Incidence et caractéristiques des hémopathies malignes au cours de l’artérite à cellules géantes

Introduction L’arterite a cellules geantes (ACG) est une vascularite du sujet âge au cours de laquelle les cellules mononucleees jouent un role physiopathologique majeur. L’hematopoiese clonale est un phenomene dont la frequence augmente egalement avec l’âge et qui conduit a l’apparition de mutations responsables de la survenue d’hemopathies malignes (HM) ou de mutations des cellules effectrices de l’immunite responsables de pathologies inflammatoires. Notre hypothese est qu’il existe une association specifique entre certaines HM et l’ACG. Nous avons pu etudier cette hypothese en croisant les donnees du registre des hemopathies de Cote d’Or (RHEMCO) et celles de tous les laboratoires d’anat…

MYST3/NCOA2-Induced Acute Myeloid Leukemia in Transgenic Fish

Abstract The MYST3/NCOA2 (MOZ/TIF2) fusion gene generated by the inv(8)(p11q13) chromosomal abnormality was described in a specific subgroup of acute myeloid leukemias (AML) that represents less than 5% of AML4/5. This abnormality fuses MYST3 (MOZ), a member of the MYST family of histone acetyl-transferases (HAT) to NCOA2 (TIF2), a member of the p160 HAT family. The transforming properties of MYST3/NCOA2 were demonstrated in mouse committed myeloid progenitors in vitro and in vivo. Hematopoiesis is very similar in zebrafish and in higher vertebrates. Homologues of a large number of genes involved in mammalian myelopoiesis were identified in this animal model. We have recently shown that nco…

PET-adapted treatment for newly diagnosed advanced Hodgkin lymphoma (AHL2011): a randomised, multicentre, non-inferiority, phase 3 study

International audience; Background: Increased-dose bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPescalated) improves progression-free survival in patients with advanced Hodgkin lymphoma compared with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), but is associated with increased risks of haematological toxicity, secondary myelodysplasia or leukaemia, and infertility. We investigated whether PET monitoring during treatment could allow dose de-escalation by switching regimen (BEACOPPescalated to ABVD) in early responders without loss of disease control compared with standard treatment without PET monitoring.Methods: AHL201…

Co-activation of VEGF and NMDA receptors promotes synaptic targeting of AMPA receptors

« Fausses et autres » artérites temporales

Resume L’arterite a cellules geantes (ACG) est la plus frequente des vascularites affectant l’artere temporale (AT). Neanmoins, d’autres types de pathologies vasculaires, qu’il s’agisse de vascularite ou non, peuvent toucher l’AT. Parmi les vascularites, on peut citer les vascularites necrosantes, en particulier les vascularites associees aux anticorps anti-cytoplasme des polynucleaires neutrophiles (ANCA) qui peuvent affecter les petits vaisseaux peri-adventitiels de la paroi de l’AT et mimer certains symptomes de l’ACG, ces derniers n’etant generalement pas isoles, ce qui doit faire rechercher les ANCA. Certaines vascularites infectieuses peuvent egalement toucher l’AT comme l’infection p…

Expression séquentielle du TGFβ1 et de son récepteur de type 1 selon la pathologie initiale du transplant rénal. Relation avec la néphropathie chronique de l’allogreffe ?

But du travail La nephropathie chronique de l’allogreffe (NCA) qui se traduit cliniquement par un dysfonctionnement chronique du transplant renal, reste la principale cause de perte tardive du transplant renal. Ses mecanismes sont multiples et encore mal compris. Le but de ce travail est d’etudier l’expression du TGFβ1 et de son recepteur de type 1 en fonction de la pathologie initiale et de rechercher un lien avec la NCA. Materiel et methodes Trente quatre transplantes renaux ont ete inclus dans cette etude. Les biopsies du transplant renal, realisees lors de dysfonctionnement ou a titre systematique ont ete classees, selon le delai ecoule apres la transplantation, en biopsie precoces (del…

Injection of Donor-Derived OX62+ Splenic Dendritic Cells With Anti-CD4 Monoclonal Antibody Generates CD4+CD25+FOXP3+ Regulatory T Cells That Prolong Allograft Skin Survival Indefinitely and Abrogate Production of Donor-Specific Antibodies in a Rat Model

Abstract Objective To examine in a rat model the ability of donor dendritic cells and anti-CD4 monoclonal antibody (mAb) to generate donor-specific CD4+CD25+ regulatory T cells (Tregs) and to evaluate the capacity of these Tregs to prolong skin allograft survival and abrogate the production of donor-specific antibodies after skin grafting. Materials and Methods OX62+ (nonplasmacytoid) splenic dendritic cells were isolated from Fischer rats using magnetic beads and injected (2 × 10 6 ) into Lewis rat recipients with or without treatment with a nondepleting anti-CD4 (W3/25) mAb. After 4 weeks, splenic CD4+CD25+FOXP3+ T cells were harvested using magnetic beads from conditioned animals and inj…

The heterogeneity of changes in incidence and survival among lymphoid malignancies in a 30-year French population-based registry.

Our specialized population-based registry has allowed us to explore changes in incidence and survival by subtype over the last 30 years. Between 1980 and 2009, 4790 cases of lymphoid malignancies were registered using the International Classification of Diseases for Oncology. The incidence rate of lymphoid malignancies was 20.5 per 100,000 inhabitants per year, and ranged from 0.1 to 4 according to subtype. Five-year net survival was 65%, and ranged from 41% to 93% according to subtype. We observed an increase in 5-year net survival between the periods 1980-1989 and 2000-2009 (58% vs. 70%). This was observed in most but not all subtypes. Our long-standing population-based registry allowed u…

Haemolytic-uraemic syndrome during severe lupus nephritis: efficacy of plasma exchange

Systemic lupus erythematosus (SLE) has been described as a cause of thrombotic microangiopathy, especially thrombotic thrombocytopenic purpura (TTP). Haemolytic-uraemic syndrome (HUS) is less frequent in SLE. We report a case of such an association during an episode of severe lupus nephritis in a young woman, who was successfully treated with steroids, cyclophosphamide and especially plasma exchange with plasma replacement. This report highlights the importance of recognising atypical HUS in SLE patients by looking for schistocytes in case of haemolytic anemia with a negative antiglobulin test, in order to begin plasma exchange.

Abstract LB-017: HSP110 sustains aberrant NFkB signaling in activated B-cell diffuse large B-cell lymphoma through MyD88 stabilization

Abstract Diffuse large B cell lymphoma (DLBCL) is an aggressive lymphoproliferative disorder of B lymphocytes accounting for 30 % of adult Non Hodgkin Lymphoma (NHL). Among DLBCL, Activated B Cell - DLBCL (ABC-DLBCL) is the most aggressive form and has a poor prognosis. Heat-shock proteins (HSPs) are molecular chaperons highly expressed in cancer cells and implicated in resistance to radio- and chemotherapy. Therefore, HSPs are envisioned as therapeutic targets in many cancers. Among the different HSPs, HSP110 has been recently identified as a pro-survival factor in germinal center-derived DLBCL (GC-DLBCL), through stabilization of the GC-DLBCL oncogene Bcl-6. Here, we have explored if HSP1…

Copy number variations inDCC/18q andERBB2/17q are associated with disease-free survival in microsatellite stable colon cancer

We conducted a prospective study to assess the prognostic impact of selected copy number variations (CNVs) in stage II-III microsatellite stable (MSS) colon cancer. A total of 401 patients were included from 01/2004 to 01/2009. The CNVs in 8 selected target genes, DCC/18q, EGFR/7p, TP53/17p, BLK/8p, MYC/8q, APC/5q, ERBB2/17q, and STK6/20q, were detected using a quantitative multiplex polymerase chain reaction of short fluorescent fragment (QMPSF) method. The primary end-point was the impact of the CNVs on the 4-year disease-free survival (DFS). The recurrence rate at 4 years was 20.9%, corresponding to 14% stage II patients vs 31% stage III patients (p<0.0001). The 4-year DFS was significan…

Transcription intermediary factor 1γ is a tumor suppressor in mouse and human chronic myelomonocytic leukemia.

Transcription intermediary factor 1γ (TIF1γ) was suggested to play a role in erythropoiesis. However, how TIF1γ regulates the development of different blood cell lineages and whether TIF1γ is involved in human hematological malignancies remain to be determined. Here we have shown that TIF1γ was a tumor suppressor in mouse and human chronic myelomonocytic leukemia (CMML). Loss of Tif1g in mouse HSCs favored the expansion of the granulo-monocytic progenitor compartment. Furthermore, Tif1g deletion induced the age-dependent appearance of a cell-autonomous myeloproliferative disorder in mice that recapitulated essential characteristics of human CMML. TIF1γ was almost undetectable in leukemic ce…

Infarctus du myocarde au cours de l’artérite à cellules géantes : étude de cohorte

Introduction Le risque d’evenement cardiovasculaire est accru au cours de l’arterite a cellules geantes (ACG), en particulier dans les premiers mois suivant le diagnostic de la vascularite [1] . L’objectif de ce travail etait de decrire les caracteristiques des infarctus du myocarde (IDM) survenant chez des patients atteints d’ACG et de les comparer avec des IDM survenant chez des patients ne presentant pas d’ACG au moment de leur IDM. Patients et methodes Les patients atteints d’ACG ont ete identifies parmi la liste des biopsies d’artere temporale (BAT) qui montraient des lesions d’ACG et qui avaient ete analysees entre le 1er janvier 2001 et le 31 decembre 2016 dans les deux laboratoires …

Injection of donor-derived splenic dendritic cells plus a nondepleting anti-CD4 monoclonal antibody to prolong primary skin graft survival indefinitely and abrogate the production of donor-specific antibodies in the Fischer-to-Lewis rat combination.

Abstract We have previously shown that injection of donor-derived Fischer rat OX62+ dendritic cells plus an anti-CD4 monoclonal antibody generates donor-specific CD4+CD25+FoxP3+ regulatory T cells in Lewis rats spleens. The regulatory T cells indefinitely prolonged the survival of skin graft from Fischer rat and abrogated the antidonor antibody response. We have now shown that an injection of 2 × 10 6 donor-derived OX62+ dendritic cells plus 2 mg nondepleting anti-CD4 monoclonal antibody (W3/25) at 28 days before grafting induced indefinite skin graft survival in this combination; whereas an injection on day −1 prolonged it only to 50 days. This effect is donor specific. In both cases, we s…

Identification of novel, clonally stable, somatic mutations targeting transcription factors PAX5 and NKX2-3, the epigenetic regulator LRIF1, and BRAF in a case of atypical B-cell chronic lymphocytic leukemia harboring a t(14;18)(q32;q21)

Diagnosis of B-cell chronic lymphocytic leukemia (B-CLL) is usually straightforward, involving clinical, immunophenotypic (Matutes score), and (immuno)genetic analyses (to refine patient prognosis for treatment). CLL cases with atypical presentation (e.g., Matutes ≤ 3) are also encountered, and for these diseases, biology and prognostic impact are less clear. Here we report the genomic characterization of a case of atypical B-CLL in a 70-yr-old male patient; B-CLL cells showed a Matutes score of 3, chromosomal translocation t(14;18)(q32;q21) (BCL2/IGH), mutated IGHV, deletion 17p, and mutations in BCL2, NOTCH1 (subclonal), and TP53 (subclonal). Quite strikingly, a novel PAX5 mutation that w…

Specific norovirus interaction with Lewis x and Lewis a on human intestinal inflammatory mucosa during refractory inflammatory bowel disease

Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are progressive diseases affecting millions of people each year. Flare-ups during IBD result in severe mucosal alterations of the small intestine (in CD) and in the colon and rectum (in CD and UC).

General oxidative stress during doxorubicin-induced cardiotoxicity in rats: Absence of cardioprotection and low antioxidant efficiency of alpha-lipoic acid

International audience; To evaluate the effects of alpha-lipoic acid (AL) in a model of doxorubicin (DOX)-induced cardiotoxicity, male Wistar rats were treated with DOX (1 mg/kg/d; 10 d) in combination or not with AL (50 mg/kg/d; 15 d). Plasma oxidative stress was determined by hydroperoxides (ROOH) and the ascorbyl radical/ascorbate ratio. One and two months later, the functional parameters of the hearts were determined in vivo by catheterization and cardiac oxidative stress was assessed by malonedialdehyde (MDA) and O₂*⁻ (dihydroethidium fluorescence) content in tissue. After two months, body weight was higher in the DOX-AL group than in DOX (+16%), but this was due to ascites. Histologic…

Th1 and Th17 lymphocytes expressing CD161 are implicated in giant cell arteritis and polymyalgia rheumatica pathogenesis.

International audience; OBJECTIVE: Giant cell arteritis (GCA) is the most frequently occurring vasculitis in elderly individuals, and its pathogenesis is not fully understood. The objective of this study was to decipher the role of the major CD4+ T cell subsets in GCA and its rheumatologic form, polymyalgia rheumatica (PMR). METHODS: A prospective study of the phenotype and the function of major CD4+ T cell subsets (Th1, Th17, and Treg cells) was performed in 34 untreated patients with GCA or PMR, in comparison with 31 healthy control subjects and with the 27 treated patients who remained after the 7 others withdrew. RESULTS: Compared with control subjects, patients with GCA and patients wi…

Stroke associated with giant cell arteritis: a population-based study

Background Giant cell arteritis (GCA) is the most common vasculitis in people ≥50 years and can be associated with stroke. We aimed to evaluate the epidemiology and characteristics of stroke in patients with GCA. Methods All patients with a biopsy-proven diagnosis of GCA were identified among residents of the city of Dijon, France (152 000 inhabitants), between 2001 and 2012 using a prospective database. Among these, patients who suffered from stroke were retrieved by crossing data from the population-based Dijon Stroke Registry. Demographics and clinical features were recorded. We considered that the stroke was GCA-related if the stroke revealed GCA or occurred between the onset of symptom…

Immunologic effects of rituximab on the human spleen in immune thrombocytopenia

Abstract Immune thrombocytopenia (ITP) is an autoimmune disease with a complex pathogenesis. As in many B cell–related autoimmune diseases, rituximab (RTX) has been shown to increase platelet counts in some ITP patients. From an immunologic standpoint, the mode of action of RTX and the reasons underlying its limited efficacy have yet to be elucidated. Because splenectomy is a cornerstone treatment of ITP, the immune effect of RTX on this major secondary lymphoid organ was investigated in 18 spleens removed from ITP patients who were treated or not with RTX. Spleens from ITP individuals had follicular hyperplasia consistent with secondary follicles. RTX therapy resulted in complete B-cell de…

Automatic Evaluation of Histological Prognostic Factors Using Two Consecutive Convolutional Neural Networks on Kidney Samples

BACKGROUND AND OBJECTIVES: The prognosis of patients undergoing kidney tumor resection or kidney donation is linked to many histologic criteria. These criteria notably include glomerular density, glomerular volume, vascular luminal stenosis, and severity of interstitial fibrosis/tubular atrophy. Automated measurements through a deep-learning approach could save time and provide more precise data. This work aimed to develop a free tool to automatically obtain kidney histologic prognostic features. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In total, 241 samples of healthy kidney tissue were split into three independent cohorts. The “Training” cohort (n=65) was used to train two convoluti…

Calreticulin Mutations in Myeloproliferative Neoplasms: Comparison of Three Diagnostic Methods

International audience; Calreticulin (CALR) mutations have recently been reported in 70-84% of JAK2V617F-negative myeloproliferative neoplasms (MPN), and this detection has become necessary to improve the diagnosis of MPN. In a large single-centre cohort of 298 patients suffering from Essential Thrombocythemia (ET), the JAK2V617F, CALR and MPL mutations were noted in 179 (60%), 56 (18.5%) and 13 (4.5%) respectively. For the detection of the CALR mutations, three methods were compared in parallel: high-resolution melting-curve analysis (HRM), product-sizing analysis and Sanger sequencing. The sensitivity for the HRM, product-sizing analysis and Sanger sequencing was 96.4%, 98.2% and 89.3% re…

Development of primary early-onset colorectal cancers due to biallelic mutations of the FANCD1/BRCA2 gene

International audience; Fanconi anaemia (FA) is characterized by progressive bone marrow failure, congenital anomalies, and predisposition to malignancy. In a minority of cases, FA results from biallelic FANCD1/BRCA2 mutations that are associated with early-onset leukaemia and solid tumours. Here, we describe the clinical and molecular features of a remarkable family presenting with multiple primary colorectal cancers (CRCs) without detectable mutations in genes involved in the Mendelian predisposition to CRCs. We unexpectedly identified, despite the absence of clinical cardinal features of FA, a biallelic mutation of the FANCD1/BRCA2 corresponding to a frameshift alteration (c.1845_1846del…

Autosomal-recessive SASH1 variants associated with a new genodermatosis with pigmentation defects, palmoplantar keratoderma and skin carcinoma

SASH1 (SAM and SH3 domain-containing protein 1) is a tumor suppressor gene involved in the tumorigenesis of a spectrum of solid cancers. Heterozygous SASH1 variants are known to cause autosomal-dominant dyschromatosis. Homozygosity mapping and whole-exome sequencing were performed in a consanguineous Moroccan family with two affected siblings presenting an unclassified phenotype associating an abnormal pigmentation pattern (hypo- and hyperpigmented macules of the trunk and face and areas of reticular hypo- and hyperpigmentation of the extremities), alopecia, palmoplantar keratoderma, ungueal dystrophy and recurrent spinocellular carcinoma. We identified a homozygous variant in SASH1 (c.1849…

Specific enrichment of 2-arachidonoyl-lysophosphatidylcholine in carotid atheroma plaque from type 2 diabetic patients

IF 3.942; International audience; Background and aims: Diabetic patients are at high risk of stroke and coronary artery disease. Recent data suggest that arachidonic acid metabolism is altered in diabetic conditions and that these alterations contribute to accelerated atherosclerosis. Little is known about how these alterations affect the metabolism and the proportions of different lipid species within the atherosclerotic plaque. The aim of our study was to perform a targeted lipidomic analysis of human atherosclerotic lesions, with a specific focus on PUFA-containing lipid species, to reveal differences in the fatty-acid composition of plaque in diabetic patients compared with non-diabetic…

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HSP27: A Therapeutic Target in Myelofibrosis

Abstract Myelofibrosis (MF) is the most aggressive myeloproliferative neoplasms (MPN) with the highest degree of morbidity and mortality, including progressive bone marrow fibrosis resulting into bone marrow failure. JAK2 kinase inhibitors have been successfully used for a few years in MPN and more particularly for MF treatment. Despite their beneficial effects on spleen size and symptoms, JAK2 inhibitors induce low molecular and survival responses underscoring the urgent need for other therapeutic approaches. Recently, heat shock protein 90 (HSP90) - known to stabilize JAK2 - has been reported as a promising therapeutic target in MPN. However HSP90 inhibitors show toxicity and induce the e…

HSP110 sustains chronic NF-κB signaling in activated B cell diffuse large B cell lymphoma through MyD88 stabilization

International audience; Activated B cell diffuse large B cell lymphoma (ABC-DLBCL) is an aggressive lymphoproliferative disorder involving chronic NF-κB activation. Several mutations in the BCR and the MyD88 signaling pathway components, such as MyD88 L265P, are implicated in this aberrant activation. Among heat-shock proteins, HSP110 has recently been identified as a pro- survival and/or proliferation factor in many cancers but its role in ABC-DLBCL survival mechanisms remained to be established. We observed that shRNA-mediated HSP110 silencing decreased the survival of several ABC-DLBCL cell lines, decreased IgM-MyD88 co-localization and subsequent NF-κB signaling. Conversely, over-expres…

Why do results conflict regarding the prognostic value of the methylation status in colon cancers? The role of the preservation method.

Abstract Background In colorectal carcinoma, extensive gene promoter hypermethylation is called the CpG island methylator phenotype (CIMP). Explaining why studies on CIMP and survival yield conflicting results is essential. Most experiments to measure DNA methylation rely on the sodium bisulfite conversion of unmethylated cytosines into uracils. No study has evaluated the performance of bisulfite conversion and methylation levels from matched cryo-preserved and Formalin-Fixed Paraffin Embedded (FFPE) samples using pyrosequencing. Methods Couples of matched cryo-preserved and FFPE samples from 40 colon adenocarcinomas were analyzed. Rates of bisulfite conversion and levels of methylation of …

MOZ/TIF2-induced acute myeloid leukaemia in transgenic fish.

The inv(8)(p11q13) chromosomal abnormality, described in acute myeloid leukaemias (AML), fuses the histone acetyl-transferase (HAT) MYST3 (MOZ) gene with another HAT gene, NCOA2 (TIF2). We generated a transgenic zebrafish in which the MYST3/NCOA2 fusion gene was expressed under control of the spi1 promoter. An AML developed in 2 of 180 MYST3/NCOA2-EGFP-expressing embryos, 14 and 26 months after injection of the fusion gene in a one-cell embryo, respectively. This leukaemia was characterised by an extensive invasion of kidneys by myeloid blast cells. This model, which is the first zebrafish model of AML, demonstrates the oncogenic potency of MYST3/NCOA2 fusion gene.

A critical role for VEGF and VEGFR2 in NMDA receptor synaptic function and fear-related behavior

Vascular endothelial growth factor (VEGF) is known to be required for the action of antidepressant therapies but its impact on brain synaptic function is poorly characterized. Using a combination of electrophysiological, single-molecule imaging and conditional transgenic approaches, we identified the molecular basis of the VEGF effect on synaptic transmission and plasticity. VEGF increases the postsynaptic responses mediated by the N-methyl-D-aspartate type of glutamate receptors (GluNRs) in hippocampal neurons. This is concurrent with the formation of new synapses and with the synaptic recruitment of GluNR expressing the GluN2B subunit (GluNR-2B). VEGF induces a rapid redistribution of Glu…

Physiopathologie des artérites à cellules géantes

Resume L’arterite a cellules geantes (ACG) et l’arterite de Takayasu sont deux vascularites granulomateuses affectant les vaisseaux de gros calibre dont la cause exacte n’est pas connue. Neanmoins, les mecanismes physiopathologiques impliques au cours de l’ACG sont de mieux en mieux identifies et ont permis l’emergence de nouvelles cibles therapeutiques comme le blocage de la signalisation de l’interleukine-6 (IL-6). Le facteur declenchant de ces vascularites n’est pas connu mais l’hypothese, jamais confirmee a ce jour, d’un agent infectieux activant les cellules dendritiques de l’adventice est privilegiee. Cette activation de la reponse immunitaire innee permet le recrutement et l’activati…

Preferential splenic CD8+ T-cell activation in rituximab-nonresponder patients with immune thrombocytopenia

The pathogenic role of B cells in immune thrombocytopenia (ITP) has justified the therapeutic use of anti-CD20 antibodies such as rituximab (RTX). However, 60% of ITP patients do not respond to RTX. To decipher the mechanisms implicated in the failure of RTX, and because the spleen plays a well-recognized role in ITP pathogenesis, 12 spleens from ITP patients who had been nonresponders to RTX therapy were compared with 11 spleens from RTX-untreated ITP patients and 9 controls. We here demonstrate that in RTX-nonresponder ITP patients, preferential Th1 and Tc1 T lymphocyte polarizations occur, associated with an increase in splenic effector memory CD8(+) T-cell frequency. Moreover, in the RT…

Pathology of Rotavirus-driven Multiple Organ Failure in a 16-month-old Boy

International audience; Autopsy investigation of a fatal case of rotavirus severe acute gastroenteritis and multiple organ failure in a 16-month boy with previous intrauterine growth retardation showed colocalization of nonstructural and structural rotavirus proteins within viroplasms in nephrons. This case brings new insights into extraintestinal rotavirus infection and new clues to its abilities to bind to human histo-blood group antigens.

High prevalence of arrhythmic and myocardial complications in patients with cardiac glycogenosis due to PRKAG2 mutations

International audience; AIMS: Mutations in PRKAG2, the gene encoding for the γ2 subunit of 5'-AMP-activated protein kinase (AMPK), are responsible for an autosomal dominant glycogenosis with a cardiac presentation, associating hypertrophic cardiomyopathy (HCM), ventricular pre-excitation (VPE), and progressive heart block. The aim of this study was to perform a retrospective time-to-event study of the clinical manifestations associated with PRKAG2 mutations.METHODS AND RESULTS: A cohort of 34 patients from 9 families was recruited between 2001 and 2010. DNA were sequenced on all exons and flanking sequences of the PRKAG2 gene using Sanger sequencing. Overall, four families carried the recur…

Hypermethylator phenotype in sporadic colon cancer: study on a population-based series of 582 cases.

Abstract The CpG island methylator phenotype (CIMP) is a distinct phenotype in colorectal cancer, associated with specific clinical, pathologic, and molecular features. However, most of the studies stratified methylation according to two subgroups (CIMP-High versus No-CIMP/CIMP-Low). In our study, we defined three different subgroups of methylation (No-CIMP, CIMP-Low, and CIMP-High) and evaluated the prognostic significance of methylation status on a population-based series of sporadic colon cancers. A total of 582 colon adenocarcinomas were evaluated using methylation-specific PCR for 5 markers (hMLH1, P16, MINT1, MINT2, and MINT31). No-CIMP status was defined as no methylated locus, CIMP-…