Prenatal diagnosis in a hereditary Peutz-Jeghers syndrome family with high cancer risk

Wang, Zhiqing; Liu, Shu; Liu, Siping; Wang, Yadong; Chen, Junsheng; Wu, Baoping

doi:10.1186/s12881-018-0594-9

Cited by 8 publications

(4 citation statements)

References 16 publications

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“…Therefore, some patients opt for preimplantation genetic testing (PGT)[ 29 ] to prevent the transmission of disease-causing mutations to future generations[ 5 , 30 ]. Some PJS patients choose to pursue a natural pregnancy[ 31 ]. In cases where the female patient or the male patient’s partner becomes pregnant, prenatal diagnosis is performed to predict whether the fetus carries STK11 or other genetic mutations[ 32 , 33 ].…”

Section: Discussionmentioning

confidence: 99%

Two missense STK11 gene variations impaired LKB1/adenosine monophosphate-activated protein kinase signaling in Peutz-Jeghers syndrome

Liu,

Zeng,

Wang

et al. 2024

World J Gastrointest Oncol

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BACKGROUND Peutz-Jeghers syndrome (PJS) is a rare hereditary neoplastic disorder mainly associated with serine/threonine kinase 11 (STK11 /LKB1 ) gene mutations. Preimplantation genetic testing can protect a patient’s offspring from mutated genes; however, some variations in this gene have been interpreted as variants of uncertain significance (VUS), which complicate reproductive decision-making in genetic counseling. AIM To identify the pathogenicity of two missense variants and provide clinical guidance. METHODS Whole exome gene sequencing and Sanger sequencing were performed on the peripheral blood of patients with PJS treated at the Reproductive and Genetic Hospital of Citic-Xiangya. Software was employed to predict the protein structure, conservation, and pathogenicity of the two missense variation sites in patients with PJS. Additionally, plasmids were constructed and transfected into HeLa cells to observe cell growth. The differences in signal pathway expression between the variant group and the wild-type group were compared using western blot and immunohistochemistry. Statistical analysis was performed using one-way analysis of variance. P < 0.05 was considered statistically significant. RESULTS We identified two missense STK11 gene VUS [c.889A>G (p.Arg297Gly) and c.733C>T (p.Leu245Phe)] in 9 unrelated PJS families who were seeking reproductive assistance. The two missense VUS were located in the catalytic domain of serine/threonine kinase, which is a key structure of the liver kinase B1 (LKB1) protein. In vitro experiments showed that the phosphorylation levels of adenosine monophosphate-activated protein kinase (AMPK) at Thr172 and LKB1 at Ser428 were significantly higher in transfected variation-type cells than in wild-type cells. In addition, the two missense STK11 variants promoted the proliferation of HeLa cells. Subsequent immunohistochemical analysis showed that phosphorylated-AMPK (Thr172) expression was significantly lower in gastric, colonic, and uterine polyps from PJS patients with missense variations than in non-PJS patients. Our findings indicate that these two missense STK11 variants are likely pathogenic and inactivate the STK11 gene, causing it to lose its function of regulating downstream phosphorylated-AMPK (Thr172), which may lead to the development of PJS. The identification of the pathogenic mutations in these two clinically characterized PJS patients has been helpful in guiding them toward the most appropriate mode of pregnancy assistance. CONCLUSION These two missense variants can be interpreted as likely pathogenic variants that mediated the onset of PJS in the two patients. These findings not only offer insights for clinical decision-making, but also serve as a foundation for further research and reanalysis of missense VUS in rare diseases.

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Section: Discussionmentioning

confidence: 99%

Two missense STK11 gene variations impaired LKB1/adenosine monophosphate-activated protein kinase signaling in Peutz-Jeghers syndrome

Liu,

Zeng,

Wang

et al. 2024

World J Gastrointest Oncol

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“…There is no literature on experience with prenatal genetic diagnosis (PND) or preimplantation genetic diagnosis (PGD) in PJS. Wang et al describe a positive prenatal genetic test for PJS with continuation of the pregnancy; PGD for a subsequent pregnancy of the PJS patient was suggested [ 86 ]. Woo et al performed a questionnaire survey about psychological wellbeing among 38 PJS patients and their relatives: 40% altered reproductive choices because of PJS and 33% were reluctant to have children due to the risk of PJS [ 87 ].…”

Section: Recommendations and Statementsmentioning

confidence: 99%

The Management of Peutz–Jeghers Syndrome: European Hereditary Tumour Group (EHTG) Guideline

Wagner

Aretz

Auranen

et al. 2021

JCM

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The scientific data to guide the management of Peutz–Jeghers syndrome (PJS) are sparse. The available evidence has been reviewed and discussed by diverse medical specialists in the field of PJS to update the previous guideline from 2010 and formulate a revised practical guideline for colleagues managing PJS patients. Methods: Literature searches were performed using MEDLINE, Embase, and Cochrane. Evidence levels and recommendation strengths were assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE). A Delphi process was followed, with consensus being reached when ≥80% of the voting guideline committee members agreed. Recommendations and statements: The only recent guidelines available were for gastrointestinal and pancreatic management. These were reviewed and endorsed after confirming that no more recent relevant papers had been published. Literature searches were performed for additional questions and yielded a variable number of relevant papers depending on the subject addressed. Additional recommendations and statements were formulated. Conclusions: A decade on, the evidence base for recommendations remains poor, and collaborative studies are required to provide better data about this rare condition. Within these restrictions, multisystem, clinical management recommendations for PJS have been formulated.

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“…9,13 However, to date, there have been few reports of the prenatal diagnosis of hereditary cancers, and the vast majority of the reports involved invasive tests. 14 Therefore, in this study, we aimed to construct a complete set of NIPT assays for PJS and FAP in the early stage of pregnancy using targeted enrichment sequencing and RHDO analysis for sophisticated clinical conditions.…”

Section: Introductionmentioning

confidence: 99%

“…Since the entire fetal genome was demonstrated to be present in a constant relative proportion to maternal DNA in maternal plasma, 3 relative haplotype dosage analysis (RHDO analysis) using target sequencing data was reported to be applicable in monogenetic diseases, 9 such as Duchenne and Becker muscular dystrophies, 10 spinal muscular atrophy, 11 congenital adrenal hyperplasia, 12 and β‐thalassemia 9,13 . However, to date, there have been few reports of the prenatal diagnosis of hereditary cancers, and the vast majority of the reports involved invasive tests 14 . Therefore, in this study, we aimed to construct a complete set of NIPT assays for PJS and FAP in the early stage of pregnancy using targeted enrichment sequencing and RHDO analysis for sophisticated clinical conditions.…”

Section: Introductionmentioning

confidence: 99%

Noninvasive prenatal testing of hereditary colorectal cancer syndromes using cell‐free DNA in maternal plasma

Wang

et al. 2022

Prenatal Diagnosis

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Objective This study aimed to establish a practical protocol for early noninvasive prenatal testing (NIPT) for fetuses at risk of Peutz‐Jeghers syndrome or familial adenomatous polyposis, two classical types of hereditary colorectal cancer syndromes, for risk evaluation and whole‐life monitoring. Method Target enrichment was performed using hybridization probes coordinating the serine‐threonine kinase 11 gene region and APC gene region, with 1458 highly heterozygous Single Nucleotide Polymorphisms included. Semitarget amplification random sequencing was used for large fragment deletion detection. For relative haplotype dosage (RHDO) analysis, haplotype construction was performed by segmented haplotype estimation and imputation tool software, the circular binary segmentation algorithm was used for recombination event calculation, and Bayes factor was used for the determination of whether the fetus was affected. Results Haplotypes were successfully constructed in the nine recruited families with different pedigree characteristics, and the results for the RHDO analysis were consistent with the amniocentesis sampling detection results. The cell‐free fetal DNA fraction can be detected as low as 2% in maternal plasma. Conclusion This is the first NIPT assay on hereditary colorectal cancer syndromes based upon RHDO analysis.

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Prenatal diagnosis in a hereditary Peutz-Jeghers syndrome family with high cancer risk

Cited by 8 publications

References 16 publications

Two missense STK11 gene variations impaired LKB1/adenosine monophosphate-activated protein kinase signaling in Peutz-Jeghers syndrome

Two missense STK11 gene variations impaired LKB1/adenosine monophosphate-activated protein kinase signaling in Peutz-Jeghers syndrome

The Management of Peutz–Jeghers Syndrome: European Hereditary Tumour Group (EHTG) Guideline

Noninvasive prenatal testing of hereditary colorectal cancer syndromes using cell‐free DNA in maternal plasma

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