Distinct Chromosomal Imbalances in Nonpolypoid and Polypoid Colorectal Adenomas Indicate Different Genetic Pathways in the Development of Colorectal Neoplasms

Richter, Hedwig; Slezak, P; Walch, Axel; Werner, Martin; Braselmann, Herbert; Jaramillo, Edgar; Öst, Åke; Hirata, Ichiro; Takahama, Kazuya; Zitzelsberger, Horst

doi:10.1016/s0002-9440(10)63652-8

Cited by 40 publications

(24 citation statements)

References 26 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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“…3,129,147 More recently quantitative comparisons of the aneuploidies of different cancers by the technique of comparative genomic hybridization have confirmed and extended the early results: The individual chromosome copy numbers of a majority of cancers from a given tissue were closely related, although those of consistent minorities were not. 9,108,109,[148][149][150][151][152] But, despite the many karyotypic similarities, "no completely specific primary or secondary karyotypic abnormality has been identified." 147 In view of this most researchers suggested that these common aneusomies encode common genes that are necessary for carcinogenesis.…”

Section: Phylogenetic Relationships Between Cancers: Another Parallelmentioning

confidence: 99%

“…147 In view of this most researchers suggested that these common aneusomies encode common genes that are necessary for carcinogenesis. 9,108,109,[147][148][149][150][151][152] It remained ©2 0 1 1 L a n d e s B i o s c i e n c e .…”

Section: Phylogenetic Relationships Between Cancers: Another Parallelmentioning

confidence: 99%

Is carcinogenesis a form of speciation?

Duesberg

Mandrioli²,

McCormack³

et al. 2011

Cell Cycle

113

138

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“…Indirect labelling of the reference DNA with digoxigenin and of the tumour DNA with biotin was performed by nick translation using a standard protocol. Hybridisation of the labelled DNA on metaphase spreads with a normal karyotype from the 102/ELxC3H/EL mouse strain was performed according to Richter et al (2003). The chromosomes were counterstained with DAPI and actinomycin D prior to image acquisition and analysis as described by Richter et al (2003).…”

Section: Human Tissuesmentioning

confidence: 99%

Novel candidate genes of thyroid tumourigenesis identified in Trk-T1 transgenic mice

Heiliger

Heß

Vitagliano

et al. 2012

Endocrine-Related Cancer

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For an identification of novel candidate genes in thyroid tumourigenesis, we have investigated gene copy number changes in a Trk-T1 transgenic mouse model of thyroid neoplasia. For this aim, 30 thyroid tumours from Trk-T1 transgenics were investigated by comparative genomic hybridisation. Recurrent gene copy number alterations were identified and genes located in the altered chromosomal regions were analysed by Gene Ontology term enrichment analysis in order to reveal gene functions potentially associated with thyroid tumourigenesis. In thyroid neoplasms from Trk-T1 mice, a recurrent gain on chromosomal bands 1C4-E2.3 (10.0% of cases), and losses on 3H1-H3 (13.3%), 4D2.3-E2 (43.3%) and 14E4-E5 (6.7%) were identified. The genes Twist2, Ptma, Pde6d, Bmpr1b, Pdlim5, Unc5c, Srm, Trp73, Ythdf2, Taf12 and Slitrk5 are located in these chromosomal bands. Copy number changes of these genes were studied by fluorescence in situ hybridisation on 30 human papillary thyroid carcinoma (PTC) samples and altered gene expression was studied by qRT-PCR analyses in 67 human PTC. Copy number gains were detected in 83% of cases for TWIST2 and in 100% of cases for PTMA and PDE6D. DNA losses of SLITRK1 and SLITRK5 were observed in 21% of cases and of SLITRK6 in 16% of cases. Gene expression was significantly up-regulated for UNC5C and TP73 and significantly down-regulated for SLITRK5 in tumours compared with normal tissue. In conclusion, a global genomic copy number analysis of thyroid tumours from Trk-T1 transgenic mice revealed a number of novel gene alterations in thyroid tumourigenesis that are also prevalent in human PTCs.

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Distinct Chromosomal Imbalances in Nonpolypoid and Polypoid Colorectal Adenomas Indicate Different Genetic Pathways in the Development of Colorectal Neoplasms

Cited by 40 publications

References 26 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

Is carcinogenesis a form of speciation?

Novel candidate genes of thyroid tumourigenesis identified in Trk-T1 transgenic mice

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