The altered activity of P53 signaling pathway by STK11 gene mutations and its cancer phenotype in Peutz-Jeghers syndrome

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.Electronic supplementary materialThe online version of this article (10.1186/s12881-018-0626-5) contains supplementary material, which is available to authorized users.

Early screening the small bowel is key to protect Peutz-Jeghers syndrome patients from surgery: a novel mutation c.243delG in STK11 gene

“…STK11 protein comes into play by participating in several pathways. For example, we noticed that impaired P53 activity caused by STK11 mutations in PJS patients is significantly related to cancer risk [12]. Multiplex ligation–dependent probe amplification (MLPA) together with direct sequencing raise the mutation detection rate to over 60% in most instances [13].…”

Hamartomatous polyposis syndrome associated malignancies: Risk, pathogenesis and endoscopic surveillance

“…As mentioned above, the LOH of STK11 or LKB1 gene is common in PJS polyps and carcinoma. A group of researchers found that abnormal p53 activity caused by a STK11 mutation leads to protein truncation and increases the risk of cancer in patients with PJS 60 . Another group showed that a possible mechanism of LKB1 inactivation resulting in colorectal malignancy led to centromere defects and genome instability via the p53‐dependent upregulation of survivin 61 …”

Role of the Serine/Threonine Kinase 11 (STK11) or Liver Kinase B1 (LKB1) Gene in Peutz-Jeghers Syndrome

“…However, further research findings by two-research groups revealed the involvement of LKB1 (liver kinase B1) gene mutation (also recognised as STK11 [serine/threonine kinase 11] gene) on expression of mucocutaneous melanosis. A 30%-70% of PJS sporadic cases associated with STK11/LKB1 gene mutation, however, the rate of spontaneous mutation in mucocutaneous melanosis is under investigation 9,10 . The main setback in identification of STK11/LKB1 gene in mucocutaneous melanosis patients is genetic mosaicism, lack of effective molecular techniques PJS loci, etc.. Later some studies on PJS revealed the link of loci on chromosome 16q and19q for expression of mucocutaneous melanosis.…”