MCC, a candidate familial polyposis gene in 5q.21, shows frequent allele loss in colorectal and lung cancer.
MCC is a gene located within human chromosome band 5q.21 that shows somatically acquired mutations in colorectal cancer, and may be identical to the gene responsible for inheritance of familial adenomatous polyposis. Here we demonstrate that alleles contiguous with or within MCC are deleted in a high proportion of sporadic colorectal carcinomas. Of 106 carcinomas that were informative concurrently at close-flanking sites both centromeric and telomeric to MCC, 41.5% showed acquired allele loss contiguous with MCC. Evidence is presented to show that the true frequency of loss of MCC alleles is higher still. In contrast, allele losses in chromosome 5 that were incompatible with involvement of MCC were very rare (2% of a total series of 201 informative tumours). Interstitial deletion was the commonest mechanism of allele loss, and L5.71-3, a probe known to include coding sequences of MCC, marks the most consistently deleted site. Moreover mapping of chromosome breakpoints with six probes within 5q.21 sited the common critical deletion in a 2.5 Mb region which included L5.71-3. However use of L5.71-3 itself suggested that critical deleted regions may lie on either side of the probed sequence. The simplest explanation for this unexpected finding is that MCC itself is the essential deleted gene, the lost exons lying sometimes centromeric to, sometimes telomeric to and occasionally within the region detected by L5.71-3. Tumours in which MCC-related alleles were lost by interstitial deletion were in general larger than those with other mechanisms of acquired homozygosity (e.g. mitotic recombination), but there were no other obvious associations with clinicopathological features. Between 20% and 25% of lung cancers also showed acquired allele losses contiguous with MCC. The significance of this observation is still to be determined, as lung tumours show allele losses at many other sites, but the specificity of the probes used in this study does establish that the 5q.21 losses in these tumours are compatible with involvement of MCC.
Ashton-Rickardt
P G
PG
Department of Pathology, University Medical School, Edinburgh, UK.
Wyllie
A H
AH
Bird
C C
CC
Dunlop
M G
MG
Steel
C M
CM
Morris
R G
RG
Piris
J
J
Romanowski
P
P
Wood
R
R
White
R
R
D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D000483:Alleles; D002872:Chromosome Deletion; D002874:Chromosome Mapping; D002895:Chromosomes, Human, Pair 5; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology