Cancer and the Peutz-Jeghers syndrome.

Spigelman, A D; Murday, Victoria; Phillips, R. K. S.

doi:10.1136/gut.30.11.1588

Cited by 283 publications

(149 citation statements)

References 16 publications

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“…It is now well recognised that cancer risks are markedly elevated in PJS (Giardello et al, 1987(Giardello et al, , 2000Spigelman et al, 1989). Diagnosing PJS in the absence of mutation data, especially in those without a prior family history of the disease, can however be difficult as pigmentation may not always be present or can fade and polyposis is not always an invariable feature.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to an elevated risk of gastrointestinal malignancies, an increased risk of cancers at other sites is recognized; in particular, breast, pancreas, ovary, uterus, cervix, lung and testicular cancers have been reported (Giardello et al, 1987(Giardello et al, , 2000Spigelman et al, 1989). Testicular sex cord and Sertoli-cell tumours may occur in prepubertal boys affected with PJS leading to sexual precocity and gynaecomastia (Wilson et al, 1986;Coen et al, 1991;Young et al, 1995).…”

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confidence: 99%

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Further observations on LKB1/STK11 status and cancer risk in Peutz–Jeghers syndrome

et al. 2003

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Germline mutations in the LKB1/STK11 tumour suppressor gene cause Peutz -Jeghers syndrome (PJS), a rare dominant disorder. In addition to typical hamartomatous gastrointestinal polyps and pigmented perioral lesions, PJS is associated with an increased risk of tumours at multiple sites. Follow-up information on carriers is limited and genetic heterogeneity makes counselling and management in PJS difficult. Here we report the analysis of the LKB1/STK11 locus in a series of 33 PJS families, and estimation of cancer risks in carriers and noncarriers. Germline mutations of LKB1/STK11 were identified in 52% of cases. This observation reinforces the hypothesis of a second PJS locus. In carriers of LKB1/STK11 mutations, the risk of cancer was markedly elevated. The risk of developing any cancer in carriers by age 65 years was 47% (95% CI: 27 -73%) with elevated risks of both gastrointestinal and breast cancer. PJS with germline mutations in LKB1/STK11 are at a very high relative and absolute risk of multiple gastrointestinal and nongastrointestinal cancers. To obtain precise estimates of risk associated with PJS requires further studies of genotype -phenotype especially with respect to LKB1/STK11 negative cases, as this group is likely to be heterogeneous.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Further observations on LKB1/STK11 status and cancer risk in Peutz–Jeghers syndrome

et al. 2003

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“…Although there is a possibility that these could transform to become carcinomas, there are several lines of evidence suggesting otherwise and that this aspect of PJS might be functionally separate from the role of LKB1 in suppressing malignant transformation (see below; 'Benign and malignant tumorigenesis'). A markedly increased incidence of carcinomas of the gastrointestinal tract including stomach, small bowel, colon and pancreatic cancer, as well as breast, ovary, uterus, cervix, lung and testis cancer has been observed through longitudinal studies of affected kindreds (Giardiello et al, 1987(Giardiello et al, , 2000Spigelman et al, 1989;Gruber et al, 1998;Lim et al, 2004;Hearle et al, 2006). In addition, rare tumors have been associated with PJS including those of a reproductive origin-including testicular and ovarian sex cord tumors, Sertoli cell tumors and adenoma malignum of the cervix-as well as non-adenocarcinoma pancreatic tumors, including pancreatic intraductal papillary mucinous neoplasia and serous cystadenomas (Podczaski et al, 1991;Young et al, 1995;Tomlinson and Houlston, 1997;Su et al, 1999;Sato et al, 2001;Yee et al, 2003).…”

Section: Peutz-jeghers Syndrome and Human Cancer Geneticsmentioning

confidence: 99%

LKB1; linking cell structure and tumor suppression

2008

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Germ line mutations in the LKB1 tumor suppressor gene are associated with the Peutz-Jeghers polyposis and cancer syndrome. Somatic mutations in Lkb1 are observed in sporadic pulmonary, pancreatic and biliary cancers and melanomas. The LKB1 serine-threonine kinase functionally and biochemically links control of cellular structure and energy utilization through activation of the AMPK family of kinases. Lkb1 regulates cell polarity through downstream kinases including AMPKs, MARKs and BRSKs, and nutrient utilization and cellular metabolism through the AMPK-mTOR pathway. LKB1 has been shown to affect normal chromosomal segregation, TGF-b signaling in the mesenchyme and WNT and p53 activity. Although each of the LKB1-dependent processes and downstream pathways have been individually delineated through work across a range of experimental systems, how they relate to Lkb1's role as a tumor suppressor remains to be fully explored and elucidated. The recent development of mouse cancer models harboring engineered mutations in Lkb1 have offered insights into how LKB1 may be functioning to restrain tumorigenesis and how its role as a master regulator of polarity and metabolism could contribute to its tumor suppressor function.

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“…1,2 PJS patients have a highly increased risk of malignant tumors, especially in the gastrointestinal tract, breast, uterine cervix, and ovary. [3][4][5] Many of these tumors acquire somatic mutations in the remaining wildtype allele of LKB1. 6,7 Moreover, various sporadic cancers are also associated with the loss of LKB1, implicating the general role of LKB1 in tumor suppression.…”

Section: Introductionmentioning

confidence: 99%

JNK pathway mediates apoptotic cell death induced by tumor suppressor LKB1 in Drosophila

et al. 2005

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Although recent progresses have unveiled the diverse in vivo functions of LKB1, detailed molecular mechanisms governing these processes still remain enigmatic. Here, we showed that Drosophila LKB1 negatively regulates organ growth by caspase-dependent apoptosis, without affecting cell size and cell cycle progression. Through genetic screening for LKB1 modifiers, we discovered the JNK pathway as a novel component of LKB1 signaling; the JNK pathway was activated by LKB1 and mediated the LKB1-dependent apoptosis. Consistently, LKB1-null mutant was defective in embryonic apoptosis and displayed a drastic hyperplasia in the central nervous system; these phenotypes were fully rescued by ectopic JNK activation as well as wild-type LKB1 expression. Furthermore, inhibition of LKB1 resulted in epithelial morphogenesis failure, which was associated with a decrease in JNK activity. Collectively, our studies unprecedentedly elucidate JNK as the downstream mediator of the LKB1-dependent apoptosis, and provide a new paradigm for understanding the diverse LKB1 functions in vivo.

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Cancer and the Peutz-Jeghers syndrome.

Cited by 283 publications

References 16 publications

Further observations on LKB1/STK11 status and cancer risk in Peutz–Jeghers syndrome

Further observations on LKB1/STK11 status and cancer risk in Peutz–Jeghers syndrome

LKB1; linking cell structure and tumor suppression

JNK pathway mediates apoptotic cell death induced by tumor suppressor LKB1 in Drosophila

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