Original Article

Digestive Diseases and Sciences

, Volume 52, Issue 8, pp 1924-1933

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

  • Hamid MehenniAffiliated withUnité 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 GenèveCentre Medical du Rond-point de Plainpalais, Unité de Gastroentérologie & Hépatologie Email author 
  • , Nicoletta RestaAffiliated withSezione di Genetica Medica Dip. di Biomedicina dell’Età Evolutiva, Università di Bari
  • , Ginevra GuantiAffiliated withSezione di Genetica Medica Dip. di Biomedicina dell’Età Evolutiva, Università di Bari
  • , Louisa Mota-VieiraAffiliated withUnidade de Genética e Patologia Moleculares, Hospital De Ponta Delgada
  • , Aaron LernerAffiliated withDepartment of Pediatrics, Haifa Hospital
  • , Mohammed PeymanAffiliated withShariati Hospital and Islamic Azad University of Najafabad
  • , Kim A. ChongAffiliated withInstituto da Criança, Hospital das Clinicas da faculdade de medicina da Universidade de Sao Paulo
  • , Larbi AissaAffiliated withService de chirurgie generale, CHU Ibn-Rochd
  • , Ali InceAffiliated withGastroenterology Clinic, Haydarpasa Numune Education and Training Hospital
    • , Angel CosmeAffiliated withServicio de Digestivo, Hospital Donostia
    • , Michael C. CostanzaAffiliated withUnité 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 GenèveDivision of Clinical Epidemiology, Geneva University Hospitals
    • , Colette RossierAffiliated withUnité 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 GenèveDepartment of Genetic Medicine and Development, University of Geneva Medical School and University Hospitals
    • , Uppala RadhakrishnaAffiliated withUnité 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 GenèveGreen Cross Blood Bank & Genetic Research Centre
    • , Randall W. BurtAffiliated withUnité 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 GenèveDepartment of Medicine, University of Utah School of Medicine
    • , Didier PicardAffiliated withUnité 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

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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.

Keywords

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