Original ArticleSTK11 gene analysis reveals a significant number of splice mutations in Chinese PJS patients
Introduction
Peutz-Jeghers syndrome (PJS; OMIM #175200) is an autosomal dominant inherited disorder, characterized by mucocutaneous pigmentation (MP), hamartomatous polyps of the gastrointestinal (GI) tract (PJPs), and an increased risk of developing of various neoplasms [1], [2]. PJS is also a type of colorectal cancer (CRC syndrome. Family history (FH) is positive in certain cases, whereas others arise de-novo. The incidence of PJS is estimated to be low, at 0.5 to 2 in 100,000 [3]; however, the incidence in a specific country or area is unknown.
As a Mendelian disorder, PJS's genetic cause has been identified as germline mutations in the serine–threonine kinase 11 (STK11) gene [4], [5]. This gene is located on chromosome 19p13.3 and comprises nine exons that encode a 433 amino-acid protein. As a tumor suppressor, STK11 works together with several partners, like STE20-related kinase adaptor alpha (STRADA) and scaffold protein 25 (MO25) [6], and takes part in many biological processes and signaling pathways, such as cell cycle arrest [7], P53-mediated apoptosis [8], Wnt signaling [9], [10], transforming growth factor beta (TGF-β) signaling [11], Ras induced cell transformation [12], and cell polarity [13], [14], [15], [16]. Its extensive participation in biological processes means that functional mutations of STK11 probably cause physiological malfunction in PJS and neoplasms in multiple sites [17].
The diagnosis of PJS consists of two aspects, clinical and genetic. The clinical criteria are taken from the comprehensive system in the Mallorca consensus statement (2007), which allows for any two of the three features (PJP, MP, and FH) or the isolated presence of two or more PJPs to diagnose PJS [3]. The genetic diagnosis is based on the identification of an STK11 germline mutation, although a single study has found an MYH11 (encoding myosin heavy chain 11) germline mutation in a PJS family [18]. The detection methods include Sanger sequencing, next generation sequencing (NGS), denaturing high performance liquid chromatography (DHPLC), single strand conformation polymorphism (SSCP), and multiple ligation-dependent probe amplification (MLPA). Until now, Sanger sequencing plus MLPA, or NGS plus MLPA, have been the best combined detection strategies, with detection rates of 65.8–87.5% [19], [20], [21], [22], [23], [24], [25], [26]. The effectiveness of the combination may vary when applied in different ethnicities. Chinese Han people are one of the most populous races, accounting for more than 20% of the human population; however, data from China are very limited. Previous reports presented PJS detection rates of 67.3% and 81.8%, respectively, using these combinations, which is a marked difference.
In the present study, we applied the combination of direct sequencing and MLPA in a cohort of patients with PJS hospitalized over the course of one year to explore the effectiveness of this strategy in Chinese Han people. We focused on the risk factors that may be associated with the occurrence of polyp-related complications and tumorigenesis.
Section snippets
Subjects
A total of 54 patients were diagnosed clinically with PJS in the Airforce General Hospital of PLA (Beijing) and Changhai Hospital (Shanghai) between Sep 2016 and Aug 2017. The clinical diagnostic criteria of PJS, as recommended by WHO were adopted: (1) Three or more histologically PJPs in the gastrointestinal tract; (2) any number of PJPs detected with a positive FH of PJS; (3) characteristic MP with a positive FH of PJS; and (4) any number of PJPs together with characteristic MP [27]. The
Clinical features
The study process was performed according to the flowchart displayed in Fig. S1. During the whole year investigated (Sep 2016–Aug 2017), 54 patients with clinically diagnosed PJS visited our hospitals and were enrolled in this investigation. The median age of this cohort for diagnosis and first intervention (polypectomy or laparotomy) were 18 and 17 years, respectively, and the proportion of men was 70.4%. Among them, 24 had family history of PJS and 30 did not. Thirty-four patients experienced
Discussion
PJS has various manifestations related to PJPs, such as abdominal pain, distention, hematochezia, chronic anemia, PRP, bowel obstruction, and clinical intussusception [32], [33], [34]. An increased risk of cancer at multiple sites is also a considerable threat to patients with PJS, and the sites range widely, including the GI tract, breast, ovary, testis, and lung [35]. The two main purposes of PJS management/surveillance are to detect sizeable GI polyps and to detect cancer at the early stage
Funding
This work was supported by the National Natural Science Foundation of China [Grant number 81500490]; Application Research of Capital Clinical Character [Grant number Z151100004015215]; the Annual Project of Airforce General Hospital [Grant numbers KZ2015026, KZ2016021]; and the National Key R&D Program of China [Grant number 2017YFC1308800].
Informed consent
Written informed consent was obtained from adult participants and from the legal guardians of child participants in this study.
Conflict of interests
The authors declare that they have no competing interests.
Acknowledgments
We thank the subjects for their participation. We very much appreciate the kind help of Dr. Wen-Sheng Lin and Dr. Hong-Yu Cheng's with the pathological and endoscopic images of the polyps.
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These authors contributed equally to this work.