Although a tentative molecular classification of PJS patients was recently made according to their LKB1 mutation status, it is difficult to clarify the genotype-phenotype relationship because of the rarity and genetic heterogeneity of this disease.
Here we review how the substrates and cellular functions of LKB1 may be linked to Peutz-Jeghers syndrome and other diseases, and discuss how some of the molecular changes associated with altered LKB1 signaling might be used in therapeutic approaches.
These findings demonstrate that exonic STK11 deletions are a common cause of PJS and provide a strong rationale for conducting a primary screen for such mutations in patients.
To seek evidence for LKB1 germline deletions or duplications by screening patients meeting clinical criteria for PJS but without detected mutations on conventional screening.
This suggests that pathogenic LKB1 mutations that lead to activation of the Wnt/beta-catenin pathway could contribute to the cancer predisposition of PJS patients.
This is the first report of a STK11 germline mutation in a PJS patient with GC and should contribute to establishing correlations between the STK11 germline mutations and GC in PJS patients.
A series of 33 PJS cases in whom no mutation in STK11/LKB1 could be identified were screened for sequence changes in the putative promoter defined by nucleotides -1090 to -1472.
Eight candidate genes mapping to the breakpoint region--U2AF2, EPN1, NALP4, NALP11, NALP5, ZNF444, PTPRH, and KIAA1811--were screened for mutations in germ-line and polyp DNA from the case and from 15 PJS cases that did not harbor germ-line STK11 mutations.
Sequencing analysis of the STK11/LKB1 gene in these IPMNs with LOH revealed a germline mutation in one IPMN that arose in a patient with PJS and a somatic mutation in 1 of the 20 sporadic IPMNs.
As a consequence of novel mutational mechanisms identified we discuss the impact of RNA based strategies for the detection of germinal STK11 mutations in PJS.