Abstract
BackgroundPeutz-Jeghers syndrome (PJS) is caused by mutations in serine/threonine kinase 11 (STK11) gene. The increased cancer risk has been connected to P53 pathway.MethodsPJS probands with STK11 mutation were included in the function analysis. P53 activity elevated by STK11 mutants was investigated using dual-luciferase reporter assay in vitro after constructing expression vectors of STK11 wild type and mutants generated by site-directed substitution. The association between the P53 activity and clinicopathological factors was analysis, especially the cancer history.ResultsThirteen probands with STK11 mutations were involved, and within the mutations, c.G924A was novel. P53 activity elevation caused by 6 truncating mutations were significantly lower than that of STK11 wild type (P < 0.05). Family history of cancer was observed in 5 families. Within them, P53 activity was reduced and cancer occurred before 40 in 2 families, while it was not significantly changed and cancers happened after 45 in the other 3 families.ConclusionsThe affected P53 activity caused by STK11 mutations in PJS patients is significantly associated with protein truncation, while cancer risk in PJS can be elevated through pathways rather than P53 pathway. P53 activity test is probably a useful supporting method to predict cancer risk in PJS, which could be helpful in clinical practice.
Highlights
Peutz-Jeghers syndrome (PJS) is caused by mutations in serine/threonine kinase 11 (STK11) gene
Backgroud Peutz-Jeghers syndrome (PJS; OMIM #175200) is an autosomal dominant disorder characterised by mucocutaneous melanin pigmentation (MP), gastrointestinal(GI) hamartomatous polyposis, and an increased risk for the development of various neoplasms [1, 2], which is rare with a low incidence of 1/50,000 [3]
We identified mutations in STK11 gene from Chinese PJS probands, and observed the changes in P53 activity brought by different STK11 mutants and their association with the canceration in PJS
Summary
PJS probands with STK11 mutation were included in the function analysis. P53 activity elevated by STK11 mutants was investigated using dual-luciferase reporter assay in vitro after constructing expression vectors of STK11 wild type and mutants generated by site-directed substitution. The association between the P53 activity and clinicopathological factors was analysis, especially the cancer history. Patient and sample collection Materials in this study were collected retrospectively. A total of 154 PJS patients were ascertained in Airforce General Hospital of PLA between May 2013 and April 2016. Blood samples of the probands and all available family members were collected after obtaining informed consent. This study was approved by the Medical Ethics Committee, Airforce General Hospital of PLA. PJS patients with both complete information and mutation detected and successfully constructed were included in final analysis. Clinical diagnosis for PJS was based on the presence of any one of the following clinical findings which was recommended by WHO [22]: (1) three or more histologically confirmed PJ polyps (PJP) in the gastrointestinal tract, (2) any number of PJPs detected with a positive family history of PJS, (3) characteristic mucocutaneous pigmentation with a positive family history of PJS, and (4) any number of PJPs together with characteristic mucocutaneous pigmentation (MP)
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