Basic Study
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Oct 21, 2021; 27(39): 6631-6646
Published online Oct 21, 2021. doi: 10.3748/wjg.v27.i39.6631
Detection and analysis of common pathogenic germline mutations in Peutz-Jeghers syndrome
Guo-Li Gu, Zhi Zhang, Yu-Hui Zhang, Peng-Fei Yu, Zhi-Wei Dong, Hai-Rui Yang, Ying Yuan
Guo-Li Gu, Zhi Zhang, Yu-Hui Zhang, Peng-Fei Yu, Zhi-Wei Dong, Hai-Rui Yang, Department of General Surgery, Air Force Medical Center, Chinese People's Liberation Army, Beijing 100142, China
Yu-Hui Zhang, Graduate School, Hebei North University, Zhangjiakou 075000, Hebei Province, China
Ying Yuan, Department of Medical Oncology, Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
Author contributions: Gu GL and Zhang Z contributed equally to this study; Gu GL and Yuan Y designed the research; Gu GL, Zhang Z, Yang HR, Yu PF, Dong ZW and Zhang YH conducted experiments and analyzed the clinical data; Gu GL and Zhang Z wrote the manuscript; and Yuan Y revised the manuscript.
Supported by Beijing Capital Medical Development Research Fund, No. Shoufa2020-2-5122.
Institutional review board statement: The study was reviewed and approved by the Ethics Committee of the Air Force Medical Center (Approval No. 2020-105-PJ01), and the Second Affiliated Hospital of Zhejiang University School of Medicine (Approval No. 2017-066).
Conflict-of-interest statement: The authors declare that they have no conflicting interests.
Data sharing statement: All patients (legal guardians of minors) understood the process and purpose of this study and signed an informed consent form. In the process of sample collection, follow the principles of informed consent in the Declaration of Helsinki, the Universal Declaration of Human Genome and Human Rights, and the Declaration of the Human Genome Ethics Committee on DNA Sampling, Control, and Acquisition. No additional data are available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Ying Yuan, MD, PhD, Chief Doctor, Professor, Department of Medical Oncology, Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou 310009, Zhejiang Province, China. yuanying1999@zju.edu.cn
Received: April 15, 2021
Peer-review started: April 15, 2021
First decision: May 24, 2021
Revised: May 31, 2021
Accepted: August 11, 2021
Article in press: August 11, 2021
Published online: October 21, 2021
Processing time: 187 Days and 22.3 Hours
Abstract
BACKGROUND

Different types of pathogenic mutations may produce different clinical phenotypes, but a correlation between Peutz-Jeghers syndrome (PJS) genotype and clinical phenotype has not been found. Not all patients with PJS have detectable mutations of the STK11/LKB1 gene, what is the genetic basis of clinical phenotypic heterogeneity of PJS? Do PJS cases without STK11/LKB1 mutations have other pathogenic genes? Those are clinical problems that perplex doctors.

AIM

The aim was to investigate the specific gene mutation of PJS, and the correlation between the genotype and clinical phenotype of PJS.

METHODS

A total of 24 patients with PJS admitted to the Air Force Medical Center, PLA (formerly the Air Force General Hospital, PLA) from November 1994 to January 2020 were randomly selected for inclusion in the study. One hundred thirty-nine common hereditary tumor-related genes including STK11/LKB1 were screened and analyzed for pathogenic germline mutations by high-throughput next-generation sequencing (NGS). The mutation status of the genes and their relationship with clinical phenotypes of PJS were explored.

RESULTS

Twenty of the 24 PJS patients in this group (83.3%) had STK11/LKB1 gene mutations, 90% of which were pathogenic mutations, and ten had new mutation sites. Pathogenic mutations in exon 7 of STK11/LKB1 gene were significantly lower than in other exons. Truncation mutations are more common in exons 1 and 4 of STK11/LKB1, and their pathogenicity was significantly higher than that of missense mutations. We also found SLX4 gene mutations in PJS patients.

CONCLUSION

PJS has a relatively complicated genetic background. Changes in the sites responsible for coding functional proteins in exon 1 and exon 4 of STK11/LKB1 may be one of the main causes of PJS. Mutation of the SLX4 gene may be a cause of genetic heterogeneity in PJS.

Keywords: Peutz-Jeghers syndrome; Genotype; Phenotype; STK11; Mutation

Core Tip: It is currently believed that Peutz-Jeghers syndrome (PJS) is an autosomal dominant genetic disease predominantly caused by germline mutations in the STK11/LKB1 gene. No correlation of the PJS genotype and clinical phenotype has been found so far. The correlation of genotype and clinical phenotype and exploration of the internal molecular mechanism of different clinical phenotypes were studied in 24 treated PJS patients with different clinical phenotypes. Peripheral venous blood or normal tissue adjacent to polyps were collected for high-throughput next-generation sequencing (NGS) of 139 hereditary colorectal tumor-related genes including STK11/LKB1. A newly discovered likely pathogenic gene (SLX4) provided new data explaining the genetic heterogeneity of PJS.