(p11.2;q13.1). Another translocation, t(12;21)(p11.2;q11.2), was found to be recurrent in a patient with ERL and in the K562 cell line. (3) MLL gene rearrangements were detected in 20% of cases (three translocations and three amplifications) and, overall, we defined 52 rearrangements (excluding deletions) with a mean of 2.3 translocations per patient. (4) Of the structural aberrations, 21% involved chromosomes 11 and 19. Most of the rearrangements were unbalanced; only 13 reciprocal translocations were observed. The general picture of chromosomal aberrations in cell lines did not reflect what occurred in patient samples. However, both primary samples and cell lines shared three common breakpoints at 19q13.1, 20q11.2, and 21q11.2. This is the first molecular cytogenetic description of the karyotype abnormalities present in patients with ERL. It should assist in the identification of genes involved in erythroleukemogenesis