Allelic imbalance at the LKB1 (STK11) locus in tumours from patients with Peutz-Jeghers' syndrome provides evidence for a hamartoma-(adenoma)-carcinoma sequence.
Patients with Peutz-Jeghers' syndrome (PJS) develop hamartomatous gastrointestinal polyps and characteristic pigmentation, as a result of germline mutations in the LKB1 gene. The hamartomas in PJS were long considered to be without malignant potential. There is, however, accumulating epidemiological evidence to suggest that PJS predisposes to cancers at several different sites (colon, pancreas, breast, ovary, testis, and cervix), although large enough patient samples are rarely available to prove this. Allelic imbalance [allele loss, loss of heterozygosity (LOH)] has previously been reported in a small number of PJS polyps, suggesting that LKB1 acts as a tumour suppressor in these tumours. This study confirms allelic loss at LKB1 in PJS polyps and shows that LOH also occurs in cancers of the colon, breast, and cervix in PJS patients. Allele loss was additionally found in a colonic adenoma from a PJS patient, strongly suggesting the existence of a hamartoma-(adenoma)-carcinoma sequence in tumourigenesis. These results provide molecular evidence that PJS patients are predisposed to cancers at several sites, as a direct result of selection for loss of the 'wild-type' LKB1 allele in tumours. Given the rare involvement of LKB1 in sporadic cancers, these data also suggest that the indirect effect on cancer risk (or 'bystander effect') proposed for hamartomas in juvenile polyposis does not apply to carcinomas in PJS.
Tumour Genetics Group, Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, U.K.
Z J
ZJ
Wang
I
I
Ellis
P
P
Zauber
T
T
Iwama
C
C
Marchese
I
I
Talbot
W H
WH
Xue
Z Y
ZY
Yan
I
I
Tomlinson
D000091162:AMP-Activated Protein Kinase Kinases; D000236:Adenoma / Q000235:genetics*; D000328:Adult; D000368:Aged; D000483:Alleles; D002277:Carcinoma / Q000235:genetics*; D018450:Disease Progression; D004591:Electrophoresis, Polyacrylamide Gel; D018095:Germ-Line Mutation; D006222:Hamartoma / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D010580:Peutz-Jeghers Syndrome / Q000473:pathology*; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*
D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases