Somatic mutations in the Peutz-Jeghers (LKB1/STKII) gene in sporadic malignant melanoms. J Invest Dermatol

Newcastle University, Newcastle-on-Tyne, England, United Kingdom
Journal of Investigative Dermatology (Impact Factor: 7.22). 04/1999; 112(4):509-511. DOI: 10.1046/j.1523-1747.1999.00551.x


Germline mutations in the LKB1/STK11 gene cause characteristic hamartomas and freckling to develop in patients with Peutz–Jeghers syndrome (PJS). The hamartomas arise as a result of somatic “second hits” at LKB1/STK11 and therefore contain a neoplastic element. The origin of the pigmented lesions in PJS is unknown and difficult to test, as these are hardly ever biopsied. PJS patients are at increased risk of benign and malignant tumors, particularly of the colon, breast, pancreas, testis, and ovary, although the increased risk for any one of these sites may be quite modest. Somatic LKB1/STK11 mutations have been found, albeit at a low frequency, in sporadic tumors of the colon, stomach, ovary, and testis. Although PJS patients are not known to have an excess of skin tumors, if the freckles of PJS patients are actually small, benign tumors, LKB1/STK11 mutations must provide these lesions with a selective advantage, and similar mutations might also give a selective advantage to related malignant tumors, such as melanomas. We have therefore screened 16 melanoma cell lines, 15 primary melanomas, and 19 metastases for LKB1/STK11 mutations. Two LKB1/STK11 mutations were found: a missense change (Y49D) accompanied by allele loss in a cell line; and a missense change (G135R), without a detected mutation in the other allele, in a primary tumor. Both these mutations are highly likely to be pathogenic. Novel polymorphisms, including an unusual heptanucleotide repeat, were also found in introns 2 and 3. LKB1/STK11 mutations occur in a significant minority of tumors of several sites, including malignant melanomas.

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Available from: Andrew J Rowan, Aug 19, 2014
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    • "As a result AMPK kinase activation, ATP binding, and hence enzymatic activity by STK11 might be compromised. If so, M136K might act like the G135R mutant, which has been reported as a frequent mutation in melanoma [32], which also compromises control of AMPK. It is also expected that this non-conservative change would impact either protein-protein interactions or the secondary structure of the mutant protein. "
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    ABSTRACT: Peutz-Jeghers syndrome (PJS) is characterized by intestinal polyposis, mucocutaneous pigmentation and an increased cancer risk, usually caused by mutations of the STK11 gene. This study collected epidemiological, clinical and genetic data from all Uruguayan PJS patients. Clinical data were obtained from public and private medical centers and updated annually. Sequencing of the STK11 gene in one member of each family was performed. 25 cases in 11 unrelated families were registered (15 males, 10 females). The average age of diagnosis and death was 18 and 41 years respectively. All patients had characteristic PJS pigmentation and gastrointestinal polyps. 72% required urgent surgery due to intestinal obstruction. 3 families had multiple cases of seizure disorder, representing 20% of cases. 28% developed cancer and two patients had more than one cancer. An STK11 mutation was found in 8 of the 9 families analyzed. A unique M136K missense mutation was noted in one family. Comparing annual live births and PJS birth records from 1970 to 2009 yielded an incidence of 1 in 155,000. The Uruguayan Registry for Peutz-Jeghers patients showed a high chance of emergent surgery, epilepsy, cancer and shortened life expectancy. The M136K missense mutation is a newly reported STK 11 mutation.
    Full-text · Article · Nov 2013 · PLoS ONE
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    • "In contrast, although allelic loss at the LKB1 locus (chromosome 19p13.3) is observed in many cancers, somatic mutations in LKB1 are relatively rare in most common tumor types, including colon [41] , breast [42] , ovarian [43] , and brain [44] cancers. However, mutations in LKB1 do occur in a small fraction of malignant melanomas [45] [46] , cervical cancers [47] [48] , and pancreatic cancers [49] [50] . "
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    ABSTRACT: Mammalian target of Rapamycin (mTOR) is aberrant activated in many cancer types, and two Rapamycin derivatives are currently approved by FDA for the treatment of renal cell carcinoma. Mechanistically, mTOR is hyperactivated in human cancers either due to the genetic activation of its upstream activating signaling pathways or the genetic inactivation of its negative regulators. The tumor suppressor liver kinase B1 (LKB1; also known as serine/threonine kinase 11, STK11) involves in cell polarity, cell detachment and adhesion, tumor metastasis, and energetic stress response. One of LKB1's key roles is to negatively regulate mTOR complex 1 (mTORC1) activity. This review summarizes the molecular basis of this negative interaction, and recent research progress in this area.
    Full-text · Article · May 2013 · Ai zheng = Aizheng = Chinese journal of cancer
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    • "Patients with PJS are tumor prone, demonstrating a significantly increased risk for several cancers (e.g., of colon, pancreas, breast, ovary, and testis) (Giardiello et al., 2000; Lim et al., 2004; Sanchez- Cespedes, 2007). Somatic LKB1 mutations also are common in sporadic cancers: most notably lung adenocarcinoma (~30%; Ji et al., 2007; Weir et al., 2007), cervical carcinoma (~15%; Forbes et al., 2011; Wingo et al., 2009), and melanoma (~10%; Forbes et al., 2011; Guldberg et al., 1999; Rowan et al., 1999). "
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    ABSTRACT: Germline mutations in LKB1 (STK11) are associated with the Peutz-Jeghers syndrome (PJS), which includes aberrant mucocutaneous pigmentation, and somatic LKB1 mutations occur in 10% of cutaneous melanoma. By somatically inactivating Lkb1 with K-Ras activation (±p53 loss) in murine melanocytes, we observed variably pigmented and highly metastatic melanoma with 100% penetrance. LKB1 deficiency resulted in increased phosphorylation of the SRC family kinase (SFK) YES, increased expression of WNT target genes, and expansion of a CD24(+) cell population, which showed increased metastatic behavior in vitro and in vivo relative to isogenic CD24(-) cells. These results suggest that LKB1 inactivation in the context of RAS activation facilitates metastasis by inducing an SFK-dependent expansion of a prometastatic, CD24(+) tumor subpopulation.
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