A Novel Epigenetic Phenotype Associated With the Most Aggressive Pathway of Bladder Tumor Progression

International audienceBackground: Epigenetic silencing can extend to whole chromosomal regions in cancer. There have been few genome-wide studies exploring its involvement in tumorigenesis.Methods: We searched for chromosomal regions affected by epigenetic silencing in cancer by using Affymetrix microarrays and real-time quantitative polymerase chain reaction to analyze RNA from 57 bladder tumors compared with normal urothelium. Epigenetic silencing was verified by gene re-expression following treatment of bladder cell lines with 5-aza-deoxycytidine, a DNA demethylating agent, and trichostatin A, a histone deacetylase inhibitor. DNA methylation was studied by bisulfite sequencing and histone methylation and acetylation by chromatin immunoprecipitation. Clustering was used to distinguish tumors with multiple regional epigenetic silencing (MRES) from those without and to analyze the association of this phenotype with histopathologic and molecular types of bladder cancer. The results were confirmed with a second panel of 40 tumor samples and extended in vitro with seven bladder cancer cell lines. All statistical tests were two-sided.Results: We identified seven chromosomal regions of contiguous genes that were silenced by an epigenetic mechanism. Epigenetic silencing was not associated with DNA methylation but was associated with histone H3K9 and H3K27 methylation and histone H3K9 hypoacetylation. All seven regions were concordantly silenced in a subgroup of 26 tumors, defining an MRES phenotype. MRES tumors exhibited a carcinoma in situ-associated gene expression signature (25 of 26 MRES tumors vs 0 of 31 non-MRES tumors, P < 10⁻¹⁴), rarely carried FGFR3 mutations (one of 26 vs 22 of 31 non-MRES tumors, P < 10⁻¹⁶), and contained 25 of 33 (76%) of the muscle-invasive tumors. Cell lines derived from aggressive bladder tumors presented epigenetic silencing of the same regions.Conclusions: We have identified an MRES phenotype characterized by the concomitant epigenetic silencing of several chromosomal regions, which, in bladder cancer, is specifically associated with the carcinoma in situ gene expression signature

Clustering heterochromatin: Sir3 promotes telomere clustering independently of silencing in yeast

Arrays of Sir3 binding sites at telomeres are sufficient to promote long-range trans-telomere interactions

Cervical determinants of anal HPV infection and high-grade anal lesions in women: a collaborative pooled analysis

Cervical cancer screening might contribute to the prevention of anal cancer in women. We aimed to investigate if routine cervical cancer screening results-namely high-risk human papillomavirus (HPV) infection and cytohistopathology-predict anal HPV16 infection, anal high-grade squamous intraepithelial lesions (HSIL) and, hence, anal cancer.International Agency for Research on Cance

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

Infections et néoplasies du col utérin associées aux papillomavirus humains chez les femmes seropositives pour le virus de l'immunodeficience humaine (influence de la trithérapie antiretrovirale)

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Le cancer du col de l’utérus, nouvelles stratégies de dépistage ?

National audienceLe cancer du col de l'utérus reste le deuxième cancer le plus fréquent chez les femmes dans le monde, alors que son dépistage, par le frottis, existe depuis plus de 50 ans. En France, le cancer du col de l'utérus est le huitième cancer féminin avec 3 387 nouveaux cas estimés en 200

Vaccins contre les papillomavirus humains (HPV)

L’âge de la vaccination contre le papillomavirus a été récemment modifié par le Haut conseil de la santé publique (HCSP). Les éléments qui ont contribué à l’élaboration de ce nouvel avis sont détaillés dans cet article, en particulier les résultats des études qui ont décrit les facteurs d’acceptabilité des vaccins par les familles et par les praticiens. L’hypothèse d’une vaccination avec seulement deux doses est posée à partir des résultats d’études concluant à l’efficacité d’un schéma simplifié. Enfin, les premiers résultats d’efficacité clinique du vaccin quadrivalent, tant sur les condylomes que sur les lésions précancéreuses du col de l’utérus, sont présentés. Au plan virologique, une diminution de la prévalence de l’infection par les virus dont les génotypes sont compris dans les vaccins a été rapportée dans plusieurs études. Cette diminution, importante et précoce après la mise en place des vaccins, semble en partie liée à l’existence d’une immunité de groupe