Refining molecular analysis in the pathways of colorectal carcinogenesis.
OBJECTIVE
In the stepwise model, specific genetic and epigenetic changes accumulate as colorectal adenomas progress to carcinomas (CRCs). CRCs also acquire global phenotypes, particularly microsatellite instability (MSI) and aneuploidy/polyploidy (chromosomal instability, CIN). Few changes specific to MSI-low or CIN+ cancers have been established.


METHODS
We investigated 100 CRCs for: mutations and loss of heterozygosity (LOH) where appropriate, of APC, K-ras, BRAF, SMAD4, and p53; deletion on 5q around APC and 18q around SMAD4; total chromosomal-scale losses and gains; MSI; and CIN.


RESULTS
As expected, CIN- cancers had fewer chromosomal changes overall than CIN+ lesions, but after correcting for this, 5q deletions alone predicted CIN+ status. 5q deletions were not, however, significantly associated with APC mutations, which were equally frequent in CIN+ and CIN- tumors. We therefore found no evidence to show that mutant APC promotes CIN. p53 mutations/LOH were more common in CIN+ than CIN- lesions, and all chromosomal amplifications were in CIN+ tumors. CIN- cancers could be subdivided according to the total number of chromosomal-scale changes into CIN-low and CIN-stable groups; 18q deletion was the best predictor, being present in nearly all CIN-low lesions and almost no CIN-stable tumors. MSI-low was not associated with CIN, any specific mutation, a mutational signature, or clinicopathologic characteristic.


CONCLUSIONS
Overall, the components of the stepwise model (APC, K-ras, and p53 mutations, plus 18q LOH) tended to co-occur randomly. We propose an updated version of this model comprising 4 pathways of CRC pathogenesis, on the basis of 5q/18q deletions, MSI (high/low), and CIN (high/low/stable).
Rowan
Andrew
A
Molecular and Population Genetics Laboratory, London Research Institute, Cancer Research UK, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
Halford
Sarah
S
Gaasenbeek
Michelle
M
Kemp
Zoe
Z
Sieber
Oliver
O
Volikos
Emmanouil
E
Douglas
Eleanor
E
Fiegler
Heike
H
Carter
Nigel
N
Talbot
Ian
I
Silver
Andrew
A
Tomlinson
Ian
I
D002277:Carcinoma / Q000235:genetics*; D043171:Chromosomal Instability; D002872:Chromosome Deletion; D015179:Colorectal Neoplasms / Q000235:genetics*; D018450:Disease Progression; D017491:Genes, APC / Q000502:physiology; D016158:Genes, p53 / Q000235:genetics; D011905:Genes, ras / Q000235:genetics; D019656:Loss of Heterozygosity; D018895:Microsatellite Repeats; D009154:Mutation