title: Impact of chromosomal instability on colorectal cancer progression and outcome.
abstract: BACKGROUND
  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).
  
  
  METHODS
  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).
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Orsetti
authors.forename: Janick
authors.initials: J
authors.lastname: Selves
authors.forename: Caroline
authors.initials: C
authors.lastname: Bascoul-Mollevi
authors.forename: Laurence
authors.initials: L
authors.lastname: Lasorsa
authors.forename: Karine
authors.initials: K
authors.lastname: Gordien
authors.forename: Frédéric
authors.initials: F
authors.lastname: Bibeau
authors.forename: Blandine
authors.initials: B
authors.lastname: Massemin
authors.forename: François
authors.initials: F
authors.lastname: Paraf
authors.forename: Isabelle
authors.initials: I
authors.lastname: Soubeyran
authors.forename: Isabelle
authors.initials: I
authors.lastname: Hostein
authors.forename: Valérie
authors.initials: V
authors.lastname: Dapremont
authors.forename: Rosine
authors.initials: R
authors.lastname: Guimbaud
authors.forename: Christophe
authors.initials: C
authors.lastname: Cazaux
authors.forename: Michel
authors.initials: M
authors.lastname: Longy
authors.affiliation: INSERM U896, F-34298 Montpellier, France. charles.theillet@inserm.fr.
authors.forename: Charles
authors.initials: C
authors.lastname: Theillet
mesh_terms: D000328:Adult; D000368:Aged; D002278:Carcinoma in Situ / Q000235:genetics; D043171:Chromosomal Instability / Q000235:genetics*; D056905:Chromosome Breakpoints; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D055028:Comparative Genomic Hybridization; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D016896:Treatment Outcome