Array Comparative Genomic Hybridization Analysis of Colorectal Cancer Cell Lines and Primary Carcinomas

Douglas, Eleanor J.; Fiegler, Heike; Rowan, Andrew; Halford, Sarah; Bicknell, David; Bodmer, W F; Tomlinson, Ian; Carter, Nigel P.

doi:10.1158/0008-5472.can-04-0328

Cited by 165 publications

(167 citation statements)

References 54 publications

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“…31 Although a few studies have reported on losses of the short arm of chr16 in CRC, this has not received much attention. 12,[32][33][34][35] Our analyses indicate that the genomic rearrangement leading to chr16p-loss is an early event occurring in $ 30% of adenomas. The frequency is even higher in carcinomas (>50%), independently of MSS and MSI status, indicating that the causing mechanism is independent of the DNA mismatch repair system.…”

Section: Discussionmentioning

confidence: 72%

Frequent genomic loss at chr16p13.2 is associated with poor prognosis in colorectal cancer

Andersen

Lamy

Thorsen

et al. 2011

Intl Journal of Cancer

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Genomic alterations play important roles in colorectal cancer (CRC) carcinogenesis. Here, we aimed to identify and characterize recurrent copy-number alterations (CNAs) associated with clinical outcome of CRC by the use of single nucleotide polymorphism arrays, genomic quantitative PCR (qPCR) and fluorescence in situ hybridization (FISH). Colorectal neoplasia specimens and paired germline samples from 144 patients (40 adenomas and 104 carcinomas) as well as 40 CRC cell lines were investigated. This large dataset revealed frequent loss, including homozygous loss, at chr16p13.2 (from 5.9 to 7.42Mb). The loss was observed in 30% of adenomas and even more frequently in carcinomas, 56%, indicating that the loss define a subset of adenomas with a propensity for invasion. Consistent with this, the loss occurred twice as frequent in villous (40%) as in tubular adenomas (20%). The loss occurred independently of microsatellite stability and could be validated by qPCR in an independent sample cohort (n 5 71). In Stage II/III, microsatellite stable (MSS) CRC it was associated with poor recurrence free survival (hazard ratio 2.4; p 5 0.02; Multivariate Cox regression analysis). No transcriptional consequences of the losses were observed, and the only gene, A2BP1, located in the region showed no mutations. Correlation with other CNAs was established for chr3p22 in carcinomas and chr20p (inverse) in adenomas. FISH documented the chr16p13.2 region to be involved in complex structural rearrangements that included translocation to chr3p22 in some cases. The findings indicate that structural rearrangements involving chr16p13.2 are very frequent in colorectal neoplasia, often lead to homozygous deletion, and are associated with poor clinical outcome.Despite major efforts over the recent years toward improving the survival outcome of patients with colorectal cancer (CRC), the disease remains a major health burden with over one million cases worldwide and a disease-specific mortality of $33% in the developed world. 1 Currently, the gold standard for prognostication is clinicopathological staging, based on the Tumor, Node, Metastasis (TNM) classifcation. However. Although CRC is often diagnosed at a stage where complete resection of the primary cancer (Stages I-III) is possible, 40-50% of patients who undergo potentially curative surgery alone relapse and die of metastatic disease. 2 Although most patients with Stage III (lymph-node positive) cancer receive adjuvant treatment, it is offered to only a subset of Stage II (localized disease) patients presenting with specific high-risk clinical features, including tumor perforation or invasion of adjacent organs. 3 This approach is clearly suboptimal, resulting in undertreatment of $20% of Stage II patients who will recur. Similarly, current adjuvant treatment is clearly ineffective in many Stage III patients, with a recurrence rate of $40% 4,5 highlighting the need for treatment with more aggressive or newly emerging targeted therapies, e.g., inhibitors of epidermal growth factor recepto...

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Section: Discussionmentioning

confidence: 72%

Frequent genomic loss at chr16p13.2 is associated with poor prognosis in colorectal cancer

Andersen

Lamy

Thorsen

et al. 2011

Intl Journal of Cancer

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“…Davidson et al, 2000;AbdelRahman et al, 2001;Karan et al, 2003;Hurst et al, 2004;Hwang et al, 2004), and more recently array CGH has begun to provide more detail of these losses (e.g. Paris et al, 2003;Douglas et al, 2004;Hurst et al, 2004;Nakao et al, 2004;Garcia et al, 2005). Distal 8p also frequently shows loss of heterozygosity (LOH), which would often reflect loss through unbalanced translocation (for references see Adams et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

High-resolution analysis of chromosome rearrangements on 8p in breast, colon and pancreatic cancer reveals a complex pattern of loss, gain and translocation

et al. 2006

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The short arm of chromosome 8, 8p, is often rearranged in carcinomas, typically showing distal loss by unbalanced translocation. We analysed 8p rearrangements in 48 breast, pancreatic and colon cancer cell lines by fluorescence in situ hybridization (FISH) and array comparative genomic hybridization, with a tiling path of 0.2 Mb resolution over 8p12 and 1 Mb resolution over chromosome 8. Selected breast lines (MDA-MB-134, MDA-MB-175, MDA-MB-361, T-47D and ZR-75-1) were analysed further. Most cell lines showed loss of 8p distal to a break that was between 31 Mb (5 0 to NRG1) and the centromere, but the translocations were accompanied by variable amplifications, deletions and inversions proximal to this break. The 8p12 translocation in T-47D was flanked by an inversion of 4 Mb, with a 100 kb deletion at the proximal end. The dicentric t(8;11) in ZR-75-1 carries multiple rearrangements including interstitial deletions, a triplicated translocation junction between NRG1 and a fragment of 11q (unconnected to CCND1), and two separate amplifications, of FGFR1 and CCND1 . We conclude that if there is a tumour suppressor gene on 8p it may be near 31 Mb, for example WRN; but the complexity of 8p rearrangements suggests that they target various genes proximal to 31 Mb including NRG1 and the amplicon centred around ZNF703/FLJ14299.

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“…23,24 These changes include amplifications on chromosome 20q, 13 and 8q, and copy number loss on the long arm of chromosome 18 and on chromosome 8p. [24][25][26][27][28] Both aberrant specimens showed amplifications of entire chromosomes: 7, 13 and 16, as well as partially overlapping aberrations on chromosome 20 (Figure 4a). …”

Section: Validation For Downstream High-throughput Technologiesmentioning

confidence: 99%

Next-generation biobanking of metastases to enable multidimensional molecular profiling in personalized medicine

et al. 2013

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Great advances in analytical technology coupled with accelerated new drug development and growing understanding of biological challenges, such as tumor heterogeneity, have required a change in the focus for biobanking. Most current banks contain samples of primary tumors, but linking molecular signatures to therapeutic questions requires serial biopsies in the setting of metastatic disease, next-generation of biobanking. Furthermore, an integration of multidimensional analysis of various molecular components, that is, RNA, DNA, methylome, microRNAome and post-translational modifications of the proteome, is necessary for a comprehensive view of a tumor's biology. While data using such biopsies are now regularly presented, the preanalytical variables in tissue procurement and processing in multicenter studies are seldom detailed and therefore are difficult to duplicate or standardize across sites and across studies. In the context of a biopsydriven clinical trial, we generated a detailed protocol that includes morphological evaluation and isolation of high-quality nucleic acids from small needle core biopsies obtained from liver metastases. The protocol supports stable shipping of samples to a central laboratory, where biopsies are subsequently embedded in support media. Designated pathologists must evaluate all biopsies for tumor content and macrodissection can be performed if necessary to meet our criteria of 460% neoplastic cells and o20% necrosis for genomic isolation. We validated our protocol in 40 patients who participated in a biopsy-driven study of therapeutic resistance in metastatic colorectal cancer. To ensure that our protocol was compatible with multiplex discovery platforms and that no component of the processing interfered with downstream enzymatic reactions, we performed array comparative genomic hybridization, methylation profiling, microRNA profiling, splicing variant analysis and gene expression profiling using genomic material isolated from liver biopsy cores. Our standard

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Array Comparative Genomic Hybridization Analysis of Colorectal Cancer Cell Lines and Primary Carcinomas

Cited by 165 publications

References 54 publications

Frequent genomic loss at chr16p13.2 is associated with poor prognosis in colorectal cancer

Frequent genomic loss at chr16p13.2 is associated with poor prognosis in colorectal cancer

High-resolution analysis of chromosome rearrangements on 8p in breast, colon and pancreatic cancer reveals a complex pattern of loss, gain and translocation

Next-generation biobanking of metastases to enable multidimensional molecular profiling in personalized medicine

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