LKB1 mutations in mucinous bronchioloalveolar carcinoma occurring in Peutz-Jeghers syndrome patients

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 11047-11047
Author(s):  
A. Osoegawa ◽  
Y. Takeda ◽  
T. Kometani ◽  
K. Ondo ◽  
S. Fukuyama ◽  
...  
Keyword(s):  
Direct Sequencing ◽  
Bronchioloalveolar Carcinoma ◽  
Lung Carcinogenesis ◽  
Gene Encoding ◽  
Independent Sequence ◽  
Ethical Approval ◽  
Mucocutaneous Pigmentation ◽  
Liver Kinase B1 ◽  
Peutz Jeghers Syndrome ◽  
Tissue Specimens

11047 Background: Mutations in the gene encoding Liver Kinase B1, LKB1, are common in patients with Peutz-Jeghers syndrome (PJS), which is characterized by mucocutaneous pigmentation, intestinal polyps and a high incidence of cancers at variable sites (colorectal, gynecological, breast, pancreas, and lung). Although tumors occurring in PJS patients are known to contain mucin-rich conmponents, mucinous bronchioloalveolar carcinomas (mBACs) arising from the PJS background have only rarely been reported. Here we report two mBAC patients with PJS. We further explored the LKB1 gene in these two patients and, in addition, eight sporadic mBAC patients. Methods: Frozen tissue specimens were collected from ten mBAC patients who underwent surgery in our department from 2002 to 2008, and high molecular weight genomic DNA was extracted from them and stocked in the bio-bank. Written informed consent was obtained from each patient, and ethical approval was obtained from the IRB. The nucleotide sequence of LKB1 (EX01–09) was determined by genomic PCR-direct sequencing. Loss of heterozygosity (LOH) was analyzed by high resolution fluorescent microsatellite analysis (HRFMA) using two microsatellite markers that encompass the LKB1 locus, D19S886 and D19S565. Results: Among 11 tumors derived from the 10 patients, 9 distinct LKB1 mutations were found in 7 tumors (4 G:C to A:T transitions; 3 G:C to C:G transversions; 2 single nucleotide insetion/deletion). All of three tumors obtained from the two PJS patients harbored a same sequence alteration. Although LOH was not observed in these tumors, independent sequence alterations were found in two of the three tumors, which may suggest biallelic inactivation of LKB1 in tumors occurred in the PJS patients. Conclusions: The relatively high frequency of LKB1 mutation in mBAC patients may suggest its implication in lung carcinogenesis, at least in mBAC, and its potential as a therapeutic target. [Table: see text] No significant financial relationships to disclose.

Gene of the month: STK11

2021 ◽  
pp. jclinpath-2021-207906
Author(s):  
Roman E Zyla ◽  
Elan Hahn ◽  
Anjelica Hodgson
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Poor Response ◽  
Loss Of Function ◽  
Hamartomatous Polyps ◽  
Lung Cancers ◽  
Physiological Processes ◽  
Mucocutaneous Pigmentation ◽  
Liver Kinase B1 ◽  
Peutz Jeghers Syndrome ◽  
Amp Activated Protein Kinase

STK11 encodes for the protein liver kinase B1, a serine/threonine kinase which is involved in a number of physiological processes including regulation of cellular metabolism, cell polarity and the DNA damage response. It acts as a tumour suppressor via multiple mechanisms, most classically through AMP-activated protein kinase-mediated inhibition of the mammalian target of rapamycin signalling pathway. Germline loss-of-function mutations in STK11 give rise to Peutz-Jeghers syndrome, which is associated with hamartomatous polyps of the gastrointestinal tract, mucocutaneous pigmentation and a substantially increased lifetime risk of many cancers. In the sporadic setting, STK11 mutations are commonly seen in a subset of adenocarcinomas of the lung in addition to a number of other tumours occurring at various sites. Mutations in STK11 have been associated with worse prognoses across a range of malignancies and may be a predictor of poor response to immunotherapy in a subset of lung cancers, though further studies are needed before the presence of STK11 mutations can be implemented as a routine clinical biomarker.

Characterisation of Type 2N von Willebrand Disease Using Phenotypic and Molecular Techniques

1996 ◽  
Vol 75 (06) ◽  
pp. 959-964 ◽  
Author(s):  
I M Nesbitt ◽  
A C Goodeve ◽  
A M Guilliatt ◽  
M Makris ◽  
F E Preston ◽  
...  
Keyword(s):  
Direct Sequencing ◽  
Von Willebrand Disease ◽  
Molecular Techniques ◽  
Haemophilia A ◽  
Binding Region ◽  
Gene Encoding ◽  
Covalently Linked ◽  
Von Willebrand ◽  
Willebrand Factor

Summaryvon Willebrand factor (vWF) is a multimeric glycoprotein found in plasma non covalently linked to factor VIII (FVIII). Type 2N von Willebrand disease (vWD) is caused by a mutation in the vWF gene that results in vWF with a normal multimeric pattern, but with reduced binding to FVIII.We have utilised methods for the phenotypic and genotypic detection of type 2N vWD. The binding of FVIII to vWF in 69 patients, 36 with type 1 vWD, 32 with mild haemophilia A and one possible haemophilia A carrier with low FVIII levels was studied. Of these, six were found to have reduced binding (five type 1 vWD, one possible haemophilia A carrier), DNA was extracted from these patients and exons 18-23 of the vWF gene encoding the FVIII binding region of vWF were analysed. After direct sequencing and chemical cleavage mismatch detection, a Thr28Met mutation was detected in two unrelated individuals, one of whom appears to be a compound heterozygote for the mutation and a null allele. No mutations were found in the region of the vWF gene encoding the FVIII binding region of vWF in the other four patients

Giant Solitary Gastric Peutz-Jeghers Polyp Mimicking a Malignant Gastric Tumor: the Largest Described in Literature

2014 ◽  
Vol 23 (3) ◽  
pp. 321-324 ◽  
Author(s):  
Sorinel Lunca ◽  
Vlad Porumb ◽  
Natalia Velenciuc ◽  
Dan Ferariu ◽  
Gabriel Dimofte
Keyword(s):  
Upper Gastrointestinal Bleeding ◽  
Rare Event ◽  
Gastric Tumor ◽  
Node Metastasis ◽  
Mucocutaneous Pigmentation ◽  
History Of ◽  
Peutz Jeghers Syndrome ◽  
Upper Gastrointestinal ◽  
Gastric Malignancy ◽  
Polypoid Tumor

A solitary Peutz-Jeghers polyp is defined as a unique polyp occurring without associated mucocutaneous pigmentation or a family history of Peutz-Jeghers syndrome. Gastric solitary localization is a rare event, with only eight reported cases to date. We report herein the case of a 43-year old woman who presented with upper gastrointestinal bleeding, severe anemia, weight loss and asthenia. Endoscopy revealed a giant polypoid tumor with signs of neoplastic invasion of the cardia, with pathological aspect suggesting a Peutz-Jeghers hamartomatous polyp. Computed tomography suggested a malignant gastric tumor and a total gastrectomy was performed. The pathological specimen showed a giant 150/70/50 mm polypoid tumor and immunochemistry established the final diagnostic of a Peutz-Jegers type polyp. This is the largest solitary Peutz-Jeghers gastric polyp reported until now, and the second one mimicking a gastric malignancy with lymph node metastasis.

scholarly journals Bladder hamartoma in Peutz-Jeghers syndrome: a rare case report

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Jai Kumar ◽  
Mohammad Irfaan Albeerdy ◽  
Nadeem Ahmed Shaikh ◽  
Abdul Hafeez Qureshi
Keyword(s):  
Urinary Bladder ◽  
Filling Defect ◽  
Hamartomatous Polyps ◽  
Case Presentation ◽  
Rare Case Report ◽  
Mucocutaneous Pigmentation ◽  
Dominant Disease ◽  
Peutz Jeghers Syndrome ◽  
Comprehensive Compilation

Abstract Background Peutz-Jeghers syndrome is an autosomal dominant disease characterized by mucocutaneous pigmentation and hamartomatous polyps in the gastrointestinal tract (GIT). There have also been cases of extra GIT polyps such as the renal pelvis, urinary bladder, lungs and nares. Bladder hamartoma is an extremely rare finding, with only 12 cases described in the literature up to now. The rarity of the condition necessitates a comprehensive compilation of managements up to now so as to provide a better tool for the treatment of such conditions in the future. Case presentation A twenty-year-old male, known to have Peutz-Jeghers syndrome, presented to us complaining of obstructive urinary symptoms. A urethrogram done showed a filling defect at the base of the urinary bladder. The mass was resected transurethrally, and histopathology revealed a hamartoma of the bladder. The patient has since remained tumor-free on follow-up. Conclusions Transurethral resection of the bladder mass proved to be an effective therapy in this patient with no recurrence on the patient’s follow-up till now. There is still, however, a dearth of knowledge regarding the management of bladder hamartomas owing to the extreme rarity of the case.

Solitary Peutz-Jeghers Type Polyp of Jejunum with Gastric Fundic and Antral Gland Lining Mucosa: A Case Report and Review of Literature

2021 ◽  
pp. 106689692110677
Author(s):  
Bella Lingjia Liu ◽  
Huifang Zhou ◽  
Martina Risech ◽  
Alex Ky ◽  
Jane Houldsworth ◽  
...  
Keyword(s):  
Family History ◽  
Small Bowel ◽  
Smooth Muscles ◽  
Fundic Gland ◽  
Muscularis Mucosa ◽  
Hamartomatous Polyp ◽  
Gi Tract ◽  
First Case ◽  
Mucocutaneous Pigmentation ◽  
Peutz Jeghers Syndrome

Solitary Peutz-Jeghers type polyps are characterized by a hamartomatous polyp of the gastrointestinal (GI) tract in a patient without mucocutaneous pigmentation, family history of Peutz-Jeghers syndrome, or STK11/LKB1 mutations. Histologically identical to the polyps in Peutz-Jeghers syndrome, these sporadic polyps can arise anywhere along the GI tract, with typical arborizing smooth muscles extending from the muscularis mucosa. While the lining mucosa is generally the same as the organ in which it arises, gastric pyloric and osseous metaplasia have been reported in intestinal polyps in Peutz-Jeghers syndrome. Herein, the authors report the first case of a small intestinal solitary Peutz-Jeghers type polyp with gastric antral and fundic gland lining mucosa. A 43-year-old male was admitted for small bowel obstruction. Diagnostic laparoscopy revealed jejuno-jejunal intussusception with an associated polyp measuring 7.2 cm. Histological examination showed a hamartomatous polyp with arborizing smooth muscle bundles extending from the muscularis mucosae. The polyp was lined by non-dysplastic gastric antral and fundic gland mucosa, and was sharply demarcated from the adjacent non-polypoid intestinal mucosa. Colonoscopy, esophagogastroduodenoscopy and small bowel enteroscopy revealed no additional polyps or masses. Thorough investigation of the patient's family history was negative for Peutz-Jeghers syndrome or mucocutaneous pigmentation. Molecular analysis of the lesion was negative for STK11/LKB1 mutations. A diagnosis of solitary Peutz-Jeghers type polyp of the small bowel with gastric antral and fundic gland mucosal lining was rendered.

scholarly journals Inherited Chronic Obstructive Pulmonary Disease: New Selective-Sequencing Workup for α1-Antitrypsin Deficiency Identifies 2 Previously Unidentified Null Alleles

2008 ◽  
Vol 54 (1) ◽  
pp. 101-107 ◽  
Author(s):  
Janke Prins ◽  
Brenda B van der Meijden ◽  
Rob J Kraaijenhagen ◽  
Jos P M Wielders
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Direct Sequencing ◽  
Null Alleles ◽  
Chronic Obstructive ◽  
Gene Encoding ◽  
Obstructive Pulmonary Disease ◽  
Antitrypsin Deficiency ◽  
Peptidase Inhibitor ◽  
Compound Heterozygotes

Abstract Background: α1-Antitrypsin (α1AT) deficiency predisposes individuals to chronic obstructive pulmonary disease (COPD) and/or liver disease. Phenotyping of the protein by isoelectric focusing is often used to characterize α1AT deficiency, but this method may lead to misdiagnosis (e.g., by missing null alleles). We evaluated a workup that included direct sequencing of the relevant parts of the gene encoding α1AT, SERPINA1 [serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 1], for patients with α1AT concentrations ≤1.0 g/L. Methods: During a 5-year period, we identified 66 patients with α1AT concentrations ≤1.0 g/L and amplified and sequenced exons 2, 3, and 5 of the α1AT gene in these patients. To ensure that no relevant genotypes were missed, we sequenced the same exons in 48 individuals with α1AT concentrations between 1.0 and 1.5 g/L. Results: Sequence analysis revealed 18 patients with combinations of disease-associated α1AT alleles: 8 homozygous for the deficient Z allele and 10 compound heterozygotes for various deficient or null alleles. We identified and named 2 new null alleles, Q0soest (Thr102→delA, which produces a TGA stop signal at codon 112) and Q0amersfoort (Tyr160→stop). No relevant disease-associated allele combinations were missed at a 1.0-g/L threshold. Conclusions: Up to 22% of the alleles in disease-associated α1AT allele combinations may be missed by conventional methods. Genotyping by direct sequencing of samples from patients with α1AT concentrations ≤1.0 g/L detected these alleles and identified 2 new null alleles.

LKB1 deficiency in T cells promotes the development of gastrointestinal polyposis

Science ◽  
2018 ◽  
Vol 361 (6400) ◽  
pp. 406-411 ◽  
Author(s):  
M. C. Poffenberger ◽  
A. Metcalfe-Roach ◽  
E. Aguilar ◽  
J. Chen ◽  
B. E. Hsu ◽  
...  
Keyword(s):  
T Cells ◽  
Cancer Progression ◽  
Immune Cell ◽  
Inflammatory Factors ◽  
Gastrointestinal Polyposis ◽  
Cancer Predisposition Syndrome ◽  
Stat3 Signaling ◽  
Liver Kinase B1 ◽  
Peutz Jeghers Syndrome ◽  
Transcription 3

Germline mutations in STK11, which encodes the tumor suppressor liver kinase B1 (LKB1), promote Peutz–Jeghers syndrome (PJS), a cancer predisposition syndrome characterized by the development of gastrointestinal (GI) polyps. Here, we report that heterozygous deletion of Stk11 in T cells (LThet mice) is sufficient to promote GI polyposis. Polyps from LThet mice, Stk11+/− mice, and human PJS patients display hallmarks of chronic inflammation, marked by inflammatory immune-cell infiltration, signal transducer and activator of transcription 3 (STAT3) activation, and increased expression of inflammatory factors associated with cancer progression [interleukin 6 (IL-6), IL-11, and CXCL2]. Targeting either T cells, IL-6, or STAT3 signaling reduced polyp growth in Stk11+/− animals. Our results identify LKB1-mediated inflammation as a tissue-extrinsic regulator of intestinal polyposis in PJS, suggesting possible therapeutic approaches by targeting deregulated inflammation in this disease.

GASTROINTESTINAL POLYPOSIS WITH MUCOCUTANEOUS PIGMENTATION IN CHILDREN (PEUTZ-JEGHERS SYNDROME)

PEDIATRICS ◽  
1961 ◽  
Vol 28 (4) ◽  
pp. 655-661
Author(s):  
James E. Wenzl ◽  
Lloyd G. Bartholomew ◽  
George A. Hallenbeck ◽  
Gunnar B. Stickler
Keyword(s):  
Small Intestine ◽  
Abdominal Pain ◽  
Surgical Treatment ◽  
Gastrointestinal Bleeding ◽  
Recurrent Abdominal Pain ◽  
Malignant Change ◽  
Review Of The Literature ◽  
Gastrointestinal Polyposis ◽  
Mucocutaneous Pigmentation ◽  
Peutz Jeghers Syndrome

A case is reported in which a child had gastrointestinal polyposis associated with mucocutaneous pigmentations (the Peutz-Jeghers syndrome). He experienced severe recurrent abdominal pain caused by intermittent intussusception. Removal of the grossly palpable polyps from the small intestine and stomach controlled his symptoms. On the basis of a review of the literature it has become apparent that this disease may first become manifest during childhood. The symptoms are primarily those of recurrent abdominal pain and gastrointestinal bleeding in the presence of mucocutaneous pigmentation. The prognosis associated with this disease is excellent, and the risk of malignant change, if it really exists, is minimal. For this reason, it is urged that surgical treatment be conservative rather than radical, to avoid unnecessary loss of intestine.

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