Dataset Information

Chromosomal instability in near-diploid colorectal cancer: a link between numbers and structure.

ABSTRACT: Chromosomal instability (CIN) plays a crucial role in tumor development and occurs mainly as the consequence of either missegregation of normal chromosomes (MSG) or structural rearrangement (SR). However, little is known about the respective chromosomal targets of MSG and SR and the way these processes combined within tumors to generate CIN. To address these questions, we karyotyped a consecutive series of 96 near-diploid colorectal cancers (CRCs) and distinguished chromosomal changes generated by either MSG or SR in tumor cells. Eighty-three tumors (86%) presented with chromosomal abnormalities that contained both MSGs and SRs to varying degrees whereas all 13 others (14%) showed normal karyotype. Using a maximum likelihood statistical method, chromosomes affected by MSG or SR and likely to represent changes that are selected for during tumor progression were found to be different and mostly mutually exclusive. MSGs and SRs were not randomly associated within tumors, delineating two major pathways of chromosome alterations that consisted of either chromosome gains by MSG or chromosomal losses by both MSG and SR. CRCs showing microsatellite instability (MSI) presented with either normal karyotype or chromosome gains whereas MSS (microsatellite stable) CRCs exhibited a combination of the two pathways. Taken together, these data provide new insights into the respective involvement of MSG and SR in near-diploid colorectal cancers, showing how these processes target distinct portions of the genome and result in specific patterns of chromosomal changes according to MSI status.

SUBMITTER: Muleris M

PROVIDER: S-EPMC2238794 | biostudies-literature | 2008 Feb

REPOSITORIES: biostudies-literature

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Chromosomal instability in near-diploid colorectal cancer: a link between numbers and structure.

Muleris Martine M Chalastanis Alexandra A Meyer Nicolas N Lae Marick M Dutrillaux Bernard B Sastre-Garau Xavier X Hamelin Richard R Fléjou Jean-Francois JF Duval Alex A

PloS one 20080220 2

Chromosomal instability (CIN) plays a crucial role in tumor development and occurs mainly as the consequence of either missegregation of normal chromosomes (MSG) or structural rearrangement (SR). However, little is known about the respective chromosomal targets of MSG and SR and the way these processes combined within tumors to generate CIN. To address these questions, we karyotyped a consecutive series of 96 near-diploid colorectal cancers (CRCs) and distinguished chromosomal changes generated ...[more]

PMID: 18286189

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Project description:BackgroundIt remains presently unclear whether disease progression in colorectal carcinoma (CRC), from early, to invasive and metastatic forms, is associated to a gradual increase in genetic instability and to a scheme of sequentially occurring Copy Number Alterations (CNAs).MethodsIn this work we set to determine the existence of such links between CRC progression and genetic instability and searched for associations with patient outcome. To this aim we analyzed a set of 162 Chromosomal Instable (CIN) CRCs comprising 131 primary carcinomas evenly distributed through stage 1 to 4, 31 metastases and 14 adenomas by array-CGH. CNA profiles were established according to disease stage and compared. We, also, asked whether the level of genomic instability was correlated to disease outcome in stage 2 and 3 CRCs. Two metrics of chromosomal instability were used; (i) Global Genomic Index (GGI), corresponding to the fraction of the genome involved in CNA, (ii) number of breakpoints (nbBP).ResultsStage 1, 2, 3 and 4 tumors did not differ significantly at the level of their CNA profiles precluding the conventional definition of a progression scheme based on increasing levels of genetic instability. Combining GGI and nbBP,we classified genomic profiles into 5 groups presenting distinct patterns of chromosomal instability and defined two risk classes of tumors, showing strong differences in outcome and hazard risk (RFS: p?=?0.012, HR?=?3; OS: p?<?0.001, HR?=?9.7). While tumors of the high risk group were characterized by frequent fractional CNAs, low risk tumors presented predominantly whole chromosomal arm CNAs. Searching for CNAs correlating with negative outcome we found that losses at 16p13.3 and 19q13.3 observed in 10% (7/72) of stage 2-3 tumors showed strong association with early relapse (p?<?0.001) and death (p?<?0.007, p?<?0.016). Both events showed frequent co-occurrence (p?<?1x10-8) and could, therefore, mark for stage 2-3 CRC susceptible to negative outcome.ConclusionsOur data show that CRC disease progression from stage 1 to stage 4 is not paralleled by increased levels of genetic instability. However, they suggest that stage 2-3 CRC with elevated genetic instability and particularly profiles with fractional CNA represent a subset of aggressive tumors.

Dataset Information

Chromosomal instability in near-diploid colorectal cancer: a link between numbers and structure.

Publications

Chromosomal instability in near-diploid colorectal cancer: a link between numbers and structure.

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