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Peutz-Jeghers syndrome

Written2015-11Francesca Clementina Radio, Paola Grammatico
Medical Genetics Laboratory, Sapienza University of Rome, San Camillo-Forlanini Hospital, Circonvallazione Gianicolense n. 87. 00152 Rome, Italy. ,
This article is an update of :
2002-02Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Abstract Peutz_Jeghers Syndrome (PJS, OMIM 175200) is a rare autosomal dominant disorder characterized by intestinal hamartomatous polyps, mucocutaneous melanotic pigmentation and predisposition to malignancies. The incidence rate of the disease ranges from 1 in 8,300 to 1 in 200,000 (Boardman,2002; Launonen,2005; Chae and Jeon,2014). Around 55% of affected patients show a family history of the disease. The clinical diagnosis of PJS can be confirmed by molecular genetic testing of STK11 (LKB1) in 80%-94% of affected individuals (Jenne et al.,1998; Hemminki et al.,1998).STK11 gene encodes a tumor suppressor serine/threonine-protein kinase involved in various processes such as cell metabolism, cell polarity, apoptosis and DNA damage response. A genotype-phenotype correlation between STK11 germline mutations and disease manifestations (e.g., the number of polyps, pigmentation pattern, cancer risk) is been proposed (Hemminki et al.,1998; Davidson,2007).
Genetic heterogeneity is suggested by several patients negative at the mutational screening of STK11 gene and multiple causative loci described to date (Alhopuro et al.,2008; Bali et al.,1995; Markie et al.,1996; Mehenni et al.,1997; Schumacher et al.,2005; Wang et al.,2014).

Keyword Peutz-Jeghers Syndrome, intestinal hamartomatous polyps, STK11, cancer prone syndrome

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Other namesHamartomatous Intestinal Polyposis
Polyps-and-Spots Syndrome
Atlas_Id 10025
Genes implicated inSTK11  
Note Syndrome associating mucocutaneous melanotic pigmentation, intestinal polyposis, and an increased risk of cancers.
Inheritance Autosomal dominant with a high penetrance; incidence rate of the disease ranges from 1 in 8,300 to 1 in 200,000; 1/3 to 1/2 of cases due to de novo mutations.


Phenotype and clinics
  • Skin numerous brown or bleuish mucocutaneous macules (melanin spots) , especially around the orifices (mouth, including the buccal mucosa, eyes, nostrils, anus, genitalia), and digits; the skin hyperpigmentation may disappear with age, in puberty and adulthood. Note: in patients with isolated mucocutaneous melanotic pigmentation (without polyps), the cancer risk is lower, and the genetic defect seems different.
  • Gastrointestinal tract (GI tract): polyps of hamartomatous origin (with a characteristic arborization of nonstriated muscles) may be found in any portion of the GI tract with varying frequencies: from 95% to 15%: (small bowel, jejunum, ileum, large intestin, rectum, stomach, duodenum). Intussusception and bleeding are common symptoms, which may be cause of death. the age of onset is variable from the first year of life onwards (median age of onset 10-25 yrs); polyps have also been reported in other organs (renal pelvis, urinary bladder, ureters, lungs, nares, gallbladder).
  • Neoplastic risk
  • Tumors develop, with a relative risk of 10-20, and a cumulative risk of more than 90% between ages 15 and 64 yrs (Giardiello et al.,2000). The mean interval between the diagnosis of PJS and the diagnosis of cancer is about 20 yrs (the mean age at the first cancer diagnosis about 41 yrs). The overall relative risk (RR) for cancer is greater in females than in males and greatest for gastrointestinal, pancreatic, and gynecologic-cervical cancers (Resta et al.,2013). In particular, the specific RR is:
    small intestin: 520
    stomach: 213
    pancreas: 140
    colon: 84
    esophagus: 57
    cervix: 55.6
    ovary: 30
    benign sex cord tumor with annular tubules in females or Sertoli cell tumors in males: 27
    lung: 17
    uterus: 16
    breast: 15.2 (comparable to that of BRCA1 / BRCA2 mutations carriers - Hearle et al.,2006)
  • Treatment Surveillance with endoscopic (GI tract) and gynecologic regular screenings, surgery when needed.
    Evolution Patients inherit mutations in one allele. The remaining allele is later inactivated generally by LOH or sometimes somatic mutation. This biallelic inactivation of STK11 leads to a loss of tumor suppressor activity, thereby promoting tumorigenesis.
    Prognosis The prognosis for individuals affected by PJS is thus mainly determined by the risk of malignancy. Although little information on prognosis is available, one report suggests that PJS-associated cancers are particularly aggressive (Spigelman et al.,1989). Several researches show that a diagnosis of PJS has great psychosocial impact, although the physical impact on the patient is not greater than that in the general population (Woo et al.,2009).

    Genes involved and Proteins

    Note STK11 (LKB1) is the only gene in which mutations has been identified as causative of PJS, to date (Hemminki et al.,1998, Jenne et al.,1998). Evidence for genetic heterogeneity are described but no other locus has been clearly associated.
    One child with a PJS hamartoma show a 19q13.4 translocation, however no pathogenic variants in candidate genes mapping to this breakpoint were identified (Hearle et al.,2004).
    Between 25 patients with PJS without STK11 pathogenic mutations, one had a heterozygous pathogenic variant of MUTYH gene, common cause of autosomal recessive form of adenomatous polyposis (Alhopuro et al.,2008).
    Moreover Wang et colleagues identified 2 germline variants which are represented in all six PJS samples analyzed and are independent of STK11 mutation (Wang et al.,2014).
    Gene NameSTK11 (serine/threonine kinase 11)
    Alias LKB1
    Location 19p13.3
    Note A majority of PJS patients shows germline mutations in STK11 gene (around 80%-94%). However, the identification of germline mutations in other genes suggests a genetic heterogeneity of PJS, no definitely known to date.
    Transcription 9 transcripts; 4 protein coding.
    Description 433 amino acids, 48.6 kDa; N-term with a nuclear localization domain and a putative cytoplasmic retention signal, a kinase domain, and a C-terminal CAAX box prenylation motif.
    Expression Ubiquitous, especially high expression in fetal liver and testis where it is required during spermiogenesis (Towler et al.,2008).
    Localisation Found in both the nucleus and the cytoplasm. Localization is thought to be dependent on interaction with proteins such as SMARCA4 (BRG1), STK11IP (LIP1), STRADA, CAB39 (MO25).
    Function Tumor suppressor serine/threonine-protein kinase that controls the activity of AMP-activated protein kinase (AMPK) family members, thereby playing a role in various processes such as cell metabolism, cell polarity, apoptosis and DNA damage response. Acts by phosphorylating the T-loop of AMPK family proteins, leading to promote their activity: phosphorylates PRKAA1 , PRKAA2 , BRSK1 , BRSK2 , MARK1 , MARK2 , MARK3 , MARK4 , NUAK1 , NUAK2 , SIK1 , SIK2 , SIK3 and SNRK but not MELK. Also phosphorylates non-AMPK family proteins such as STRADA and possibly p53/TP53. Acts as a key upstream regulator of AMPK by mediating phosphorylation and activation of AMPK catalytic subunits PRKAA1 and PRKAA2: it thereby regulates inhibition of signaling pathways that promote cell growth and proliferation when energy levels are low, glucose homeostasis in liver, activation of autophagy when cells undergo nutrient deprivation, B-cell differentiation in the germinal center in response to DNA damage. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton. Required for cortical neurons polarization by mediating phosphorylation and activation of BRSK1 and BRSK2, leading to axon initiation and specification. Involved in DNA damage response: interacts with p53/TP53 and recruited to the CDKN1A/WAF1 promoter to participate in transcription activation. Able to phosphorylate p53/TP53; the relevance of such result in vivo is however unclear and phosphorylation may be indirect and mediated by downstream STK11/LKB1 kinase NUAK1 Also acts as a mediator p53/TP53-dependent apoptosis via interaction with p53/TP53: translocates to mitochondrion during apoptosis and regulates p53/TP53-dependent apoptosis pathways (Karuman et al.,2001; Baas et al.,2003; Boudeau et al.,2003; Baas et al.,2004; Lizcano et al.,2004; Jaleel et al.,2005; Zeng et al.,2006; Hou et al.,2011).
    Homology Orthologs found in several species and include: Xenopus laevis egg and embryonic kinase 1(XEEK1), Caenorhabditis elegans partitioning defective gene 4 (PAR4), mouse LKB1 and drosophila LKB1.
    Germinal Around 200 pathogenic mutations of STK11 gene has been reported to date, including missense, nonsense, splice site variants, small deletions, small insertions, small indels, large deletions, large insertions and complex rearrangements. Between them more than 90% are associated with PJS. In addition are described: one individual with a nonsense variant and diagnosis of gonadotropin-independent precocious puberty and one patient with a large insertion and diagnosis of juvenile polyposis syndrome.
    Somatic Many of the polyps that develop in PJS show loss of heterozygosity or second somatic mutation of SKT11 gene. Somatic mutations rarely occur in sporadic tumors. However, somatic mutations of STK11 gene can be frequent revealed in lung adenocarcinoma (Matsumoto et al.,2007).


    Peutz-Jeghers syndrome maps to chromosome 1p
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    Am J Hum Genet. 1995;57.
    Somatic mutation analysis of MYH11 in breast and prostate cancer
    Alhopuro P, Karhu A, Winqvist R, Waltering K, Visakorpi T, Aaltonen LA
    BMC Cancer 2008 Sep 17;8:263
    PMID 18796164
    Activation of the tumour suppressor kinase LKB1 by the STE20-like pseudokinase STRAD
    Baas AF, Boudeau J, Sapkota GP, Smit L, Medema R, Morrice NA, Alessi DR, Clevers HC
    EMBO J 2003 Jun 16;22(12):3062-72
    PMID 12805220
    Complete polarization of single intestinal epithelial cells upon activation of LKB1 by STRAD
    Baas AF, Kuipers J, van der Wel NN, Batlle E, Koerten HK, Peters PJ, Clevers HC
    Cell 2004 Feb 6;116(3):457-66
    PMID 15016379
    Heritable colorectal cancer syndromes: recognition and preventive management
    Boardman LA
    Gastroenterol Clin North Am 2002 Dec;31(4):1107-31
    PMID 12489281
    MO25alpha/beta interact with STRADalpha/beta enhancing their ability to bind, activate and localize LKB1 in the cytoplasm
    Boudeau J, Baas AF, Deak M, Morrice NA, Kieloch A, Schutkowski M, Prescott AR, Clevers HC, Alessi DR
    EMBO J 2003 Oct 1;22(19):5102-14
    PMID 14517248
    Mutation-specific RAS oncogenicity explains NRAS codon 61 selection in melanoma
    Burd CE, Liu W, Huynh MV, Waqas MA, Gillahan JE, Clark KS, Fu K, Martin BL, Jeck WR, Souroullas GP, Darr DB, Zedek DC, Miley MJ, Baguley BC, Campbell SL, Sharpless NE
    Cancer Discov 2014 Dec;4(12):1418-29
    PMID 25252692
    Analysis of patient reports on the referral process to two NSW cancer genetic services
    Butel-Simoes GI, Spigelman AD
    Fam Cancer 2014 Sep;13(3):333-43
    PMID 24648127
    Hamartomatous Tumors in the Gastrointestinal Tract
    Cauchin E, Touchefeu Y, Matysiak-Budnik T
    Gastrointest Tumors 2015 Sep;2(2):65-74
    PMID 26672891
    Peutz-Jeghers syndrome with germline mutation of STK11
    Chae HD, Jeon CH
    Ann Surg Treat Res 2014 Jun;86(6):325-30
    PMID 24949325
    Mapping of a translocation breakpoint in a Peutz-Jeghers hamartoma to the putative PJS locus at 19q13
    Hearle N, Lucassen A, Wang R, Lim W, Ross F, Wheeler R, Moore I, Shipley J, Houlston R
    4 and mutation analysis of candidate genes in polyp and STK11-negative PJS cases Genes Chromosomes Cancer
    PMID 15287029
    STK11 status and intussusception risk in Peutz-Jeghers syndrome
    Hearle N, Schumacher V, Menko FH, Olschwang S, Boardman LA, Gille JJ, Keller JJ, Westerman AM, Scott RJ, Lim W, Trimbath JD, Giardiello FM, Gruber SB, Offerhaus GJ, Rooij FW, Wilson JH, Hansmann A, Möslein G, Royer-Pokora B, Vogel T, Phillips RK, Spigelman AD, Houlston RS
    J Med Genet 2006 Aug;43(8):e41
    PMID 16882735
    Molecular insights into Peutz-Jeghers syndrome: two probands with a germline mutation of LKB1
    Hosogi H, Nagayama S, Kawamura J, Koshiba Y, Nomura A, Itami A, Okabe H, Satoh S, Watanabe G, Sakai Y
    J Gastroenterol 2008;43(6):492-7
    PMID 18600394
    A new role of NUAK1: directly phosphorylating p53 and regulating cell proliferation
    Hou X, Liu JE, Liu W, Liu CY, Liu ZY, Sun ZY
    Oncogene 2011 Jun 30;30(26):2933-42
    PMID 21317932
    Identification of the sucrose non-fermenting related kinase SNRK, as a novel LKB1 substrate
    Jaleel M, McBride A, Lizcano JM, Deak M, Toth R, Morrice NA, Alessi DR
    FEBS Lett 2005 Feb 28;579(6):1417-23
    PMID 15733851
    Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase
    Jenne DE, Reimann H, Nezu J, Friedel W, Loff S, Jeschke R, Müller O, Back W, Zimmer M
    Nat Genet 1998 Jan;18(1):38-43
    PMID 9425897
    The Peutz-Jegher gene product LKB1 is a mediator of p53-dependent cell death
    Karuman P, Gozani O, Odze RD, Zhou XC, Zhu H, Shaw R, Brien TP, Bozzuto CD, Ooi D, Cantley LC, Yuan J
    Mol Cell 2001 Jun;7(6):1307-19
    PMID 11430832
    Genetic susceptibility to pancreatic cancer
    Klein AP
    Mol Carcinog 2012 Jan;51(1):14-24
    PMID 22162228
    LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1
    Lizcano JM, Göransson O, Toth R, Deak M, Morrice NA, Boudeau J, Hawley SA, Udd L, Mäkelä TP, Hardie DG, Alessi DR
    EMBO J 2004 Feb 25;23(4):833-43
    PMID 14976552
    A pericentric inversion of chromosome six in a patient with Peutz-Jeghers' syndrome and the use of FISH to localise the breakpoints on a genetic map
    Markie D, Huson S, Maher E, Davies A, Tomlinson I, Bodmer WF
    Hum Genet 1996 Aug;98(2):125-8
    PMID 8698325
    Peutz-Jeghers Syndrome With Diffuse Gastrointestinal Polyposis: Three Cases in a Family With Different Manifestations and No Evidence of Malignancy During 14 Years Follow Up
    Matini E, Houshangi H, Jangholi E, Farjad Azad P, Najibpour R, Farshad A
    Iran Red Crescent Med J 2015 Dec 19;17(12):e19271
    PMID 26756003
    Prevalence and specificity of LKB1 genetic alterations in lung cancers
    Matsumoto S, Iwakawa R, Takahashi K, Kohno T, Nakanishi Y, Matsuno Y, Suzuki K, Nakamoto M, Shimizu E, Minna JD, Yokota J
    Oncogene 2007 Aug 30;26(40):5911-8
    PMID 17384680
    Peutz-Jeghers syndrome: confirmation of linkage to chromosome 19p13
    Mehenni H, Blouin JL, Radhakrishna U, Bhardwaj SS, Bhardwaj K, Dixit VB, Richards KF, Bermejo-Fenoll A, Leal AS, Raval RC, Antonarakis SE
    3 and identification of a potential second locus, on 19q13 4
    PMID 9399902
    Cancer risk associated with STK11/LKB1 germline mutations in Peutz-Jeghers syndrome patients: results of an Italian multicenter study
    Resta N, Pierannunzio D, Lenato GM, Stella A, Capocaccia R, Bagnulo R, Lastella P, Susca FC, Bozzao C, Loconte DC, Sabbà C, Urso E, Sala P, Fornasarig M, Grammatico P, Piepoli A, Host C, Turchetti D, Viel A, Memo L, Giunti L, Stigliano V, Varesco L, Bertario L, Genuardi M, Lucci Cordisco E, Tibiletti MG, Di Gregorio C, Andriulli A, Ponz de Leon M; AIFEG
    Dig Liver Dis 2013 Jul;45(7):606-11
    PMID 23415580
    A novel short splice variant of the tumour suppressor LKB1 is required for spermiogenesis
    Towler MC, Fogarty S, Hawley SA, Pan DA, Martin DM, Morrice NA, McCarthy A, Galardo MN, Meroni SB, Cigorraga SB, Ashworth A, Sakamoto K, Hardie DG
    Biochem J 2008 Nov 15;416(1):1-14
    PMID 18774945
    Exome sequencing revealed novel germline mutations in Chinese Peutz-Jeghers syndrome patients
    Wang HH, Xie NN, Li QY, Hu YQ, Ren JL, Guleng B
    Dig Dis Sci 2014 Jan;59(1):64-71
    PMID 24154639
    LKB1 is recruited to the p21/WAF1 promoter by p53 to mediate transcriptional activation
    Zeng PY, Berger SL
    Cancer Res 2006 Nov 15;66(22):10701-8
    PMID 17108107


    This paper should be referenced as such :
    Francesca Clementina Radio, Paola Grammatico
    Peutz-Jeghers syndrome
    Atlas Genet Cytogenet Oncol Haematol. 2016;20(11):583-586.
    Free journal version : [ pdf ]   [ DOI ]
    On line version :
    History of this paper:
    Huret, JL. Peutz-Jeghers syndrome. Atlas Genet Cytogenet Oncol Haematol. 2002;6(2):145-146.

    Other genes implicated (Data extracted from papers in the Atlas) [ 5 ]


    External links

    OrphanetPeutz-Jeghers syndrome
    Other databasePeutz-Jeghers syndrome (GARD)
    Genes implicated inSTK11   [ Atlas ]   [ Entrez ]  [ LOVD ]  [ GeneReviews ]  

    REVIEW articlesautomatic search in PubMed
    Last year articlesautomatic search in PubMed

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