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 gastroint estinal polyps and characteristic pigmentation, as a result of germline mut ations in the LKB1 gene, The hamartomas in PJS were long considered to be w ithout malignant potential, There is, however, accumulating epidemiological evidence to suggest that PJS predisposes to cancers at several different s ites (colon, pancreas, breast, ovary, testis, and cervix), although large e nough patient samples are rarely available to prove this. Allelic imbalance [allele loss, loss of heterozygosity (LOH)] has previously been reported i n a small number of PJS polyps, suggesting that LKB1 acts as a tumour suppr essor in these tumours, This stud confirms allelic loss at LKB1 in PJS poly ps and shows that LOH also occurs in cancers of the colon, breast, and cerv ix in PJS patients. Allele loss,vas additionally found in a colonic adenoma from a PJS patient, strongly suggesting the existence of a hamartoma-(aden oma)-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 tum ours, Given the rare involvement of LKB1 in sporadic cancers, these data al so suggest that the indirect effect on cancer risk (or 'bystander effect') proposed for hamartomas in juvenile polyposis does not apply to carcinomas in PJS, Copyright (C) 1999 John Wiley & Sons, Ltd.