High Cancer Risk in Peutz–Jeghers Syndrome: A Systematic Review and Surveillance Recommendations

Lier, Margot G F van; Wagner, Anja; Mathus-Vliegen, E. M. H.; Kuipers, Ernst J.; Steyerberg, Ewout W.; Leerdam, Monique E. van

doi:10.1038/ajg.2009.725

Cited by 457 publications

(308 citation statements)

References 61 publications

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“…The fact that sensitivity is conferred by loss of a tumor suppressor predicts a favorable therapeutic index, and indeed metformin is well tolerated systemically at doses that inhibit growth in the LKB1-deficient tumor model. Somatic cell mutations of LKB1 are common in human lung, cervical and squamous cancers (Sanchez-Cespedes et al, 2002;Ji et al, 2007;Wingo et al, 2009) and a variety of LKB1 null neoplasms arise in patients with Peutz-Jeghers syndrome (van Lier et al, 2010). Although LKB1 functions upstream of 12 AMPK-related kinases (Shackelford and Shaw, 2009) and shRNA against LKB1 may also affect these related kinases, we attributed our results to impaired activation of AMPK and downstream targets, as our results are consistent with those observed in AMPK null mouse embryonic fibroblasts under similar experimental conditions as shown in Buzzai et al (2007).…”

Section: Discussionmentioning

confidence: 99%

Diet and tumor LKB1 expression interact to determine sensitivity to anti-neoplastic effects of metformin in vivo

et al. 2010

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Hypothesis-generating epidemiological research has suggested that cancer burden is reduced in diabetics treated with metformin and experimental work has raised questions regarding the role of direct adenosine monophosphate-activated protein kinase (AMPK)-mediated antineoplastic effects of metformin as compared with indirect effects attributable to reductions in circulating insulin levels in the host. We treated both tumor LKB1 expression and host diet as variables, and observed that metformin inhibited tumor growth and reduced insulin receptor activation in tumors of mice with diet-induced hyperinsulinemia, independent of tumor LKB1 expression. In the absence of hyperinsulinemia, metformin inhibited only the growth of tumors transfected with short hairpin RNA against LKB1, a finding attributable neither to an effect on host insulin level nor to activation of AMPK within the tumor. Further investigation in vitro showed that cells with reduced LKB1 expression are more sensitive to metformin-induced adenosine triphosphate depletion owing to impaired ability to activate LKB1-AMPK-dependent energy-conservation mechanisms. Thus, loss of function of LKB1 can accelerate proliferation in contexts where it functions as a tumor suppressor, but can also sensitize cells to metformin. These findings predict that any clinical utility of metformin or similar compounds in oncology will be restricted to subpopulations defined by host insulin levels and/or loss of function of LKB1.

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Section: Discussionmentioning

confidence: 99%

Diet and tumor LKB1 expression interact to determine sensitivity to anti-neoplastic effects of metformin in vivo

et al. 2010

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“…LKB1 was first recognized as a tumor-suppressor gene because its mutations cause Peutz-Jeghers syndrome, characterized by gastrointestinal hamartoma with an increased cancer risk (Giardiello et al, 2000;van Lier et al, 2010). This gene was later found to be a target for mutational inactivation in human malignancies including non-small cell lung carcinoma (Sanchez-Cespedes et al, 2002;Carretero et al, 2004;Ji et al, 2007;Matsumoto et al, 2007;Makowski and Hayes, 2008;Komiya et al, 2010;Mahoney et al, 2009), cervical carcinoma (Wingo et al, 2009), melanoma (Guldberg et al, 1999;Rowan et al, 1999) and others (Sanchez-Cespedes, 2007).…”

Section: Introductionmentioning

confidence: 99%

Altered LKB1/CREB-regulated transcription co-activator (CRTC) signaling axis promotes esophageal cancer cell migration and invasion

et al. 2011

Oncogene

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LKB1 is a tumor susceptibility gene for the Peutz-Jeghers cancer syndrome and is a target for mutational inactivation in sporadic human malignancies. LKB1 encodes a serine/threonine kinase that has critical roles in cell growth, polarity and metabolism. A novel and important function of LKB1 is its ability to regulate the phosphorylation of CREB-regulated transcription co-activators (CRTCs) whose aberrant activation is linked with oncogenic activities. However, the roles and mechanisms of LKB1 and CRTC in the pathogenesis of esophageal cancer have not been previously investigated. In this study, we observed altered LKB1-CRTC signaling in a subset of human esophageal cancer cell lines and patient samples. LKB1 negatively regulates esophageal cancer cell migration and invasion in vitro. Mechanistically, we determined that CRTC signaling becomes activated because of LKB1 loss, which results in the transcriptional activation of specific downstream targets including LYPD3, a critical mediator for LKB1 loss-of-function. Our data indicate that de-regulated LKB1-CRTC signaling might represent a crucial mechanism for esophageal cancer progression.

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“…1) and malignancies. Oral selective mTOR inhibitors such as rapamycin and everolimus have been successfully used in several exploratory studies [1], [2]. The report of a successful treatment of a PJS patient with pancreatic cancer with everolimus was the starting point for a more comprehensive study: the EVAMP trial [3].…”

Section: Discussionmentioning

confidence: 99%

“…Mutation spectrum: Peutz‐Jeghers syndrome (PJS) is an autosomal dominant condition characterized by multiple hamartomatous polyps of the gastrointestinal tract, the presence of mucocutaneous hyperpigmentation, and an elevated lifetime risk to develop cancer, varying between 37% and 93% [1]. The genetic abnormality responsible for the syndrome is a mutation in the LKB1/STK11 gene, which maps to 19p13 [2].…”

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confidence: 99%

Chemoprevention in Patients with Peutz-Jeghers Syndrome: Lessons Learned

et al. 2018

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Lessons Learned. Motivating patients to enroll in chemopreventive studies is challenging.Chemoprevention with toxic drugs is not feasible.Background.LKB1 mutations are the underlying genetic abnormality causing Peutz‐Jeghers syndrome (PJS) and are a potential target for everolimus. In this phase II study, the efficacy of everolimus on polyp and tumor growth in PJS patients was investigated.Methods.Adult patients with a proven LKB1 mutation and who were suitable for everolimus treatment were included in two different PJS cohorts: (a) patients with unresectable malignancies and (b) patients with high‐risk polyps. Treatment in both groups was oral everolimus, 10 mg daily. Response rates were primary endpoints for both cohorts.Results.Between October 2011 and April 2016, only two patients were enrolled, one in each cohort. A 49‐year‐old patient with advanced pancreatic cancer in cohort 1 was progressive after 2 months. A 52‐year‐old male patient in cohort 2 experienced severe toxicity and refused treatment after 4 months, even though endoscopy suggested stabilization of polyps. Adverse events included dental inflammations, mucositis, and rash. In 2016, the trial was aborted for lack of accrual, despite extensive accrual efforts in an area where PJS is highly prevalent and care is highly centralized.Conclusion.Due to accrual problems, no conclusions can be drawn about the value of everolimus in PJS treatment, questioning the feasibility of this agent for chemoprevention.

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High Cancer Risk in Peutz–Jeghers Syndrome: A Systematic Review and Surveillance Recommendations

Cited by 457 publications

References 61 publications

Diet and tumor LKB1 expression interact to determine sensitivity to anti-neoplastic effects of metformin in vivo

Diet and tumor LKB1 expression interact to determine sensitivity to anti-neoplastic effects of metformin in vivo

Altered LKB1/CREB-regulated transcription co-activator (CRTC) signaling axis promotes esophageal cancer cell migration and invasion

Chemoprevention in Patients with Peutz-Jeghers Syndrome: Lessons Learned

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