Comprehensive Analysis of Copy Number and Allele Status Identifies Multiple Chromosome Defects Underlying Follicular Lymphoma Pathogenesis

Abstract

Purpose: Follicular lymphoma (FL) constitutes the second most common non-Hodgkin's lymphoma in the Western world. The clinical course is variable and only in part explained by known tumor-intrinsic or -extrinsic factors. FL carries the hallmark chromosomal translocation t(14;18), deregulating the expression of Bcl-2, but this is not sufficient to explain either FL biology or clinical behavior. Experimental Design: We have employed high-density genomic profiling technology using the Affymetrix 50K-XbaI oligonucleotide single nucleotide polymorphism^chip platform to interrogate the genomes of 58 fluorescence-activated cell^sorted (FACS) FL specimens for chromosomal copy number changes and 46 specimens for loss of heterozygosity (LOH). Results: We report (a) previously unknown high-frequency copy-neutral LOH (uniparental disomy) in FL on chromosomes1p (f50%) and 6p (f30%); (b) that del6q is complex, as reported, with at least two regions of minimal common loss at 6q13-15 and 6q23-24, and that in addition, f8% of FL specimens contain a homozygous deletion at 6q23.3-24.1 that spans the negative NFnB regulator A20 and the p53 apoptosis effector PERP ; (c) that combined analysis of chromosome 17p for LOH, copy number, and p53 mutations shows that most p53 mutations in FL do not involve del17p. Finally, we map high-frequency LOH with and without copy loss on chromosomes 9p, 10q, and 16p and genomic gains on 2p15-16 and 8q24.22-24.3. Conclusions: This comprehensive description of the pathologic anatomy of the FL genome uncovers novel genetic lesions and should aid with identification of genes relevant to FL biology and clinical behavior.

Microarray‐based genomic profiling reveals novel genomic aberrations in follicular lymphoma which associate with patient survival and gene expression status

“…The probe sets FAIM2 was not represented on the Affymetrix TM U133A chip. However, the gain 8q involving PTK2 was also identified and confirmed using SNP-chip and RQ-PCR analysis which underlines its potential role as a candidate gene in FL (Ross et al, 2007).…”

“…6q26 deletions versus balanced cases, a differential mRNA expression was observed only for the gene ESR1 on 6q25.1. Summarizing, the architecture of deletions on 6q is complex and still controversial as was recently suggested by data obtained by SNP-chip analysis locating the minimal deleted region to a more centromeric position (6q13 and 6q23, Ross et al, 2007).…”

“…However, gene deregulation triggered by genomic alterations represents only one critical biological mechanism in this entity. There is increasing evidence, that also epigenetic phenomenons, RNA interference, copy neutral LOH (uniparental disomies), or specific gene mutations lead to altered expression of disease relevant genes (Hayslip and Montero, 2006;Lawrie et al, 2007;Ross et al, 2007). The heterogeneous individual clinical course may not be determined by the genomic phenotype of the tumor cells alone.…”

“…However, the sole presence of this translocation is not sufficient for emergence of FL (McDonnell and Korsmeyer 1991). In this context, a large number of genomic gains and losses were described using chromosome banding analysis, conventional comparative genomic hybridization (CGH), or single nucleotide polymorphism chip technologies (Tilly et al, 1994;Bentz et al, 1996;Avet-Loiseau et al, 1997;Horsman et al, 2001;Neat et al, 2001;Viardot et al, 2001Viardot et al, , 2002Ott et al, 2002;Hö glund et al, 2004;Berglund et al, 2007;Ross et al, 2007). Because of the restricted spatial resolution of most of these techniques, it can be speculated that a large number of aberrations have not been identified so far.…”

Genome-wide profiling of follicular lymphoma by array comparative genomic hybridization reveals prognostically significant DNA copy number imbalances

“…The reported recurrent copy number alterations have consistently included losses of 1p32-36, 6q, 10q, and 17p, and gains of 1q, 2p, 7, 9p, 12, 17q, 18q, and X. [14][15][16][17][18][19][20][21][22][23][24][25] The analysis by Hoglund et al utilized computational analysis of a large number of published G-banded FL karyotypes to define early from late accruing genetic imbalances and demonstrated 4 putative pathways of clonal evolution in FL. 26 This karyotype-based study was hampered by the inherent inaccuracies of G-banding analysis and excluded from consideration all marker chromosomes and unbalanced chromosomal additions that are common features of FL karyotypes.…”