Polyposis and tumorigenesis in Peutz-Jeghers Syndrome

Peutz-Jeghers Syndrome is a dominantly inherited disorder characterized by mucocutaneous melanin pigmentation, hamartomatous polyps and an increased cancer risk. The molecular characteristics of PJS polyposis and tumorigenesis are still not completely understood and although LKB1 mutations have been described in the germline of PJS patients, not in all PJS patients an inactivation of LKB1 has been identified. We performed an LKB1 mutation analysis and exon deletion screen in a panel of 22 PJS patients and identified LKB1 inactivating mutations in 91% of PJS patients consisting of point mutations in 77% and exon deletions in 14% of patients. Therefore the presence of a second PJS gene was suggested. It has already been described that interaction between LKB1 and STRAD results in the polarization of single intestinal epithelial cells. This polarity function of LKB1 might underlie PJS symptoms and tumorigenesis in general, since LKB1 is inactivated in sporadic tumours as well. An LKB1 interacting protein like STRAD might also be involved in this process. We could, however, not identify any germline mutations in STRAD in PJS patients without LKB1 mutation. Since the MARK proteins have been shown to be activated by LKB1 and a MARK homologue is involved in cell polarity like LKB1, we hypothesized that the MARK genes might be interesting candidates for a second PJS gene. However, we did not find any mutations in the MARK genes. Based on the lack of mutations in these candidate genes and genes examined in literature we speculate that alterations in LKB1 will prove to be the sole cause of PJS. Analysis of molecular markers in PJS polyps and tumours showed that COX-2 was over-expressed in hamartomas and carcinomas, providing a rationale for chemopreventive studies with NSAIDs or COX-2-inhibitors against carcinogenesis in PJS. We furthermore showed that nasal PJS polyps are a distinct histopathologic and molecular entity. PJS polyp formation remains unclear and also whether PJS polyps carry any pre-neoplastic risk remains debated. We postulated that PJS polyps develop due to mucosal prolapse. This hypothesis is based on the observation that the histopathology of PJS polyps is consistent with mucosal prolapse. Furthermore, analysis of model systems designed to investigate LKB1 or the LKB1 interacting protein par1 demonstrates that inactivation of these proteins results in consistent phenotypes of epithelial prolapse. Therefore, the LKB1 germline defect may predispose to epithelial prolapse and this may contribute to the formation of PJS polyps. This would implicate that PJS polyps are polyclonal expansions and therefore harbor no neoplastic potential. We tested this hypothesis and confirmed that PJS polyps are indeed polyclonal expansions. Loss of polarity has also been suggested to lead to expansion of the stem cell compartment and we therefore assessed the length of the progenitor cell compartment in these polyps and found that the progenitor zone in normal intestinal epithelium of PJS patients is elongated compared to normal intestinal epithelium. Loss of the polarity function of LKB1 may result in deregulation of stem cell divisions ultimately leading to both polyp and tumour formation in PJS