title: Increasing genomic and epigenomic complexity in the clonal evolution from in situ to manifest t(14;18)-positive follicular lymphoma.
abstract: Follicular lymphoma (FL) is characterized besides the t(14;18)(q32;q21), by recurrent chromosomal alterations and somatic mutations. In this study, we analyzed cases of FL in situ (FLIS) without manifest FL (mFL), partial involvement by FL (PFL) and paired cases of FLIS and mFL to detect possible early chromosomal imbalances, mutations, as well as DNA-methylation patterns of genomic regions of selected genes. We demonstrate that all paired FLIS and mFL cases were clonally related, based on IGH rearrangement patterns and BCL2 breakpoint sequences. FLIS and PFL had no or few secondary chromosomal imbalances detectable by array comparative genomic hybridization (FLIS 0.8 copy number alterations (CNA)/case; PFL 2.0 CNA/case; mFL 6.3 CNA/case) and a lower level of DNA methylation of genes recurrently de novo methylated in lymphomas, as compared with mFL. EZH2 Tyr641 mutations were detected in a subset of both FLIS (2/9) and PFL (1/3) cases. In conclusion, these findings provide evidence that FLIS represents a FL precursor lesion of long-lived clonal B cells carrying the t(14;18) with no or few secondary genetic changes. Our data suggest that there may be more than one distinct lesion driving the progression from FLIS to manifest lymphoma.
authors.affiliation: Institute of Pathology and Comprehensive Cancer Center, Eberhard-Karls-University of Tübingen, Tübingen, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Schmidt
authors.affiliation: Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University, Kiel, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Salaverria
authors.affiliation: Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University, Kiel, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Haake
authors.affiliation: Institute of Pathology and Comprehensive Cancer Center, Eberhard-Karls-University of Tübingen, Tübingen, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Bonzheim
authors.affiliation: Institute of Pathology and Comprehensive Cancer Center, Eberhard-Karls-University of Tübingen, Tübingen, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Adam
authors.affiliation: Department of Pathology, Hospital Universitario Marqués de Valdecilla, Instituto de Formación e Investigación Marqués de Valdecilla, Santander, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Montes-Moreno
authors.affiliation: Department of Pathology, Hospital Universitario Marqués de Valdecilla, Instituto de Formación e Investigación Marqués de Valdecilla, Santander, Spain.
authors.forename: M A
authors.initials: MA
authors.lastname: Piris
authors.affiliation: Institute of Pathology and Comprehensive Cancer Center, Eberhard-Karls-University of Tübingen, Tübingen, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Fend
authors.affiliation: Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University, Kiel, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Siebert
authors.affiliation: Institute of Pathology and Comprehensive Cancer Center, Eberhard-Karls-University of Tübingen, Tübingen, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Quintanilla-Martinez
mesh_terms: D000328:Adult; D000368:Aged; D002883:Chromosomes, Human, Pair 14; D002887:Chromosomes, Human, Pair 18; D055028:Comparative Genomic Hybridization; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008224:Lymphoma, Follicular / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D014178:Translocation, Genetic