STK11 Domain XI Mutations: Candidate Genetic Drivers Leading to the Development of Dysplastic Polyps in Peutz-Jeghers Syndrome

Zhiqing Wang, Baoping Wu, Rebecca A. Mosig, Yulan Chen, Fei Ye, Yali Zhang, Wei Gong, Lanbo Gong, Fei Huang, Xinying Wang, Biao Nie, Haoxuan Zheng, Miao Cui, Yadong Wang, Juan Wang, Chudi Chen, Alexandros D. Polydorides, David Y. Zhang, John A. Martignetti, Bo Jiang

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

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.

Original languageEnglish
Pages (from-to)851-858
Number of pages8
JournalHuman Mutation
Volume35
Issue number7
DOIs
StatePublished - Jul 2014

Keywords

  • Dysplastic polyp
  • Hereditary cancer
  • LKB1
  • Malignancy
  • Peutz-Jeghers syndrome
  • STK11

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