Generalized Intestinal Polyposis and Melanin Spots of the Oral Mucosa, Lips and Digits

Jeghers, Harold; McKusick, Victor A.; Katz, Kermit H.

doi:10.1056/nejm194912292412601

Cited by 496 publications

(162 citation statements)

References 13 publications

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“…Real-time quantitative RT-PCR on 15 tumors confirmed the upregulation of the homeobox MEIS2 and of the AMP-metabolism AMPD3 transcripts in LKB1-mutant tumors. In addition, immunohistochemistry in 10 of the lung tumors showed the absence of phosphorylated FRAP1/mTOR protein in LKB1-mutant tumors, indicating that LKB1 mutations do not lead to FRAP1/mTOR Introduction Germ-line mutations of the LKB1 gene, also named STK11, cause Peutz-Jeghers syndrome (PJS) (Hemminki et al, 1998;Jenne et al, 1998), an autosomal dominant genetic disorder that predisposes to a wide variety of malignancies predominantly of the gastrointestinal tract and also the genitourinary tract, breast and lung (Jeghers et al, 1949;Giardiello et al, 1987). We recently detected somatic LKB1 gene-inactivating mutations in one-third of sporadic lung adenocarcinomas (LADs) and in half of lung cancer cell lines of the LAD histological type, indicating that LKB1 plays a relevant role in an extremely frequent cancer type such as is that of the lung (Sanchez-Cespedes et al, 2002;Carretero et al, 2004).…”

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confidence: 99%

Distinctive gene expression of human lung adenocarcinomas carrying LKB1 mutations

et al. 2004

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LKB1, a tumor-suppressor gene that codifies for a serine/ threonine kinase, is mutated in the germ-line of patients affected with the Peutz-Jeghers syndrome (PJS), which have an increased incidence of several cancers including gastrointestinal, pancreatic and lung carcinomas. Regarding tumors arising in non-PJS patients, we recently observed that at least one-third of lung adenocarcinomas (LADs) harbor somatic LKB1 gene mutations, supporting a role for LKB1 in the origin of some sporadic tumors. To characterize the pattern of LKB1 mutations in LADs further, we first screened for LKB1 gene alterations (gene mutations, promoter hypermethylation and homozygous deletions) in 19 LADs and, in agreement with our previous data, five of them (26%) were shown to harbor mutations, all of which gave rise to a truncated protein. Recent reports demonstrate that LKB1 is able to suppress cell growth, but little is known about the specific mechanism by which it functions. To further our understanding of LKB1 function, we analysed global expression in lung primary tumors using cDNA microarrays to identify LKB1-specific variations in gene expression. In all, 34 transcripts, 24 of which corresponded to known genes, differed significantly between tumors with and without LKB1 gene alterations. Among the most remarkable findings was deregulation of transcripts involved in signal transduction (e.g. FRAP1/mTOR, ARAF1 and ROCK2), cytoskeleton (e.g. MPP1), transcription factors (e.g. MEIS2, ATF5), metabolism of AMP (AMPD3 and APRT) and ubiquitinization (e.g. USP16 and UBE2L3). Real-time quantitative RT-PCR on 15 tumors confirmed the upregulation of the homeobox MEIS2 and of the AMP-metabolism AMPD3 transcripts in LKB1-mutant tumors. In addition, immunohistochemistry in 10 of the lung tumors showed the absence of phosphorylated FRAP1/mTOR protein in LKB1-mutant tumors, indicating that LKB1 mutations do not lead to FRAP1/mTOR protein kinase activation. In conclusion, our results reveal that several important factors contribute to LKB1-mediated carcinogenesis in LADs, confirming previous observations and identifying new putative pathways that should help to elucidate the biological role of LKB1.

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confidence: 99%

Distinctive gene expression of human lung adenocarcinomas carrying LKB1 mutations

et al. 2004

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“…P eutz-Jeghers syndrome (PJS) is a rare inherited disease in which patients develop gastrointestinal hamartomatous polyps in early adulthood and exhibit mucocutaneous pigmentation on the skin and oral mucosa (1,2). PJS polyposis is frequently associated with bleeding, intussusception, and obstruction.…”

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Induction of cyclooxygenase-2 in a mouse model of Peutz–Jeghers polyposis

Rossi

Ylikorkala

Korsisaari

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

111

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Inactivating germ-line mutations of LKB1 lead to Peutz-Jeghers syndrome (PJS). We have generated mice heterozygous for a targeted inactivating allele of Lkb1 and found that they develop severe gastrointestinal polyposis. In all cases, the polyps arising in the Lkb1 ؉/؊ mice were found to be hamartomas that were histologically indistinguishable from polyps resected from PJS patients, indicating that Lkb1 ؉/؊ mice model human PJS polyposis. No evidence for inactivation of the remaining wild-type Lkb1 allele in Lkb1 ؉/؊ -associated polyps was observed. Moreover, polyps and other tissues in heterozygote animals exhibited reduced Lkb1 levels and activity, indicating that Lkb1 was haploinsufficient for tumor suppression. Analysis of the molecular mechanisms characterizing Lkb1 ؉/؊ polyposis revealed that cyclooxygenase-2 (COX-2) was highly up-regulated in murine polyps concomitantly with activation of the extracellular signal-regulated kinases 1 and 2 (Erk1͞2). Subsequent examination of a large series of human PJS polyps revealed that COX-2 was also highly up-regulated in the majority of these polyps. These findings thereby identify COX-2 as a potential target for chemoprevention in PJS patients.tumor suppressor ͉ mitogen-activated protein kinase ͉ serine-threonine kinase ͉ hamartoma ͉ biallelic inactivation

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“…PJS is a rare autosomal dominant disorder associated with mucocutaneous pigmentation (buccal mucosa, lips, fingers, and toes) and a family history of this condition [3] . Solitary PJ-type polyps, defined as hamartomatous polyps without any of the clinical symptoms of PJS, are characterized histologically by tree-like branching of smooth muscle fibers, with a core of smooth muscle, covered by mucosal tissue of nearnormal appearance [4] .…”

Section: Discussionmentioning

confidence: 99%

Endoscopic snare papillectomy for a solitary Peutz-Jeghers-type polyp in the duodenum with ingrowth into the common bile duct: Case report

Suzuki

Higuchi

Shimizu

et al. 2015

WJG

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Solitary duodenal Peutz-Jeghers (PJ)-type hamartomatous polyps are rare and considered a different disease entity than classic PJ syndrome. We describe the case of an 89-year-old man admitted to our emergency department with symptoms of acute cholangitis, liver dysfunction, and slight jaundice. Magnetic resonance imaging showed multiple signal voids, reflecting choledocholithiasis, and an ovalshaped tumor in the common bile duct (CBD). Following endoscopic retrograde cholangiopancreatography, the patient was diagnosed with a lower CBD tumor 20 mm in diameter. Endoscopic sphincterotomy was performed for choledocholithotomy, resulting in the expulsion of a large tumor with a stalk connected to the papilla of Vater. The tumor was successfully excised en bloc by endoscopic snare papillectomy. Histopathologic examination showed that the tumor was a PJ-type hamartomatous polyp. No mucocutaneous pigmentation of the skin was evident and the patient's family history was negative. Solitary duodenal PJ-type hamartomatous polyps are usually diagnosed incidentally during endoscopy for other indications because most of these tumors are asymptomatic or have nonspecific presentations. To our knowledge, this is the first reported solitary PJ-type polyp with intra-CBD growth treated by endoscopic snare papillectomy.

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Generalized Intestinal Polyposis and Melanin Spots of the Oral Mucosa, Lips and Digits

Cited by 496 publications

References 13 publications

Distinctive gene expression of human lung adenocarcinomas carrying LKB1 mutations

Distinctive gene expression of human lung adenocarcinomas carrying LKB1 mutations

Induction of cyclooxygenase-2 in a mouse model of Peutz–Jeghers polyposis

Endoscopic snare papillectomy for a solitary Peutz-Jeghers-type polyp in the duodenum with ingrowth into the common bile duct: Case report

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