Whole Genome Sequencing Applied in Familial Hamartomatous Polyposis Identifies Novel Structural Variations

Kariv, Revital; Dahary, Dvir; Yaron, Yuval; Petel-Galil, Yael; Malcov, Mira; Rosner, Guy

doi:10.3390/genes13081408

Cited by 3 publications

(3 citation statements)

References 12 publications

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“…Our study found that the age of first intussusception was significantly younger in mutant-type PJS than in wild-type PJS, and its cumulative risk of intussusception at the age of 20 years was 68.3%, which was significantly higher than that of wild-type PJS (Figure 2 ). This is consistent with the findings of domestic and international studies[ 19 , 20 ]. As a result, complications such as intestinal obstruction and intussusception are more likely to occur in mutant-type PJS than in wild-type, and occur earlier.…”

Section: Discussionsupporting

confidence: 93%

Peutz-Jeghers syndrome without STK11 mutation may correlate with less severe clinical manifestations in Chinese patients

Jiang¹,

Chen²,

Xu³

et al. 2023

World J Gastroenterol

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BACKGROUND Peutz-Jeghers syndrome (PJS) is an autosomal dominant genetic disease with skin mucosal pigment spots and gastrointestinal (GI) multiple hamartoma polyps as clinical characteristics. At present, it is considered that the germline mutation of STK11 gene is the genetic cause of PJS. However, not all PJS patients can be detected STK11 germline mutations. The specific clinical characteristics of these PJS patients without STK11 mutation is an interesting clinical question. Or, like wild type GI stromal tumor, whether these PJS without STK11 mutation are also called PJS is worth discussing. Therefore, we designed the study to understand the clinical characteristics of these PJS patients without STK11 mutation. AIM To investigates whether PJS patients with known STK11 mutations have a more severe spectrum of clinical phenotypes compared to those without. METHODS A total of 92 patients with PJS admitted to the Air Force Medical Center from 2010 to 2022 were randomly selected for study. Genomic DNA samples were extracted from peripheral blood samples, and pathogenic germline mutations of STK11 were detected by high-throughput next-generation gene sequencing. Clinical-pathologic manifestations of patients with and without STK11/LKB1 mutations were compared. RESULTS STK11 germline mutations were observed in 73 patients with PJS. Among 19 patients with no detectable STK11 mutations, six had no pathogenic germline mutations of other genes, while 13 had other genetic mutations. Compared with PJS patients with STK11 mutations, those without tended to be older at the age of initial treatment, age of first intussusception and age of initial surgery. They also had a lower number of total hospitalizations relating to intussusception or intestinal obstruction, and a lower load of small intestine polyps. CONCLUSION PJS patients without STK11 mutations might have less severe clinical-pathologic manifestations than those with.

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Section: Discussionsupporting

confidence: 93%

Peutz-Jeghers syndrome without STK11 mutation may correlate with less severe clinical manifestations in Chinese patients

Jiang¹,

Chen²,

Xu³

et al. 2023

World J Gastroenterol

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“…PJS patients affected by the disease naturally do not want their offspring to experience the same effects[ 28 ]. 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 ].…”

Section: Discussionmentioning

confidence: 99%

“…The annual incidence of PJS ranges from 1: 8300 to 1: 29000 and does not differ by sex, race, or ethnicity[ 2 - 4 ]. PJS has extremely high penetrance and clinical heterogeneity[ 5 ] and can lead to the formation of hamartomatous polyps in many organs, such as the jejunum, ileum, duodenum, stomach, colon, and gallbladder[ 6 , 7 ]. Even at a very young age, PJS patients with pathological hamartomatous polyps can experience numerous GI complications, including bleeding, anemia, abdominal pain, intussusception, obstruction, and infarction[ 8 ].…”

Section: Introductionmentioning

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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Progress report: Peutz–Jeghers syndrome

Jelsig,

Karstensen,

Overeem Hansen

2024

Familial Cancer

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Whole Genome Sequencing Applied in Familial Hamartomatous Polyposis Identifies Novel Structural Variations

Cited by 3 publications

References 12 publications

Peutz-Jeghers syndrome without STK11 mutation may correlate with less severe clinical manifestations in Chinese patients

Peutz-Jeghers syndrome without STK11 mutation may correlate with less severe clinical manifestations in Chinese patients

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

Progress report: Peutz–Jeghers syndrome

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