title: Prognostic impact of epigenetic classification in chronic lymphocytic leukemia: The case of subset #2.
abstract: Based on the methylation status of 5 single CpG sites, a novel epigenetic classification of chronic lymphocytic leukemia (CLL) was recently proposed, classifying CLL patients into 3 clinico-biological subgroups with different outcome, termed memory like CLL (m-CLL), naïve like CLL (n-CLL), and a third intermediate CLL subgroup (i-CLL). While m-CLL and n-CLL patients at large corresponded to patients carrying mutated and unmutated IGHV genes, respectively, limited information exists regarding the less defined i-CLL group. Using pyrosequencing, we investigated the prognostic impact of the proposed 5 CpG signature in a well-characterized CLL cohort (135 cases), including IGHV-mutated and unmutated patients as well as clinically aggressive stereotyped subset #2 patients. Overall, we confirmed the signature's association with established prognostic markers. Moreover, in the presence of the IGHV mutational status, the epigenetic signature remained independently associated with both time-to-first-treatment and overall survival in multivariate analyses. As a prime finding, we observed that subset #2 patients were predominantly classified as i-CLL, probably reflecting their borderline IGHV mutational status (97-99% germline identity), though having a similarly poor prognosis as n-CLL patients. In summary, we validated the epigenetic classifier as an independent factor in CLL prognostication and provide further evidence that subset #2 is a member of the i-CLL group, hence supporting the existence of a third, intermediate epigenetic subgroup.
authors.affiliation: a Department of Immunology , Genetics and Pathology, Science for Life Laboratory, Uppsala University , Sweden.
authors.forename: Sujata
authors.initials: S
authors.lastname: Bhoi
authors.affiliation: a Department of Immunology , Genetics and Pathology, Science for Life Laboratory, Uppsala University , Sweden.
authors.forename: Viktor
authors.initials: V
authors.lastname: Ljungström
authors.affiliation: a Department of Immunology , Genetics and Pathology, Science for Life Laboratory, Uppsala University , Sweden.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Baliakas
authors.affiliation: a Department of Immunology , Genetics and Pathology, Science for Life Laboratory, Uppsala University , Sweden.|b Department of Medical Sciences , Uppsala University , Uppsala , Sweden.
authors.forename: Mattias
authors.initials: M
authors.lastname: Mattsson
authors.affiliation: c Department of Medicine Solna , Clinical Epidemiology Unit, Karolinska Institutet , Stockholm , Sweden.
authors.forename: Karin E
authors.initials: KE
authors.lastname: Smedby
authors.affiliation: d Department of Laboratory Medicine , Stem Cell Center, Hematology and Transplantation, Lund University , Lund , Sweden.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Juliusson
authors.affiliation: a Department of Immunology , Genetics and Pathology, Science for Life Laboratory, Uppsala University , Sweden.
authors.forename: Richard
authors.initials: R
authors.lastname: Rosenquist
authors.affiliation: a Department of Immunology , Genetics and Pathology, Science for Life Laboratory, Uppsala University , Sweden.
authors.forename: Larry
authors.initials: L
authors.lastname: Mansouri
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics / Q000592:standards*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D054403:Leukemia, Prolymphocytic, B-Cell / Q000145:classification* / Q000175:diagnosis / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D016019:Survival Analysis
chemical_list: D014408:Biomarkers, Tumor
keywords: CLL; epigenetic classification; methylation; prognosis