Defining ‘chromosomal instability’

Geigl, Jochen B.; Obenauf, Anna C.; Schwarzbraun, Thomas; Speicher, Michael R.

doi:10.1016/j.tig.2007.11.006

Cited by 282 publications

(278 citation statements)

References 45 publications

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“…An important conceptual leap has therefore been to include all genetic alterations associated with CIN in a single definition, according to which CIN refers to the combined instability of entire chromosomes and large chromosome fragments. 6 Since a single definition should correspond to a single mechanism, this has an important consequence for CIN; whereas aneuploidy explicitly refers to intact chromosomes, chromosome fragments have their origin in a break. The recent discovery of centromeric DNA damage in cells with spindle defects has provided evidence for a single mechanism explaining both aneuploidy and breakage.…”

Section: Are Aneuploidy and Chromosome Breakage Caused By A Cingle Mementioning

confidence: 99%

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Are aneuploidy and chromosome breakage caused by a CINgle mechanism?

Martı́nez-A

Wely

2010

Cell Cycle

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G enetic instability is a hallmark of cancer. Most tumors show complex patterns of translocations, amplifications and deletions, which have occupied scientists for decades. A specific problem arises in carcinomas with a genetic defect termed chromosomal instability; these solid tumors undergo gains and losses of entire chromosomes, as well as segmental defects caused by chromosome breaks. To date, the apparent inconsistency between intact and broken chromosomes has precluded identification of an underlying mechanism. The recent identification of centromeric breaks alongside aneuploidy in cells with spindle defects indicates that a single mechanism could account for all genetic alterations characteristic of chromosomal instability. Since a poorly controlled spindle can cause merotelic attachments, kinetochore distortion and subsequent chromosome breakage, spindle defects can generate the sticky ends necessary to start a breakagefusion-bridge cycle. The characteristic breakpoint of spindle-generated damage, adjacent to the centromere, also explains the losses and gains of whole chromosome arms, which are especially prominent in low-grade tumors. The recent data indicate that spindle defects are an early event in tumor formation, and an important initiator of carcinogenesis.

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Section: Are Aneuploidy and Chromosome Breakage Caused By A Cingle Mementioning

confidence: 99%

“…Many tumor samples, too, show a connection between aneuploidy levels and the complexity of genetic alterations; both are proportional to tumor grade. 10,11 Since the recent single definition of CIN includes both of these characteristics, 6 could a single mechanism account for both?…”

Section: The Two Faces Of Cinmentioning

confidence: 99%

Are aneuploidy and chromosome breakage caused by a CINgle mechanism?

Martı́nez-A

Wely

2010

Cell Cycle

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“…14 CIN involves gains or losses of whole chromosomes and/or chromosomal fractions and is considered to result from defects in chromosomal segregation, telomere stability, and DNA damage repair. 15,16 In B80% of colon cancers, CIN and/or MSI are found. A share of 20% of colorectal cancers, however, is microsatellite and chromosomally stable (MACS), and the molecular pathogenesis of these colorectal cancers is not completely understood.…”

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confidence: 99%

Genetics and epigenetics of small bowel adenocarcinoma: the interactions of CIN, MSI, and CIMP

et al. 2011

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Characterization of tumor genetics and epigenetics allows to stratify a tumor entity according to molecular pathways and may shed light on the interactions of different types of DNA alterations during tumorigenesis. Small intestinal adenocarcinoma is rare, and to date the interrelation of genomic instability and epigenetics has not been investigated in this tumor type. We therefore analyzed 37 primary small bowel carcinomas with known microsatellite instability and KRAS status for chromosomal instability using comparative genomic hybridization, for the presence of aberrant methylation (CpG island methylation phenotype) by methylation-specific polymerase chain reaction, and for BRAF mutations. Chromosomal instability was detected in 22 of 37 (59%) tumors (3 of 9 microsatellite instable, and 19 of 28 microsatellite stable carcinomas). Nine carcinomas (24%) were microsatellite and chromosomally stable. High-level DNA methylation was found in 16% of chromosomal instable tumors and in 44% of both microsatellite instable and microsatellite and chromosomally stable carcinomas. KRAS was mutated in 55, 0, and 10% of chromosomal instable, microsatellite instable, and microsatellite and chromosomally stable tumors, respectively whereas the frequencies of BRAF mutations were 6% for chromosomal instable and 22% for both microsatellite instable and microsatellite and chromosomally stable carcinomas. In conclusion, in this study we show that chromosomal instable carcinomas of the small intestine are distinguished from microsatellite instable and microsatellite and chromosomally stable tumors by a high frequency of KRAS mutations, low frequencies of CpG island methylation phenotype, and BRAF mutations. In microsatellite instable and microsatellite and chromosomally stable cancers, CpG island methylation phenotype and BRAF/KRAS mutations are similarly distributed, indicating common mechanisms of tumor initiation or progression in their molecular pathogenesis.

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“…5 Cytogenetic and molecular cytogenetic analyses have revealed that tumor-specific gains and losses of entire chromosomes or chromosome arms are early genome mutations. [6][7][8][9] The genomic imbalances show a strikingly conserved recurrent pattern that is characteristic for colorectal carcinomas and is distinct from other solid tumors. 6 For a comprehensive overview, please see http://cgap.…”

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confidence: 99%

Genomic instability and oncogene amplifications in colorectal adenomas predict recurrence and synchronous carcinoma

et al. 2011

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Individual colorectal adenomas have different propensities to progress to invasive disease. In this study, we explored whether these differences could be explained by gene copy number alterations. We evaluated 18 adenomas of patients without synchronous or subsequent carcinoma (6.5 years follow-up), 23 adenomas of carcinoma patients, and 6 related carcinomas. All samples were measured for their DNA ploidy status. Centromere probes for chromosomes 17 and 18, as well as gene-specific probes for SMAD7, EGFR, NCOA3, TP53, MYC, and RAB20 were assessed by multicolor fluorescence in situ hybridization. An increased genomic instability index of CEP17, SMAD7, and EGFR, as well as TP53 deletions and MYC amplifications defined adenomas of patients with synchronous carcinoma (Po0.05). Diploid NCOA3 signal counts were associated with longer adenoma recurrence-free surveillance (P ¼ 0.042). In addition, NCOA3, MYC, EGFR, and RAB20 amplifications, as well as TP53 deletions correlated with increased DNA stem line values and/or aneuploidy in adenomas (Po0.05). Furthermore, aberrations of NCOA3, MYC, and RAB20 were associated with histopathologically defined high-risk adenomas (Po0.05). RAB20 amplifications were also correlated with high-grade dysplastic adenomas (P ¼ 0.002). We conclude that genomic instability in colorectal adenomas is reflected by EGFR, MYC, NCOA3, and RAB20 amplifications that do correlate with histomorphological features and are indicative for adenoma recurrence and the presence of synchronous carcinomas.

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Defining ‘chromosomal instability’

Cited by 282 publications

References 45 publications

Are aneuploidy and chromosome breakage caused by a CINgle mechanism?

Are aneuploidy and chromosome breakage caused by a CINgle mechanism?

Genetics and epigenetics of small bowel adenocarcinoma: the interactions of CIN, MSI, and CIMP

Genomic instability and oncogene amplifications in colorectal adenomas predict recurrence and synchronous carcinoma

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