title: STK11 domain XI mutations: candidate genetic drivers leading to the development of dysplastic polyps in Peutz-Jeghers syndrome.
abstract: Peutz-Jeghers syndrome (PJS) is a rare hereditary disorder resulting from mutations in serine/threonine kinase 11 (STK11) and characterized by gastrointestinal (GI) hamartomatous polyps, mucocutaneous pigmentation, and an increased risk for specific cancers. Little is known about the genetic implications of specific STK11 mutations with regard to their role in dysplastic and malignant transformation of GI polyps. Peripheral blood genomic DNA samples from 116 Chinese PJS patients from 52 unrelated families were investigated for STK11 mutations. Genotype-phenotype correlations were investigated. The mutation detection rate was 67.3% (51.9% point mutations, 15.4% large deletions). Fourteen out of the 25 point mutations identified were novel. Nearly one-third of all mutations, 8/27 (29.6%), were in exon 7, the shortest out of the nine exons. Strikingly, mutations affecting protein kinase domain XI, encoded in part by exon 7, correlated with a 90% (9/10) incidence of GI polyp dysplasia. In contrast, only two out of 17 (11.8%) nondomain XI mutations were linked to polyp dysplasia (P = 0.0001). The extent of the association between dysplasia and the development of GI-related cancers is currently unknown but our results highlight a novel STK11 genotype-phenotype association as the basis for future genetic counseling and basic research studies.
authors.affiliation: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Zhiqing
authors.initials: Z
authors.lastname: Wang
authors.forename: Baoping
authors.initials: B
authors.lastname: Wu
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Mosig
authors.forename: Yulan
authors.initials: Y
authors.lastname: Chen
authors.forename: Fei
authors.initials: F
authors.lastname: Ye
authors.forename: Yali
authors.initials: Y
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Gong
authors.forename: Lanbo
authors.initials: L
authors.lastname: Gong
authors.forename: Fei
authors.initials: F
authors.lastname: Huang
authors.forename: Xinying
authors.initials: X
authors.lastname: Wang
authors.forename: Biao
authors.initials: B
authors.lastname: Nie
authors.forename: Haoxuan
authors.initials: H
authors.lastname: Zheng
authors.forename: Miao
authors.initials: M
authors.lastname: Cui
authors.forename: Yadong
authors.initials: Y
authors.lastname: Wang
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.forename: Chudi
authors.initials: C
authors.lastname: Chen
authors.forename: Alexandros D
authors.initials: AD
authors.lastname: Polydorides
authors.forename: David Y
authors.initials: DY
authors.lastname: Zhang
authors.forename: John A
authors.initials: JA
authors.lastname: Martignetti
authors.forename: Bo
authors.initials: B
authors.lastname: Jiang
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000293:Adolescent; D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D002648:Child; D002675:Child, Preschool; D005091:Exons; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D007438:Introns; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009369:Neoplasms / Q000175:diagnosis / Q000209:etiology; D010580:Peutz-Jeghers Syndrome / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D054730:Protein Interaction Domains and Motifs / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases
keywords: LKB1; Peutz-Jeghers syndrome; STK11; dysplastic polyp; hereditary cancer; malignancy