Characterisation of a subtype of colorectal cancer combining features of the suppressor and mild mutator pathways.
BACKGROUND
10% of sporadic colorectal cancers are characterised by a low level of microsatellite instability (MSI-L). These are not thought to differ substantially from microsatelite-stable (MSS) cancers, but MSI-L and MSS cancers are distinguished clinicopathologically and in their spectrum of genetic alterations from cancers showing high level microsatellite instability (MSI-H).


OBJECTIVE
To study the distribution of molecular alterations in a series of colorectal cancers stratified by DNA microsatellite instability.


METHODS
A subset of an unselected series of colorectal cancers was grouped by the finding of DNA MSI at 0 loci (MSS) (n = 51), 1-2 loci (MSI-L) (n = 38) and 3-6 loci (MSI-H) (n = 25). The frequency of K-ras mutation, loss of heterozygosity (LOH) at 5q, 17p and 18q, and patterns of p53 and beta catenin immunohistochemistry was determined in the three groups.


RESULTS
MSI-H cancers had a low frequency of K-ras mutation (7%), LOH on chromosomes 5q (0%), 17p (0%) and 18q (12.5%), and a normal pattern of immunostaining for p53 and beta catenin. MSI-L cancers differed from MSS cancers in terms of a higher frequency of K-ras mutation (54% v 27%) (p = 0.01) and lower frequency of 5q LOH (23% v 48%) (p = 0.047). Whereas aberrant beta catenin expression and 5q LOH were concordant (both present or both absent) in 57% of MSS cancers, concordance was observed in only 20% of MSI-L cancers (p = 0.01).


CONCLUSIONS
MSI-L colorectal cancers are distinct from both MSI-H and MSS cancers. This subset combines features of the suppressor and mutator pathways, may be more dependent on K-ras than on the APC gene in the early stages of neoplastic evolution, and a proportion may be related histogenetically to the serrated (hyperplastic) polyp.
Jass
J R
JR
Department of Pathology, University of Queensland Medical School, Herston, Australia. j.jass@mailbox.uq.edu.au
Biden
K G
KG
Cummings
M C
MC
Simms
L A
LA
Walsh
M
M
Schoch
E
E
Meltzer
S J
SJ
Wright
C
C
Searle
J
J
Young
J
J
Leggett
B A
BA
D000236:Adenoma / Q000235:genetics*; D002886:Chromosomes, Human, Pair 17; D002887:Chromosomes, Human, Pair 18; D002895:Chromosomes, Human, Pair 5; D015179:Colorectal Neoplasms / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000032:analysis; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D018895:Microsatellite Repeats / Q000235:genetics*; D009154:Mutation; D011127:Polyps / Q000235:genetics; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin