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

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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.

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References

  1. Lindor NM (2004) Recognition of genetic syndromes in families with suspected hereditary colon cancer syndromes. Clin Gastroenterol Hepatol 2:366–375

    Article  PubMed  CAS  Google Scholar 

  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 316:1511–1514

    Article  PubMed  CAS  Google Scholar 

  3. Spigelman AD, Murday V, Phillips RK (1989) Cancer and the Peutz-Jeghers syndrome. Gut 30:1588–1590

    PubMed  CAS  Google Scholar 

  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 128:896–899

    PubMed  CAS  Google Scholar 

  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 15:87–90

    Article  PubMed  CAS  Google Scholar 

  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 391:184–187

    Article  PubMed  CAS  Google Scholar 

  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 18:38–43

    Article  PubMed  CAS  Google Scholar 

  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 96:9248–9251

    Article  PubMed  CAS  Google Scholar 

  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 63:1641–1650

    Article  PubMed  CAS  Google Scholar 

  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 8:45–51

    Article  PubMed  CAS  Google Scholar 

  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 35:42–44

    Article  PubMed  CAS  Google Scholar 

  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 62:282–287

    Article  PubMed  CAS  Google Scholar 

  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 61:1327–1334

    Article  PubMed  CAS  Google Scholar 

  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 41:163–169

    Article  PubMed  CAS  Google Scholar 

  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 16:23–30

    Article  PubMed  CAS  Google Scholar 

  16. Antonarakis SE (1998) Recommendations for a nomenclature system for human gene mutations. Nomenclature Working Group. Hum Mutat 11:1–3

    Article  PubMed  CAS  Google Scholar 

  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 58:4799–4801

    PubMed  CAS  Google Scholar 

  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 36:365–368

    PubMed  CAS  Google Scholar 

  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 13:476–481

    Article  PubMed  CAS  Google Scholar 

  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 38:356–360

    Article  PubMed  CAS  Google Scholar 

  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 21:172

    Article  PubMed  CAS  Google Scholar 

  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 12:415–418

    Article  PubMed  CAS  Google Scholar 

  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 89:308–313

    Article  PubMed  CAS  Google Scholar 

  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 41:327–333

    Article  PubMed  CAS  Google Scholar 

  25. Marignani PA, Kanai F, Carpenter CL (2001) LKB1 associates with Brg1 and is necessary for Brg1-induced growth arrest. J Biol Chem 276:32415–32418

    Article  PubMed  CAS  Google Scholar 

  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 20:577–582

    PubMed  CAS  Google Scholar 

  27. Ossipova O, Bardeesy N, DePinho RA, Green JB (2003) LKB1 (XEEK1) regulates Wnt signalling in vertebrate development. Nat Cell Biol 5:889–894

    Article  PubMed  CAS  Google Scholar 

  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 22:4752–4756

    Article  PubMed  CAS  Google Scholar 

  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 7:1307–1319

    Article  PubMed  CAS  Google Scholar 

  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 10:2869–2877

    Article  PubMed  CAS  Google Scholar 

  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 6:91–99

    Article  PubMed  CAS  Google Scholar 

  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 14:2209–2219

    Article  PubMed  CAS  Google Scholar 

  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 97:171–178

    Article  PubMed  CAS  Google Scholar 

  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 92:1126–1129

    Article  PubMed  CAS  Google Scholar 

  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 58:1091–1095

    Article  PubMed  CAS  Google Scholar 

  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 419:162–167

    Article  PubMed  CAS  Google Scholar 

  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 63:1382–1388

    PubMed  CAS  Google Scholar 

  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 126:1788–1794

    Article  PubMed  CAS  Google Scholar 

  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 154:1835–1840

    PubMed  CAS  Google Scholar 

  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 16:686–691

    Article  PubMed  Google Scholar 

  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 17:281–287

    PubMed  CAS  Google Scholar 

  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):122–126

    Article  PubMed  Google Scholar 

  43. Knudson AG Jr (1985) Hereditary cancer, oncogenes, and antioncogenes. Cancer Res 45:1437–1443

    PubMed  CAS  Google Scholar 

  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 47:272–276

    Article  PubMed  CAS  Google Scholar 

  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 58:5267–5270

    PubMed  CAS  Google Scholar 

  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 188:9–13

    Article  PubMed  CAS  Google Scholar 

  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 54:126–131

    Article  PubMed  CAS  Google Scholar 

  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 159:2017–2022

    PubMed  CAS  Google Scholar 

  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 153:363–366

    PubMed  CAS  Google Scholar 

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Acknowledgments

The authors thank all the members of the PJS families for their collaboration. We thank Pooya Daemi (University of Esfahan, Iran) and Marc Martinez Llordella (University of Geneva, Switzerland) for their help in the collection of blood samples. We are deeply indebted to Pr Daniel Burdick for the valuable collaboration (Department of Surgery, Syracuse, New York). We also express our gratitude to Angela Quagliarella (Università di Bari, Italy) for technical assistance. We thank Dr M. Tinguely (Department of Clinical Pathology, Geneva Cantonal Hospital, Switzerland) for laser capture dissection of the samples. This study was supported by the Ligue Suisse, Ligue Genevoise contre le Cancer, and MIUR-FIRB grant RBAUO1SZHB_001 (G.G).

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Authors and Affiliations

  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-intestinaux, Université de Genève, Genève, Switzerland

    Hamid Mehenni & Didier Picard

  2. Sezione di Genetica Medica Dip. di Biomedicina dell’Età Evolutiva, Università di Bari, Bari, Italy

    Nicoletta Resta & Ginevra Guanti

  3. Unidade de Genética e Patologia Moleculares, Hospital De Ponta Delgada, Ponta Delgada, Açores, Portugal

    Louisa Mota-Vieira

  4. Department of Pediatrics, Haifa Hospital, Haifa, Israel

    Aaron Lerner

  5. Shariati Hospital and Islamic Azad University of Najafabad, Najafabad, Esfahan, Iran

    Mohammed Peyman

  6. Instituto da Criança, Hospital das Clinicas da faculdade de medicina da Universidade de Sao Paulo, Sao Paulo, Brazil

    Kim A. Chong

  7. Service de chirurgie generale, CHU Ibn-Rochd, Casablanca, Morocco

    Larbi Aissa

  8. Gastroenterology Clinic, Haydarpasa Numune Education and Training Hospital, Istanbul, Turkey

    Ali Ince

  9. Servicio de Digestivo, Hospital Donostia, Edificio Aranzazu, San Sebastian, Spain

    Angel Cosme

  10. Division of Clinical Epidemiology, Geneva University Hospitals, Geneva, Switzerland

    Michael C. Costanza

  11. Department of Genetic Medicine and Development, University of Geneva Medical School and University Hospitals, Geneva, Switzerland

    Colette Rossier

  12. Green Cross Blood Bank & Genetic Research Centre, Paldi, Ahmedabad, India

    Uppala Radhakrishna

  13. Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah

    Randall W. Burt

  14. Centre Medical du Rond-point de Plainpalais, Unité de Gastroentérologie & Hépatologie, 12-14 rue de Carouge, 1205, Genève, Switzerland

    Hamid Mehenni

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  1. Hamid Mehenni
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  2. Nicoletta Resta
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  3. Ginevra Guanti
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  8. Larbi Aissa
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  9. Ali Ince
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  15. Didier Picard
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Correspondence to Hamid Mehenni.

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Mehenni, H., Resta, N., Guanti, G. et al. Molecular and Clinical Characteristics in 46 Families Affected with Peutz–Jeghers Syndrome. Dig Dis Sci 52, 1924–1933 (2007). https://doi.org/10.1007/s10620-006-9435-3

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