Comprehensive whole genome array CGH profiling of mantle cell lymphoma model genomes

Abstract

Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin's lymphoma with median patient survival times of approximately 3 years. Although the characteristic t(11;14)(q13;q32) is found in virtually all cases, experimental evidence suggests that this event alone is insufficient to result in lymphoma and secondary genomic alterations are required. Using a newly developed DNA microarray of 32 433 overlapping genomic segments spanning the entire human genome, we can for the first time move beyond marker based analysis and comprehensively search for secondary genomic alterations concomitant with the t(11;14) in eight commonly used cell models of MCL (Granta-519, HBL-2, NCEB-1, Rec-1, SP49, UPN-1, Z138C and JVM-2). Examining these genomes at tiling resolution identified an unexpected average of 35 genetic alterations per cell line, with equal numbers of amplifications and deletions. Recurrent high-level amplifications were identified at 18q21 containing BCL2, and at 13q31 containing GPC5. In addition, a recurrent homozygous deletion was identified at 9p21 containing p15 and p16. Alignment of these profiles revealed 14 recurrent losses and 21 recurrent gains as small as 130 kb. Remarkably, even the intra immunoglobulin gene deletions at 2p11 and 22q11 were detected, demonstrating the power of combining the detection sensitivity of array comparative genomic hybridization (CGH) with the resolution of an overlapping whole genome tiling-set. These alterations not only coincided with previously described aberrations in MCL, but also defined 13 novel regions. Further characterization of such minimally altered genomic regions identified using whole genome array CGH will define novel dominant oncogenes and tumor suppressor genes that play important roles in the pathogenesis of MCL.

Differential disruption of cell cycle pathways in small cell and non-small cell lung cancer

“…The minimal common alteration within this amplified area in the SCLC cell lines contains only one gene, MAD1L1 (validated by Coe et al, 2006). Although this is a checkpoint gene involved in growth inhibition, its gain has been reported in other cancers (Jin et al, 1999;Tsukasaki et al, 2001;de Leeuw et al, 2004 amplification in the NSCLC samples as well suggests that this gene may play an essential role in the development of lung cancers (Garnis et al, 2006). It is noteworthy that a subset of the genomic similarities between the SCLC and NSCLC cell lines could be the result of adaptation to culturing conditions.…”

“…In addition, genomic imbalances were identified using aCGH-Smooth which uses a genetic local search algorithm to identify breakpoints defining segmental DNA copy number changes by using a maximum likelihood estimation to optimise breakpoint location (Jong et al, 2004). As previously described, the Lambda and breakpoint per chromosome settings were set to 6.75 and 100, respectively (Jong et al, 2004;de Leeuw et al, 2004). The frequency of alteration for each BAC was then individually determined for each lung cancer cell type as described previously and plotted in SeeGH Frequency Plot to visualise areas of recurrent deletion and amplification (Coe et al, 2006).…”

Allelic genotyping reveals a hierarchy of genomic alterations in mantle cell lymphoma associated to cell proliferation

“…However, this translocation alone is not sufficient to promote MCL development but additional genomic alterations appear to be essential for malignant transformation [30]. To identify secondary genetic alterations involved, several groups have applied different techniques such as cytogenetic analysis, comparative genomic hybridization or DNA microarray [1,5,11,19,28,44]. In this study, we used a comprehensive method of allelotyping for the detection of genomic gains and losses in MCL [24].…”

ACTuDB, a new database for the integrated analysis of array-CGH and clinical data for tumors

“…The website is powered by an Apache server. Blaveri et al (2005) 92.9 Bredel et al (2005) 91.7 Gysin et al (2005) 92.6 Janoueix- Lerosey et al (2005) 97.4 Mosse et al (2005) 61.7 Patil et al (2005) 92.8 Snijders et al (2005) 93.2 de Leeuw et al (2004) 71.5 Douglas et al (2004) 99.3 Nakao et al (2004) 93.0 Woodfine et al (2004) 99.8 Veltman et al (2003) 74.2 Chen et al (2002) 83.8 Pollack et al (2002) 88.5 Snijders et al (2001) 89 …”

“…Many studies have been carried out on bladder cancer (Veltman et al, 2003;Blaveri et al, 2005;Stransky et al, 2006), brain cancer (Bredel et al, 2005;Kotliarov et al, 2006), breast cancer (Pollack et al, 2002;Fridlyand et al, 2006), colon cancer (Douglas et al, 2004;Nakao et al, 2004), liver cancer (Patil et al, 2005), lymphoma (de Leeuw et al, 2004), neuroblastoma (JanoueixLerosey et al, 2005;Mosse et al, 2005), mouth cancer (Snijders et al, 2005), pancreas cancer (Gysin et al, 2005) and replication timing (Woodfine et al, 2004;Janoueix-Lerosey et al, 2005). Comparisons of the results of experiments from different laboratories, on different types of cancer, are required to validate results or hypotheses and to improve our understanding of the recurrent alterations involved in cancer.…”