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J Clin Pathol. 2001 February; 54(2): 126–131.
PMCID: PMC1731344

Molecular genetic alterations in hamartomatous polyps and carcinomas of patients with Peutz-Jeghers syndrome


Aim—To investigate whether mutations in the STK11/LKB1 gene and genes implicated in the colorectal adenoma–carcinoma sequence are involved in Peutz-Jeghers syndrome (PJS) related tumorigenesis.

Methods—Thirty nine polyps and five carcinomas from 17 patients (from 13 families) with PJS were analysed for loss of heterozygosity (LOH) at 19p13.3 (STK11/LKB1 gene locus), 5q21 (APC gene locus), 18q21–22 (Smad4 and Smad2 gene locus), and 17p13 (p53 gene locus), and evaluated for immunohistochemical staining of p53. In addition, mutational analysis of K-ras codon 12, APC, and p53 and immunohistochemistry for Smad4 expression were performed on all carcinomas.

Results—LOH at 19p was seen in 15 of the 39 polyps and in all carcinomas (n = 5). Interestingly, six of the seven polyps from patients with cancer had LOH, compared with nine of the 31 polyps from the remaining patients (p = 0.01). In one polyp from a patient without a germline STK11/LKB1 mutation, no LOH at 19p or at three alternative PJS candidate loci (19q, 6p, and 6q) was found. No LOH at 5q was observed. However, mutational analysis revealed an APC mutation in four of the five carcinomas. LOH at 17p was not seen in polyps or carcinomas; immunohistochemistry showed expression of p53 in one carcinoma and focal expression in three polyps. At subsequent sequence analysis, no p53 mutation was found. One carcinoma had an activating K-ras codon 12 mutation and another carcinoma showed 18q LOH; however, no loss of Smad4 expression was seen.

Conclusions—These results provide further evidence that STK11/LKB1 acts as a tumour suppressor gene, and may be involved in the early stages of PJS tumorigenesis. Further research is needed to see whether LOH in PJS polyps could be used as a biomarker to predict cancer. Differences in molecular genetic alterations noted between the adenoma–carcinoma sequence and PJS related tumours suggest the presence of a distinct pathway of carcinogenesis.

Key Words: Peutz-Jeghers syndrome • carcinogenesis • STK11/LKB1 • hamartoma

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Figure 1 (A) Loss of heterozygosity (LOH) at the STK11/LKB1 locus 19p in a hamartomatous polyp (P) and a colonic carcinoma (C) from patients with Peutz-Jeghers syndrome. DNA extracted from normal tissue (N) is displayed next to tumour DNA. (B) LOH at ...
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Figure 2 Denaturing gradient gel electrophoresis pattern of an APC gene mutation in fragment S3 of the APC mutation cluster region (MCR) in a Peutz-Jeghers syndrome (PJS) carcinoma (lane 1). Wild-type fragment S3 from a different PJS carcinoma (lane ...
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Figure 3 Immunohistochemical expression of p53 in a colon carcinoma of a patient with Peutz-Jeghers syndrome.

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