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Peutz−Jeghers Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The STK11 gene (also known as LKB1) located on chromosome 19p13.3 is composed of 10 exons spanning 22.6 kb and encodes a 433 aa serine/threonine-protein kinase (STK11) with a central kinase catalytic domain (residues 49–309), regulatory N- and C-terminal domains, and a nuclear localization signal near the N-terminal. Present in the cytoplasm and translocated to mitochondria during apoptosis, STK11 regulates cell differentiation and proliferation by interfering G1 cell cycle arrest in a p53-independent manner, induces epithelial cell apoptosis in a p53-dependent manner, and maintains cellular polarity (via tubulin stabilization, tight junction formation, and E-cadherin localization), metabolism, and energy homeostasis through phosphorylation/activation of adenosine monophosphate–activated protein kinase (AMPK) [3,4]. Furthermore, use of STK11+/− mouse model confirms upregulation of cyclooxygenase-2 (COX-2) in polyp tissue, in line of overexpression of COX-2 in 60%–80% of PJS hamartomas and PJS-associated tumors.
Colorectal cancer syndromes
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
Other forms of polyposis include the following. Peutz-Jeghers syndrome (autosomal dominant): This is characterised externally by circumoral pigment spots as well as by polyps and neoplasms, which may occur throughout the gastrointestinal tract and also increase risks for extra-intestinal malignancy including breast and testicular cancers. The risk of malignancy is lower than in polyposis coli but is considerable and less preventable owing to the wider distribution of lesions. Most cases are associated with inherited mutations in LKB1/STK11.Juvenile polyposis syndrome (autosomal dominant): This is characterised by occurrence of hamartomatous gastrointestinal polyps and increased colorectal cancer risk. It is caused by pathogenic mutations in SMAD4 or BMPR1A.MutYH-associated polyposis (MAP) (autosomal recessive): This is associated with attenuated polyposis and colorectal cancer due to defects in the DNA repair gene MutYH. This disorder is of considerable significance, since it means that one can no longer assume that all familial colorectal cancers and polyposis are dominantly inherited.
Hereditary Colorectal Cancer
Published in Peter Sagar, Andrew G. Hill, Charles H. Knowles, Stefan Post, Willem A. Bemelman, Patricia L. Roberts, Susan Galandiuk, John R.T. Monson, Michael R.B. Keighley, Norman S. Williams, Keighley & Williams’ Surgery of the Anus, Rectum and Colon, 2019
Patients with PJS and their families should be referred to centres with expertise in the multi-disciplinary management of hereditary colorectal cancer. STK11 sequencing should be offered to patients clinically affected with PJS and, if a mutation is detected, their at-risk relatives. Enrollment of patients into a cancer or polyposis registry may optimise patient and family education and maximise adherence to surveillance and research in PJS.
Gastric-type mucinous adenocarcinoma of the cervix in a woman with Peutz-Jeghers syndrome: a case report
Published in Acta Chirurgica Belgica, 2023
Tong Tong, Qiong Fan, Shu Shi, Yuhong Li, Yudong Wang
PJS may be defined by a mutation of the STK11 gene (chromosome 19p13.3). STK11 encodes a serine/threonine kinase, which participates in cell metabolism and proliferation [16]. In ∼94% of patients with PJS [17,18], a germline mutation of STK11 was detected. In the present case, the patient was found to harbor an STK11 mutation on chromosome 19 in exon 4. A number of mutations, including deletion, insertion and inversion mutations, have been reported to date in almost every coding exon, but mainly in exons 1, 5, 6 and 7 [19,20]. However, the reports on genotype-phenotype correlation associated with STK11 pathogenic variants are conflicting. The major source of morbidity and mortality among young patients is intestinal intussusception. Another cause is the increased cumulative risk of cancer. The most common types of cancer associated with PJS are breast and colon cancer, with the cumulative risk being >30%, while the respective risks in the general population are 12.4 and 5% [1]. The risk of cervical cancer in patients with PJS is 10%, while in the general population it is <1%. The PJS-specific cancer surveillance guidelines are summarized in Table 1 [1].
Preimplantation genetic testing in two Danish couples affected by Peutz–Jeghers syndrome
Published in Scandinavian Journal of Gastroenterology, 2023
Anna Byrjalsen, Laura Roos, Tue Diemer, John Gásdal Karstensen, Kristine Løssl, Anne Marie Jelsig
Peutz–Jeghers Syndrome (PJS) is a rare tumor predisposition syndrome (TPDS) characterized by the development of hamartomatous polyps in the gastrointestinal (GI) tract (Figure 1), mucocutaneous pigmentations and an increased risk of developing cancer in various organ systems [1]. The major sites of cancer are within the GI tract (esophageal, stomach, duodenum, colon and pancreatic) and breast cancer in females, corresponding to a lifetime cancer risk of 50−60% and 50%, respectively [1]. A pathogenic variant in STK11 can be detected in up to 90% of cases with clinical PJS [2]. PJS is inherited in an autosomal dominant manner, with 100% penetrance but variable expressivity. Patients with PJS are offered extensive surveillance (starting at the age of eight years in Denmark) to identify cancers at an early stage and allow for minimally invasive treatment options in relation to polyp burden [3].
Five years after PACIFIC: update on multimodal treatment efficacy based on real-world reports
Published in Expert Opinion on Investigational Drugs, 2023
Farkhad Manapov, Alexander Nieto, Lukas Käsmann, Julian Taugner, Saskia Kenndoff, Benedikt Flörsch, Julian Guggenberger, Kerstin Hofstetter, Sophie Kröninger, Janina Lehmann, Helene Kravutske, Carolyn Pelikan, Claus Belka, Chukwuka Eze
Immunotherapy responsiveness is multifaceted and only a few mechanisms of therapy resistance have been described. STK11 (serine/threonine kinase 11) mutations have been implicated in immune checkpoint inhibitor (ICI) failure and occur frequently in the Foundation Medicine LUAC cohort (16.7%), especially in the KRAS (Kirsten rat sarcoma virus)-mutated subgroup. STK11 mutations in KRAS-mutated lung adenocarcinoma were shown to be a driver of primary resistance to immunotherapy [36]. Nevertheless, prospective and real-world validation should be performed as exceptions may exist. For example, a retrospective transcriptomic and proteomic profiling study on NSCLC revealed potentially immune responsive NSCLC patients with STK11/TP53 co-mutations that exhibited increased immune- and STING (stimulator of interferon genes)-related gene expression [37]. Recently, An et al. reported on the prognostic value of STK11 mutational status in stage III NSCLC patients who received definitive CRT [38]. With similar clinical and demographic parameters (age, histology, KRAS mutational status, TP53 mutational status, rate of maintenance ICI after CRT) the multivariable analysis showed worse PFS (HR 2.25; 95%CI, 1.03–4.88; p = 0.04) for the 11 STK11 mutated patients compared to 59 wild-type patients, but no difference in OS (HR 1.47; 95%CI: 0.49–4.38; p = 0.49) [38].