Impact of chromosomal instability on colorectal cancer progression and outcome
1 INSERM U896, F-34298 Montpellier, France
2 Institut de Recherche en Cancérologie de Montpellier, Université Montpellier1, F-34298 Montpellier, France
3 Institut régional du Cancer Montpellier, F-34298 Montpellier, France
4 University Hospital of Purpan, Toulouse, France
5 Cancer Research Center of Toulouse – UMR 1037 INSERM, University of Toulouse, Toulouse, France
6 Centre Hospitalier Universitaire Dupuytren and EA 3842 Faculté de Médecine, Limoges, France
7 Cancer genetics unit, Institut Bergonié, Bordeaux, France
8 University Hospital of Rangueil, Toulouse, France
9 Cancer Research Center of Toulouse, INSERM U1037 CNRS ERL5994, University Paul Sabatier, University of Toulouse, Toulouse, France
10 INSERM U916, Institut Bergonié, Université de Bordeaux, Bordeaux, France
11 Institut de Recherche en Cancérologie de Montpellier, INSERM U896, 208 Rue des apothicaires, 34298 Montpellier cedex 5, France
BMC Cancer 2014, 14:121 doi:10.1186/1471-2407-14-121Published: 22 February 2014
It 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).
In 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).
Stage 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.
Our 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.