Digestive Diseases and Sciences

, Volume 52, Issue 8, pp 1924–1933 | Cite as

Molecular and Clinical Characteristics in 46 Families Affected with Peutz–Jeghers Syndrome

  • Hamid Mehenni
  • Nicoletta Resta
  • Ginevra Guanti
  • Louisa Mota-Vieira
  • Aaron Lerner
  • Mohammed Peyman
  • Kim A. Chong
  • Larbi Aissa
  • Ali Ince
  • Angel Cosme
  • Michael C. Costanza
  • Colette Rossier
  • Uppala Radhakrishna
  • Randall W. Burt
  • Didier Picard
Original Article

Abstract

Germline mutations of the tumor suppressor gene LKB1/STK11 are responsible for the Peutz–Jeghers syndrome (PJS), an autosomal-dominant disorder characterized by mucocutaneous pigmentation, hamartomatous polyps, and an increased risk of associated malignancies. In this study, we assessed the presence of pathogenic mutations in the LKB1/STK11 gene in 46 unrelated PJS families, and also carried genotype–phenotype correlation in regard of the development of cancer in 170 PJS patients belonging to these families. All LKB1/STK11 variants detected with single-strand conformational polymorphism were confirmed by direct sequencing, and those without LKB1/STK11 mutation were further submitted to Southern blot analysis for detection of deletions/rearrangements. Statistical analysis for genotype–phenotype correlation was performed. In 59% (27/46) of unrelated PJS cases, pathogenic mutations in the LKB1/STK11 gene, including 9 novel mutations, were identified. The new mutations were 2 splice site deletion–insertions, 2 missenses, 1 nonsense, and 4 abnormal splice sites. Genotype–phenotype analysis did not yield any significant differences between patients carrying mutations in LKB1/STK11 versus those without mutations, even with respect to primary biliary adenocarcinoma. This study presents the molecular characterization and cancer occurrence of a large cohort of PJS patients, increases the mutational spectrum of LKB1/STK11 allelic variants worldwide, and provides a new insight useful for clinical diagnosis and genetic counseling of PJS families.

Keywords

Cancer Genotype–phenotype analysis Pathogenic LKB1/STK11 gene mutations Peutz–Jeghers syndrome 

References

  1. 1.
    Lindor NM (2004) Recognition of genetic syndromes in families with suspected hereditary colon cancer syndromes. Clin Gastroenterol Hepatol 2:366–375PubMedCrossRefGoogle Scholar
  2. 2.
    Giardiello FM, Welsh SB, Hamilton SR, Offerhaus GJ, Gittelsohn AM, Booker SV, Krush AJ, Yardley JH, Luk GD (1987) Increased risk of cancer in the Peutz-Jeghers syndrome. N Engl J Med 316:1511–1514PubMedCrossRefGoogle Scholar
  3. 3.
    Spigelman AD, Murday V, Phillips RK (1989) Cancer and the Peutz-Jeghers syndrome. Gut 30:1588–1590PubMedGoogle Scholar
  4. 4.
    Boardman LA, Thibodeau SN, Schaid DJ, Lindor NM, McDonnell SK, Burgart LJ, Ahlquist DA, Podratz KC, Pittelkow M, Hartmann LC (1998) Increased risk for cancer in patients with the Peutz-Jeghers syndrome. Ann Intern Med 128:896–899PubMedGoogle Scholar
  5. 5.
    Hemminki A, Tomlinson I, Markie D, Jarvinen H, Sistonen P, Bjorkqvist AM, Knuutila S, Salovaara R, Bodmer W, Shibata D, de la Chapelle A, Aaltonen LA (1997) Localization of a susceptibility locus for Peutz-Jeghers syndrome to 19p using comparative genomic hybridization and targeted linkage analysis. Nat Genet 15:87–90PubMedCrossRefGoogle Scholar
  6. 6.
    Hemminki A, Markie D, Tomlinson I, Avizienyte E, Roth S, Loukola A, Bignell G, Warren W, Aminoff M, Hoglund P, Jarvinen H, Kristo P, Pelin K, Ridanpaa M, Salovaara R, Toro T, Bodmer W, Olschwang S, Olsen AS, Stratton MR, de la Chapelle A, Aaltonen LA (1998) A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature 391:184–187PubMedCrossRefGoogle Scholar
  7. 7.
    Jenne DE, Reimann H, Nezu J, Friedel W, Loff S, Jeschke R, Muller O, Back W, Zimmer M (1998) Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nat Genet 18:38–43PubMedCrossRefGoogle Scholar
  8. 8.
    Tiainen M, Ylikorkala A, Makela TP (1999) Growth suppression by Lkb1 is mediated by a G(1) cell cycle arrest. Proc Natl Acad Sci USA 96:9248–9251PubMedCrossRefGoogle Scholar
  9. 9.
    Mehenni H, Gehrig C, Nezu J, Oku A, Shimane M, Rossier C, Guex N, Blouin JL, Scott HS, Antonarakis SE (1998) Loss of LKB1 kinase activity in Peutz-Jeghers syndrome, and evidence for allelic and locus heterogeneity. Am J Hum Genet 63:1641–1650PubMedCrossRefGoogle Scholar
  10. 10.
    Ylikorkala A, Avizienyte E, Tomlinson IP, Tiainen M, Roth S, Loukola A, Hemminki A, Johansson M, Sistonen P, Markie D, Neale K, Phillips R, Zauber P, Twama T, Sampson J, Jarvinen H, Makela TP, Aaltonen LA (1999) Mutations and impaired function of LKB1 in familial and non-familial Peutz-Jeghers syndrome and a sporadic testicular cancer. Hum Mol Genet 8:45–51PubMedCrossRefGoogle Scholar
  11. 11.
    Olschwang S, Markie D, Seal S, Neale K, Phillips R, Cottrell S, Ellis I, Hodgson S, Zauber P, Spigelman A, Iwama T, Loff S, McKeown C, Marchese C, Sampson J, Davies S, Talbot I, Wyke J, Thomas G, Bodmer W, Hemminki A, Avizienyte E, de la Chapelle A, Aaltonen L, Tomlinson I, et al. (1998) Peutz-Jeghers disease: most, but not all, families are compatible with linkage to 19p13.3. J Med Genet 35:42–44PubMedCrossRefGoogle Scholar
  12. 12.
    Scott RJ, Crooks R, Meldrum CJ, Thomas L, Smith CJ, Mowat D, McPhillips M, Spigelman AD (2002) Mutation analysis of the STK11/LKB1 gene and clinical characteristics of an Australian series of Peutz-Jeghers syndrome patients. Clin Genet 62:282–287PubMedCrossRefGoogle Scholar
  13. 13.
    Mehenni H, Blouin JL, Radhakrishna U, Bhardwaj SS, Bhardwaj K, Dixit VB, Richards KF, Bermejo-Fenoll A, Leal AS, Raval RC, Antonarakis SE (1997) Peutz-Jeghers syndrome: confirmation of linkage to chromosome 19p13.3 and identification of a potential second locus, on 19q13.4. Am J Hum Genet 61:1327–1334PubMedCrossRefGoogle Scholar
  14. 14.
    Hearle N, Lucassen A, Wang R, Lim W, Ross F, Wheeler R, Moore I, Shipley J, Houlston R (2004) Mapping of a translocation breakpoint in a Peutz-Jeghers hamartoma to the putative PJS locus at 19q13.4 and mutation analysis of candidate genes in polyp and STK11-negative PJS cases. Genes Chromosomes Cancer 41:163–169PubMedCrossRefGoogle Scholar
  15. 15.
    Boardman LA, Couch FJ, Burgart LJ, Schwartz D, Berry R, McDonnell SK, Schaid DJ, Hartmann LC, Schroeder JJ, Stratakis CA, Thibodeau SN (2000) Genetic heterogeneity in Peutz-Jeghers syndrome. Hum Mutat 16:23–30PubMedCrossRefGoogle Scholar
  16. 16.
    Antonarakis SE (1998) Recommendations for a nomenclature system for human gene mutations. Nomenclature Working Group. Hum Mutat 11:1–3PubMedCrossRefGoogle Scholar
  17. 17.
    Resta N, Simone C, Mareni C, Montera M, Gentile M, Susca F, Gristina R, Pozzi S, Bertario L, Bufo P, Carlomagno N, Ingrosso M, Rossini FP, Tenconi R, Guanti G (1998) STK11 mutations in Peutz-Jeghers syndrome and sporadic colon cancer. Cancer Res 58:4799–4801PubMedGoogle Scholar
  18. 18.
    Wang ZJ, Churchman M, Avizienyte E, McKeown C, Davies S, Evans DG, Ferguson A, Ellis I, Xu WH, Yan ZY, Aaltonen LA, Tomlinson IP (1999) Germline mutations of the LKB1 (STK11) gene in Peutz-Jeghers patients. J Med Genet 36:365–368PubMedGoogle Scholar
  19. 19.
    Westerman AM, Entius MM, Boor PP, Koole R, de Baar E, Offerhaus GJ, Lubinski J, Lindhout D, Halley DJ, de Rooij FW, Wilson JH (1999) Novel mutations in the LKB1/STK11 gene in Dutch Peutz-Jeghers families. Hum Mutat 13:476–481PubMedCrossRefGoogle Scholar
  20. 20.
    Olschwang S, Boisson C, Thomas G (2001) Peutz-Jeghers families unlinked to STK11/LKB1 gene mutations are highly predisposed to primitive biliary adenocarcinoma. J Med Genet 38:356–360PubMedCrossRefGoogle Scholar
  21. 21.
    Boudeau J, Kieloch A, Alessi DR, Stella A, Guanti G, Resta N (2003) Functional analysis of LKB1/STK11 mutants and two aberrant isoforms found in Peutz-Jeghers syndrome patients. Hum Mutat 21:172PubMedCrossRefGoogle Scholar
  22. 22.
    Le Meur N, Martin C, Saugier-Veber P, Joly G, Lemoine F, Moirot H, Rossi A, Bachy B, Cabot A, Joly P, Frebourg T (2004) Complete germline deletion of the STK11 gene in a family with Peutz-Jeghers syndrome. Eur J Hum Genet 12:415–418PubMedCrossRefGoogle Scholar
  23. 23.
    Lim W, Hearle N, Shah B, Murday V, Hodgson SV, Lucassen A, Eccles D, Talbot I, Neale K, Lim AG, O’Donohue J, Donaldson A, Macdonald RC, Young ID, Robinson MH, Lee PW, Stoodley BJ, Tomlinson I, Alderson D, Holbrook AG, Vyas S, Swarbrick ET, Lewis AA, Phillips RK, Houlston RS (2003) Further observations on LKB1/STK11 status and cancer risk in Peutz-Jeghers syndrome. Br J Cancer 89:308–313PubMedCrossRefGoogle Scholar
  24. 24.
    Amos CI, Keitheri-Cheteri MB, Sabripour M, Wei C, McGarrity TJ, Seldin MF, Nations L, Lynch PM, Fidder HH, Friedman E, Frazier ML (2004) Genotype-phenotype correlations in Peutz-Jeghers syndrome. J Med Genet 41:327–333PubMedCrossRefGoogle Scholar
  25. 25.
    Marignani PA, Kanai F, Carpenter CL (2001) LKB1 associates with Brg1 and is necessary for Brg1-induced growth arrest. J Biol Chem 276:32415–32418PubMedCrossRefGoogle Scholar
  26. 26.
    Saitoh T, Mine T, Katoh M (2002) Molecular cloning and characterization of human GIPC3, a novel gene homologous to human GIPC1 and GIPC2. Int J Oncol 20:577–582PubMedGoogle Scholar
  27. 27.
    Ossipova O, Bardeesy N, DePinho RA, Green JB (2003) LKB1 (XEEK1) regulates Wnt signalling in vertebrate development. Nat Cell Biol 5:889–894PubMedCrossRefGoogle Scholar
  28. 28.
    Spicer J, Rayter S, Young N, Elliott R, Ashworth A, Smith D (2003) Regulation of the Wnt signalling component PAR1A by the Peutz-Jeghers syndrome kinase LKB1. Oncogene 22:4752–4756PubMedCrossRefGoogle Scholar
  29. 29.
    Karuman P, Gozani O, Odze RD, Zhou XC, Zhu H, Shaw R, Brien TP, Bozzuto CD, Ooi D, Cantley LC, Yuan J (2001) The Peutz-Jegher gene product LKB1 is a mediator of p53-dependent cell death. Mol Cell 7:1307–1319PubMedCrossRefGoogle Scholar
  30. 30.
    Smith DP, Rayter SI, Niederlander C, Spicer J, Jones CM, Ashworth A (2001) LIP1, a cytoplasmic protein functionally linked to the Peutz-Jeghers syndrome kinase LKB1. Hum Mol Genet 10:2869–2877PubMedCrossRefGoogle Scholar
  31. 31.
    Shaw RJ, Bardeesy N, Manning BD, Lopez L, Kosmatka M, DePinho RA, Cantley LC (2004) The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 6:91–99PubMedCrossRefGoogle Scholar
  32. 32.
    Mehenni H, Lin-Marq N, Buchet-Poyau K, Reymond A, Collart MA, Picard D, Antonarakis SE (2005) LKB1 interacts with and phosphorylates PTEN: a functional link between two proteins involved in cancer predisposing syndromes. Hum Mol Genet 14:2209–2219PubMedCrossRefGoogle Scholar
  33. 33.
    Buchet-Poyau K, Mehenni H, Radhakrishna U, Antonarakis SE (2002) Search for the second Peutz-Jeghers syndrome locus: exclusion of the STK13, PRKCG, KLK10, and PSCD2 genes on chromosome 19 and the STK11IP gene on chromosome 2. Cytogenet Genome Res 97:171–178PubMedCrossRefGoogle Scholar
  34. 34.
    Alhopuro P, Katajisto P, Lehtonen R, Ylisaukko-Oja SK, Naatsaari L, Karhu A, Westerman AM, Wilson JH, de Rooij FW, Vogel T, Moeslein G, Tomlinson IP, Aaltonen LA, Makela TP, Launonen V (2005) Mutation analysis of three genes encoding novel LKB1-interacting proteins, BRG1, STRADalpha, and MO25alpha, in Peutz-Jeghers syndrome. Br J Cancer 92:1126–1129PubMedCrossRefGoogle Scholar
  35. 35.
    de Leng WW, Keller JJ, Luiten S, Musler AR, Jansen M, Baas AF, de Rooij FW, Gille JJ, Menko FH, Offerhaus GJ, Weterman MA (2005) STRAD in Peutz-Jeghers syndrome and sporadic cancers. J Clin Pathol 58:1091–1095PubMedCrossRefGoogle Scholar
  36. 36.
    Bardeesy N, Sinha M, Hezel AF, Signoretti S, Hathaway NA, Sharpless NE, Loda M, Carrasco DR, DePinho RA (2002) Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformation. Nature 419:162–167PubMedCrossRefGoogle Scholar
  37. 37.
    Jimenez AI, Fernandez P, Dominguez O, Dopazo A, Sanchez-Cespedes M (2003) Growth and molecular profile of lung cancer cells expressing ectopic LKB1: down-regulation of the phosphatidylinositol 3′-phosphate kinase/PTEN pathway. Cancer Res 63:1382–1388PubMedGoogle Scholar
  38. 38.
    Lim W, Olschwang S, Keller JJ, Westerman AM, Menko FH, Boardman LA, Scott RJ, Trimbath J, Giardiello FM, Gruber SB, Gille JJ, Offerhaus GJ, de Rooij FW, Wilson JH, Spigelman AD, Phillips RK, Houlston RS (2004) Relative frequency and morphology of cancers in STK11 mutation carriers. Gastroenterology 126:1788–1794PubMedCrossRefGoogle Scholar
  39. 39.
    Su GH, Hruban RH, Bansal RK, Bova GS, Tang DJ, Shekher MC, Westerman AM, Entius MM, Goggins M, Yeo CJ, Kern SE (1999) Germline and somatic mutations of the STK11/LKB1 Peutz-Jeghers gene in pancreatic and biliary cancers. Am J Pathol 154:1835–1840PubMedGoogle Scholar
  40. 40.
    Sahin F, Maitra A, Argani P, Sato N, Maehara N, Montgomery E, Goggins M, Hruban RH, Su GH (2003) Loss of Stk11/Lkb1 expression in pancreatic and biliary neoplasms. Mod Pathol 16:686–691PubMedCrossRefGoogle Scholar
  41. 41.
    Nakanuma Y, Harada K, Kaji K, Terasaki S, Tsuneyama K, Moteki S, Van de Water J, Leung PS, Gershwin ME (1997) Clinicopathological study of primary biliary cirrhosis negative for antimitochondrial antibodies. Liver 17:281–287PubMedGoogle Scholar
  42. 42.
    Holzinger F, Z’Graggen K, Buchler MW (1999) Mechanisms of biliary carcinogenesis: a pathogenetic multi-stage cascade towards cholangiocarcinoma. Ann Oncol 10(suppl 4):122–126PubMedCrossRefGoogle Scholar
  43. 43.
    Knudson AG Jr (1985) Hereditary cancer, oncogenes, and antioncogenes. Cancer Res 45:1437–1443PubMedGoogle Scholar
  44. 44.
    Trojan J, Brieger A, Raedle J, Esteller M, Zeuzem S (2000) 5’-CpG island methylation of the LKB1/STK11 promoter and allelic loss at chromosome 19p13.3 in sporadic colorectal cancer. Gut 47:272–276PubMedCrossRefGoogle Scholar
  45. 45.
    Gruber SB, Entius MM, Petersen GM, Laken SJ, Longo PA, Boyer R, Levin AM, Mujumdar UJ, Trent JM, Kinzler KW, Vogelstein B, Hamilton SR, Polymeropoulos MH, Offerhaus GJ, Giardiello FM (1998) Pathogenesis of adenocarcinoma in Peutz-Jeghers syndrome. Cancer Res 58:5267–5270PubMedGoogle Scholar
  46. 46.
    Wang ZJ, Ellis I, Zauber P, Iwama T, Marchese C, Talbot I, Xue WH, Yan ZY, Tomlinson I (1999) Allelic imbalance at the LKB1 (STK11) locus in tumours from patients with Peutz-Jeghers’ syndrome provides evidence for a hamartoma-(adenoma)-carcinoma sequence. J Pathol 188:9–13PubMedCrossRefGoogle Scholar
  47. 47.
    Entius MM, Keller JJ, Westerman AM, van Rees BP, van Velthuysen ML, de Goeij AF, Wilson JH, Giardiello FM, Offerhaus GJ (2001) Molecular genetic alterations in hamartomatous polyps and carcinomas of patients with Peutz-Jeghers syndrome. J Clin Pathol 54:126–131PubMedCrossRefGoogle Scholar
  48. 48.
    Sato N, Rosty C, Jansen M, Fukushima N, Ueki T, Yeo CJ, Cameron JL, Iacobuzio-Donahue CA, Hruban RH, Goggins M (2001) STK11/LKB1 Peutz-Jeghers gene inactivation in intraductal papillary-mucinous neoplasms of the pancreas. Am J Pathol 159:2017–2022PubMedGoogle Scholar
  49. 49.
    Wang ZJ, Taylor F, Churchman M, Norbury G, Tomlinson I (1998) Genetic pathways of colorectal carcinogenesis rarely involve the PTEN and LKB1 genes outside the inherited hamartoma syndromes. Am J Pathol 153:363–366PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Hamid Mehenni
    • 1
    • 14
  • Nicoletta Resta
    • 2
  • Ginevra Guanti
    • 2
  • Louisa Mota-Vieira
    • 3
  • Aaron Lerner
    • 4
  • Mohammed Peyman
    • 5
  • Kim A. Chong
    • 6
  • Larbi Aissa
    • 7
  • Ali Ince
    • 8
  • Angel Cosme
    • 9
  • Michael C. Costanza
    • 10
  • Colette Rossier
    • 11
  • Uppala Radhakrishna
    • 12
  • Randall W. Burt
    • 13
  • Didier Picard
    • 1
  1. 1.Unité de Gastroentérologie & Hépatologie, Centre Médico-Chirurgical Rond-Point-Plainpalais et Département de biologie cellulaire, Unité de recherche des maladies prédisposant aux cancers gastro-intestinauxUniversité de GenèveGenèveSwitzerland
  2. 2.Sezione di Genetica Medica Dip. di Biomedicina dell’Età EvolutivaUniversità di BariBariItaly
  3. 3.Unidade de Genética e Patologia MolecularesHospital De Ponta DelgadaPonta DelgadaPortugal
  4. 4.Department of PediatricsHaifa HospitalHaifaIsrael
  5. 5.Shariati Hospital and Islamic Azad University of NajafabadNajafabadIran
  6. 6.Instituto da CriançaHospital das Clinicas da faculdade de medicina da Universidade de Sao PauloSao PauloBrazil
  7. 7.Service de chirurgie generaleCHU Ibn-RochdCasablancaMorocco
  8. 8.Gastroenterology ClinicHaydarpasa Numune Education and Training HospitalIstanbulTurkey
  9. 9.Servicio de DigestivoHospital DonostiaSan SebastianSpain
  10. 10.Division of Clinical EpidemiologyGeneva University HospitalsGenevaSwitzerland
  11. 11.Department of Genetic Medicine and DevelopmentUniversity of Geneva Medical School and University HospitalsGenevaSwitzerland
  12. 12.Green Cross Blood Bank & Genetic Research CentrePaldiIndia
  13. 13.Department of MedicineUniversity of Utah School of MedicineSalt Lake CityUtah
  14. 14.Centre Medical du Rond-point de PlainpalaisUnité de Gastroentérologie & HépatologieGenèveSwitzerland

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