Malignant STK11 adnexal tumor harboring a somatic mutation in a woman previously diagnosed with mesothelioma, a case report.

STK11 germline pathogenic variants are typically associated with Peutz-Jeghers syndrome, an autosomal dominant disease characterized by hamartomatous polyps in the gastrointestinal tract, hyperpigmented patches, and increased risk of stomach, colorectal, small bowel, and breast cancers (Beggs et al., 2010). Mutations in this gene have also been identified in skin, pancreatic, testicular, and stromal ovarian cancer (Fagerberg et al., 2014). To date, there have been less than 30 cases of ovarian cancer reported associated with mutated STK11 (Bennett et al., 2021). In this report, we discuss a rare case of a STK11 adnexal tumor in a 39-year-old woman previously diagnosed with malignant mesothelioma. After 33 months with no evidence of disease following cytoreductive surgery with HIPEC and adjuvant chemotherapy, a new retroperitoneal lesion was noted on imaging. After resection, molecular testing indicated an STK11 mutation, and histology was consistent with an STK11 adnexal tumor. A high index of suspicion is required to make the diagnosis of STK11 adnexal tumor due to its non-distinct pathology and IHC staining. Due to the rarity of this neoplasm, analysis of current and future cases of the STK11 adnexal tumor is necessary to understand its pathogenesis, genetic mutational analysis, clinical course, and best treatment options.

High-throughput screening of the natural STK11 agonist dauricine: A biphenylisoquinoline alkaloid exerting anti-NSCLC effects and reversing gefitinib resistance.

BACKGROUND: Serine/threonine kinase 11 (STK11) deletion and downregulation caused cancer progression, and were widely associated with drug resistance. Accurate screening of natural small molecules about anti-cancer and anti-drug resistance is the key to the development and utilization of natural product application, which could promote traditional Chinese medicine in the treatment of cancer. Dauricine, which is derived from the rhizome of Menispermum dauricum DC., has certain potential but unexplored mechanism for the treatment of cancer. PURPOSE: The aim of this study was to screen and validate the role and mechanism of natural STK11 agonists with anti-drug resistance from plants in the treatment of NSCLC. METHODS: A lentiviral STK11 overexpression cell model was employed for the screening of natural STK11 agonists. The efficacy of dauricine in the treatment of NSCLC was validated on PC-9 and HCC827 cells. In vivo validation of dauricine activity was performed using nude mouse models equipped with PC9 xenografts. To investigate the anti-resistant effects of dauricine, gefitinib-resistant PC9 cell models were constructed. RESULTS: As a natural agonist of STK11, it causes the activation of the STK11/AMPK pathway and inhibits the growth of PC-9 cells. Dauricine synergises the inhibitory effect with gefitinib on PC9. The up-regulation of STK11 protein expression by dauricine was demonstrated in vitro and in vivo, while restoring the sensitivity of PC9/GR to gefitinib by down-regulating the protein expression of Nrf2 and Pgp. CONCLUSION: Dauricine, a natural agonist of STK11, effectively inhibited NSCLC, and its combination treatment with gefitinib reversed drug-resistant NSCLC.

Corrigendum: TP53 co-mutations in advanced lung adenocarcinoma: comparative bioinformatic analyses suggest ambivalent character on overall survival alongside KRAS, STK11 and KEAP1 mutations.

[This corrects the article DOI: 10.3389/fonc.2024.1357583.].

Metformin promotes anti-tumor immunity in STK11 mutant NSCLC through AXIN1-dependent upregulation of multiple nucleotide metabolites.

Background: Metformin has pleiotropic effects beyond glucose reduction, including tumor inhibition and immune regulation. It enhanced the anti-tumor effects of programmed cell death protein 1 (PD-1) inhibitors in serine/threonine kinase 11 (STK11) mutant non-small cell lung cancer (NSCLC) through an axis inhibition protein 1 (AXIN1)-dependent manner. However, the alterations of tumor metabolism and metabolites upon metformin administration remain unclear. Methods: We performed untargeted metabolomics using liquid chromatography (LC)-mass spectrometry (MS)/MS system and conducted cell experiments to verify the results of bioinformatics analysis. Results: According to the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database, most metabolites were annotated into metabolism, including nucleotide metabolism. Next, the differentially expressed metabolites in H460 (refers to H460 cells), H460_met (refers to metformin-treated H460 cells), and H460_KO_met (refers to metformin-treated Axin1 -/- H460 cells) were distributed into six clusters based on expression patterns. The clusters with a reversed expression pattern upon metformin treatment were selected for further analysis. We screened out metabolic pathways through KEGG pathway enrichment analysis and found that multiple nucleotide metabolites enriched in this pathway were upregulated. Furthermore, these metabolites enhanced the cytotoxicity of activated T cells on H460 cells in vitro and can activate the stimulator of the interferon genes (STING) pathway independently of AXIN1. Conclusion: Relying on AXIN1, metformin upregulated multiple nucleotide metabolites which promoted STING signaling and the killing of activated T cells in STK11 mutant NSCLC, indicating a potential immunotherapeutic strategy for STK11 mutant NSCLC.

Pancreatic Cancer Screening among High-risk Individuals.

Pancreatic ductal adenocarcinoma (PDAC) continues to remain one of the leading causes of cancer-related death. Unlike other malignancies where universal screening is recommended, the same cannot be said for PDAC. The purpose of this study is to review which patients are at high risk of developing PDAC and therefore candidates for screening, methods/frequency of screening, and risk for these groups of patients.

TP53 co-mutations in advanced lung adenocarcinoma: comparative bioinformatic analyses suggest ambivalent character on overall survival alongside KRAS, STK11 and KEAP1 mutations.

Background: Recently, we could show that the co-mutations of KRAS + KEAP1, STK11 + KEAP1 and KRAS + STK11 + KEAP1 lead to a significantly shorter median overall survival (mOS) across treatments by analyzing multiple datasets. TP53, a tumor suppressor gene, plays a crucial role in regulating cell cycle progression. Its mutations occur in approximately 40-50% of non-small lung cancer (NSCLC). Co-occurrence of all four mentioned mutations has been a matter of debate for years. The aim of this study was to assess the distribution of these four mutations and the influence of the different co-mutational patterns on survival. Methods: We present a comparative bioinformatic analysis and refer to data of 4,109 patients with lung adenocarcinoma (LUAD). Results: Most of the mutations within the LUAD belong to TP53-only (29.0%), quadruple-negative (25.9%) and KRAS-only (13.4%). Whereas TP53-mutations seem to have protective effects in the context of further KEAP1- and KRAS + KEAP1-alterations (improved mOS), their role seems contrary if acquired in an already existing combination of mutations as KRAS + STK11, KRAS + STK11 + KEAP1 and STK1 + KEAP1. TP53 co-mutationshad a negative influence on KRAS-only mutated LUAD (mOS reduced significantly by more than 30%). Discussion: These data underline the need for complex mutational testing to estimate prognosis more accurately in patients with advanced LUAD.

STK11 (LKB1) immunohistochemistry is a sensitive and specific marker for STK11 adnexal tumours.

AIMS: STK11 adnexal tumour is a rare, recently described malignant neoplasm that is associated with Peutz-Jeghers syndrome. [Correction added on 3 October 2024, after first online publication: 'ST11' in preceding sentence has been corrected to 'STK11' in this version.] It predominantly originates from the para-adnexal soft tissues and often shows secondary involvement of the fallopian tube and ovary. STK11 adnexal tumours have a broad differential diagnosis due to their variable morphology and non-specific immunoprofile, and diagnostic confirmation currently requires sequencing to identify an STK11 mutation. We investigate the diagnostic utility of STK11 (LKB1) immunohistochemistry (IHC) in a cohort of STK11 adnexal tumours and morphological mimics. METHODS AND RESULTS: IHC for STK11 was performed on 122 tumours, including 17 STK11 adnexal tumours and 105 morphological mimics (10 female adnexal tumours of Wolffian origin, 22 adult granulosa cell tumours, 10 juvenile granulosa cell tumours, four Sertoli-Leydig cell tumours, two Leydig cell tumours, one Sertoli cell tumour, one steroid cell tumour, four extra-ovarian sex cord-stromal tumours, 16 ovarian endometrioid carcinomas, eight tubo-ovarian high-grade serous carcinomas, five ovarian mesonephric-like adenocarcinomas, 14 ovarian carcinosarcomas, five peritoneal malignant mesotheliomas, two pelvic plexiform leiomyomata and one ovarian solid pseudopapillary tumour). All STK11 adnexal tumours showed complete loss of cytoplasmic staining for STK11. All other tumour types showed retained cytoplasmic staining, except for one endometrioid carcinoma with mucinous differentiation which showed complete loss of STK11 expression and a high-grade serous carcinoma with subclonal loss. CONCLUSIONS: STK11 is a highly sensitive and specific immunohistochemical marker for distinguishing STK11 adnexal tumour from its histological mimics, and can obviate the need for confirmatory molecular studies in the appropriate morphological context.

Immune profiling of premalignant lesions in patients with Peutz-Jeghers syndrome.

BACKGROUND: Peutz-Jeghers syndrome (PJS), is a rare autosomal dominant hereditary disease characterized by an elevated risk of various cancers. Serine/Threonine Kinase 11 (STK11) gene is a major tumor suppressor crucial for immune evasion with and beyond tumorigenic cells. It has garnered increasing attention in the realm of oncology treatment, particularly in the context of immunotherapy development. OBJECTIVE: This study aimed to assess the suitability of polyps obtained from individuals with PJS, resulting from germline STK11 deficiency, for immunotherapy. Additionally, we seek to identify potential shared mechanisms related to immune evasion between PJS polyps and cancers. To achieve this, we examined PJS polyps alongside familial adenomatous polyposis (FAP) and sporadic polyps. METHODS: Polyps were compared among themselves and with either the paracancerous tissues or colon cancers. Pathological and gene expression profiling approaches were employed to characterize infiltrating immune cells and assess the expression of immune checkpoint genes. RESULTS: Our findings revealed that PJS polyps exhibited a closer resemblance to cancer tissues than other polyps in terms of their immune microenvironment. Notably, PJS polyps displayed heightened expression of the immune checkpoint gene CD80 and an accumulation of myeloid cells, particularly myeloid-derived suppressor cells (MDSCs). CONCLUSION: The findings suggest an immunobiological foundation for the increased cancer susceptibility in PJS patients, paving the way for potential immune therapy applications in this population. Furthermore, utilizing PJS as a model may facilitate the exploration of immune evasion mechanisms, benefiting both PJS and cancer patients.

Evaluating Safety and Clinical Activity of Front-line Treatment with Cadonilimab plus Chemotherapy in Advanced/Metastatic Nonsmall Cell Lung Cancer Harboring STK11 Genetic Aberration: A Protocol of Phase II Study.

BACKGROUND: Cadonilimab is a first-in-class bispecific PD-1/CTLA-4 antibody. Serine/threonine kinase (STK11) mutation was shown to be related to low PD-L1 expression and objective response rate (ORR) in nonsmall cell lung cancer (NSCLC), resulting in poor progression-free survival (PFS) and overall survival (OS). Herein, we hypothesized that combining cadonilimab with chemotherapy could enhance antitumor immunity and extend survival in these patients. Consequently, we designed this study to explore the clinical activity and safety of cadonilimab combined with chemotherapy in patients with advanced/metastatic NSCLC harboring STK11 alteration. TRIAL DESIGN: This single-center, open-label, single-arm phase II trial is conducted at the first affiliated hospital of Guangzhou Medical University. Treatment-naïve advanced/metastatic NSCLC patients harboring STK11 mutation will be enrolled in this study. Eligible patients will receive either cadonilimab (10mg/kg on Day 1) plus pemetrexed (500 mg/m2) and carboplatin (AUC = 5) for nonsquamous NSCLC or abraxane (100 mg/m2) and carboplatin (AUC = 5) for squamous NSCLC for 4 cycles, followed by maintenance therapy (cadonilimab plus pemetrexed or abraxane). The treatment will be discontinued when disease progression, intolerability to cadonilimab, and/or chemotherapy occurs. Measurable lesions were assessed according to the Response Evaluation Criteria in Solid Tumors (1.1). The main endpoint is ORR and safety. Subordinate endpoints include PFS, disease control rate, and duration of response. RESULTS: The study commenced enrolment in September 2023, with preliminary findings regarding the primary endpoint anticipated by January 2025.

Metabolic stress induces a double-positive feedback loop between AMPK and SQSTM1/p62 conferring dual activation of AMPK and NFE2L2/NRF2 to synergize antioxidant defense.

Co-occurring mutations in KEAP1 in STK11/LKB1-mutant NSCLC activate NFE2L2/NRF2 to compensate for the loss of STK11-AMPK activity during metabolic adaptation. Characterizing the regulatory crosstalk between the STK11-AMPK and KEAP1-NFE2L2 pathways during metabolic stress is crucial for understanding the implications of co-occurring mutations. Here, we found that metabolic stress increased the expression and phosphorylation of SQSTM1/p62, which is essential for the activation of NFE2L2 and AMPK, synergizing antioxidant defense and tumor growth. The SQSTM1-driven dual activation of NFE2L2 and AMPK was achieved by inducing macroautophagic/autophagic degradation of KEAP1 and facilitating the AXIN-STK11-AMPK complex formation on the lysosomal membrane, respectively. In contrast, the STK11-AMPK activity was also required for metabolic stress-induced expression and phosphorylation of SQSTM1, suggesting a double-positive feedback loop between AMPK and SQSTM1. Mechanistically, SQSTM1 expression was increased by the PPP2/PP2A-dependent dephosphorylation of TFEB and TFE3, which was induced by the lysosomal deacidification caused by low glucose metabolism and AMPK-dependent proton reduction. Furthermore, SQSTM1 phosphorylation was increased by MAP3K7/TAK1, which was activated by ROS and pH-dependent secretion of lysosomal Ca2+. Importantly, phosphorylation of SQSTM1 at S24 and S226 was critical for the activation of AMPK and NFE2L2. Notably, the effects caused by metabolic stress were abrogated by the protons provided by lactic acid. Collectively, our data reveal a novel double-positive feedback loop between AMPK and SQSTM1 leading to the dual activation of AMPK and NFE2L2, potentially explaining why co-occurring mutations in STK11 and KEAP1 happen and providing promising therapeutic strategies for lung cancer.Abbreviations: AMPK: AMP-activated protein kinase; BAF1: bafilomycin A1; ConA: concanamycin A; DOX: doxycycline; IP: immunoprecipitation; KEAP1: kelch like ECH associated protein 1; LN: low nutrient; MAP3K7/TAK1: mitogen-activated protein kinase kinase kinase 7; MCOLN1/TRPML1: mucolipin TRP cation channel 1; MEFs: mouse embryonic fibroblasts; MTORC1: mechanistic target of rapamycin kinase complex 1; NAC: N-acetylcysteine; NFE2L2/NRF2: NFE2 like bZIP transcription factor 2; NSCLC: non-small cell lung cancer; PRKAA/AMPKα: protein kinase AMP-activated catalytic subunit alpha; PPP2/PP2A: protein phosphatase 2; ROS: reactive oxygen species; PPP3/calcineurin: protein phosphatase 3; RPS6KB1/p70S6K: ribosomal protein S6 kinase B1; SQSTM1/p62: sequestosome 1; STK11/LKB1: serine/threonine kinase 11; TCL: total cell lysate; TFEB: transcription factor EB; TFE3: transcription factor binding to IGHM enhancer 3; V-ATPase: vacuolar-type H+-translocating ATPase.

Evaluating predictors of kinase activity of STK11 variants identified in primary human non-small cell lung cancers.

Critical evaluation of computational tools for predicting variant effects is important considering their increased use in disease diagnosis and driving molecular discoveries. In the sixth edition of the Critical Assessment of Genome Interpretation (CAGI) challenge, a dataset of 28 STK11 rare variants (27 missense, 1 single amino acid deletion), identified in primary non-small cell lung cancer biopsies, was experimentally assayed to characterize computational methods from four participating teams and five publicly available tools. Predictors demonstrated a high level of performance on key evaluation metrics, measuring correlation with the assay outputs and separating loss-of-function (LoF) variants from wildtype-like (WT-like) variants. The best participant model, 3Cnet, performed competitively with well-known tools. Unique to this challenge was that the functional data was generated with both biological and technical replicates, thus allowing the assessors to realistically establish maximum predictive performance based on experimental variability. Three out of the five publicly available tools and 3Cnet approached the performance of the assay replicates in separating LoF variants from WT-like variants. Surprisingly, REVEL, an often-used model, achieved a comparable correlation with the real-valued assay output as that seen for the experimental replicates. Performing variant interpretation by combining the new functional evidence with computational and population data evidence led to 16 new variants receiving a clinically actionable classification of likely pathogenic (LP) or likely benign (LB). Overall, the STK11 challenge highlights the utility of variant effect predictors in biomedical sciences and provides encouraging results for driving research in the field of computational genome interpretation.

Loss of the tumour suppressor LKB1/STK11 uncovers a leptin-mediated sensitivity mechanism to mitochondrial uncouplers for targeted cancer therapy.

Non-small cell lung cancer (NSCLC) constitutes one of the deadliest and most common malignancies. The LKB1/STK11 tumour suppressor is mutated in ∼ 30% of NSCLCs, typically lung adenocarcinomas (LUAD). We implemented zebrafish and human lung organoids as synergistic platforms to pre-clinically screen for metabolic compounds selectively targeting LKB1-deficient tumours. Interestingly, two kinase inhibitors, Piceatannol and Tyrphostin 23, appeared to exert synthetic lethality with LKB1 mutations. Although LKB1 loss alone accelerates energy expenditure, unexpectedly we find that it additionally alters regulation of the key energy homeostasis maintenance player leptin (LEP), further increasing the energetic burden and exposing a vulnerable point; acquired sensitivity to the identified compounds. We show that compound treatment stabilises Hypoxia-inducible factor 1-alpha (HIF1A) by antagonising Von Hippel-Lindau (VHL)-mediated HIF1A ubiquitination, driving LEP hyperactivation. Importantly, we demonstrate that sensitivity to piceatannol/tyrphostin 23 epistatically relies on a HIF1A-LEP-Uncoupling Protein 2 (UCP2) signaling axis lowering cellular energy beyond survival, in already challenged LKB1-deficient cells. Thus, we uncover a pivotal metabolic vulnerability of LKB1-deficient tumours, which may be therapeutically exploited using our identified compounds as mitochondrial uncouplers.

Genetic variation at a splicing branch point in intron 7 of STK11: a rare variant decreasing its expression in a Chinese family with Peutz-Jeghers syndrome.

BACKGROUND: Peutz-Jeghers syndrome (PJS), a rare dominantly inherited disease, is primarily characterized by hamartomatous polyps and melanotic macules as well as by an increased risk of cancer. The current study aimed to identify the pathogenic gene and pathogenic mechanism of a proband with PJS, thereby offering precise prevention and treatment strategies for PJS. METHODS: A detailed clinical examination was performed of the proband diagnosed with PJS and her family members. In addition, peripheral venous blood was collected from the family members to extract genomic DNA. The pathogenic genes of the proband were identified using whole-exome sequencing, and the candidate pathogenic variants were verified via Sanger sequencing. Meanwhile, co-segregation tests were performed among six family members. Finally, reverse transcription-polymerase chain reaction (RT-PCR) was performed to assess transcript variants in the peripheral blood cells of patients and non-related healthy controls. RESULTS: Genetic testing revealed a rare splicing variant c.921-1G > C in STK11 in the proband and in her sister and nephew, and the variant co-segregated among the affected family members and nonrelated healthy controls. The proband phenotypically presented with a rare gastric-type adenocarcinoma of the cervix. RT-PCR revealed that the STK11 c.921-1G > C variant could produce two transcripts. Of note, 40 base pairs were deleted in the aberrant transcript between exons 3 and 4, resulting in a frameshift variant and premature termination of the amino acid in exon 6 and ultimately leading to the loss of its functional domain in the STK11 protein. Finally, RT-PCR showed that compared with healthy controls, STK11 mRNA expression level was < 50% in patients. CONCLUSION: The present study results indicated that the rare splicing variant c.921-1G > C in intron 7 of STK11 may be a pathogenic variant in patients with PJS. However, this variant (in intron 7) may not produce abnormal transcripts (deletion of 40 base pairs between exons 3 and 4), and PJS may be attributed to the decrease in STK11 expression. Therefore, this study emphasized the importance of genetic counseling, pre-symptomatic monitoring, and early complication management in PJS.

Somatic STK11 mosaicism in a Turkish patient with Peutz-Jeghers syndrome.

Peutz-Jeghers syndrome (PJS) is an autosomal dominant disorder, caused by germline variants in the serine/threonine kinase 11 (STK11) gene. However, mosaic variants in STK11 gene have been rarely described. A 25-year-old woman diagnosed with PJS due to multiple hamartomatous polyps in the gastrointestinal tract was referred to our clinic. In the molecular diagnosis, the patient was evaluated using the STK11 gene sequence analysis and multiplex ligation-dependent probe amplification (MLPA) method, which suggested no pathogenic variant to account for the clinical picture. Given that the clinical findings of the patient were consistent with those of PJS, the raw data from next-generation sequencing (NGS) were re-examined for mosaicism which led to the detection of a novel mosaic c.920 + 1G > T variant in STK11 gene with a rate of 23% (1860x). Deep read-level NGS was performed on buccal mucosa and polyp samples to determine mosaicism levels in other tissues. Variant frequencies were 29% (710x) and 31% (1301x), respectively. Mosaicism should be considered in cases with clear clinical diagnostic criteria, such as PJS, where the pathogenic variant cannot be detected by sequence analysis and MLPA methods. Identification of mosaicism in these patients is very important as it can have an impact on patient follow-up and genetic counseling for relatives.

When synchronous mucinous metaplasia and neoplasia of the female genital tract and peutz-jeghers syndrome meet: a case report and literature reviews.

BACKGROUND: Peutz-Jeghers syndrome (PJS) is characterized by the presence of hamartomatous polyps in the gastrointestinal tract and mucocutaneous pigmentation on the lips, oral mucosa, nose, fingers, and toes. Synchronous mucinous metaplasia and neoplasia of the female genital tract (SMMN-FGT) refers to the occurrence of multifocal mucinous lesions in at least two sites, including the cervix, uterus, fallopian tubes, and ovaries, in the female genital tract. SMMN-FGT and PJS are rare diseases with a very low incidence, especially when occurring simultaneously. CASE PRESENTATION: We report a case in which a woman with a large mass on the left ovary underwent a gynecological surgery and was diagnosed with cervical gastric-type adenocarcinoma and mucinous lesions in the endometrium, bilateral fallopian tubes, and ovary, i.e., SMMN-FGT, by postoperative paraffin pathology. The patient sought medical attention for abdominal distension and enlargement. A gynecological ultrasound revealed a multilocular cystic mass in the pelvis, while serum tumor markers were within normal limits, with mildly elevated carbohydrate antigen 199 and carbohydrate antigen 125 levels. Cervical thin-prep cytology test result was negative. The patient had a family history of PJS with black spots on her skin and mucous membranes since the age of 8 years. She underwent multiple partial small bowel resections and gastrointestinal polypectomy owing to intestinal obstruction and intussusception. She underwent left adnexectomy, hysterectomy, right salpingectomy, greater omental resection, appendectomy and right ovary biopsy, and received six courses of adjuvant chemotherapy with Lopressor plus Carboplatin. Genetic testing revealed a heterozygous serine threonine kinase 11 germline mutation and there were no signs of recurrence during the 18-month follow-up period after treatment. CONCLUSIONS: This is a rare case in which PJS was complicated by SMMN-FGT. Owing to its extreme rarity, there are no guidelines, but reported cases appear to indicate a poor prognosis. We retrospectively reviewed all cases of collisions between PJS and SMMN-FGT and explored the clinical features, pathological characteristics, diagnosis, treatment methods, and prognosis when the two diseases coexisted. The aim is to deepen the clinicians' understanding of this disease for early detection, diagnosis and treatment.

Peutz-Jeghers Syndrome: A Comprehensive Review of Genetics, Clinical Features, and Management Approaches.

A relatively rare inherited condition known as Peutz-Jeghers syndrome (PJS) causes mucocutaneous pigmentation and gastrointestinal hamartomatous polyps. These polyps are non-cancerous, but the presence of PJS significantly increases the chances of developing various types of cancers, such as colorectal, pancreatic, gastric, and breast cancer. The purpose of this review article is to give an abbreviated summary of what is currently known about this syndrome, covering its clinical symptoms, pathophysiology, genetics, and management. PJS also raises the risk of getting many malignancies, especially gastrointestinal and pelvic cancers. Symptoms of the gastrointestinal tract brought on by hamartomatous polyps are frequent and include stool blockage, bleeding, and stomach pain. The pigmentation commonly appears as prominent bluish-black macules and frequently affects the skin and mucous membranes. Small macules and large regions of lentiginous pigmentation are both possible. Numerous areas, including the perioral area, buccal mucosa, fingers, and lips, exhibit pigmentation. Bowel obstruction and intussusception risk can be decreased by early identification and routine surveillance of gastrointestinal polyps. The gene serine/threonine kinase 11 (STK11) controls several biological functions, including cell polarity, growth, and proliferation. Genetic counseling is recommended for the affected individuals and their families. This can help assess the risk of passing on the condition to future generations and provide information about available reproductive options. Regular surveillance is crucial for managing the syndrome and reducing the risk of cancer development. Other syndromes and extra-gastrointestinal characteristics, such as somatic tumor polyps outside the gastrointestinal tract, are also linked to this syndrome.

Prognostic implications of STK11 with different mutation status and its relationship with tumor-infiltrating immune cells in non-small cell lung cancer.

Background: Mutations in STK11 (STK11Mut) gene may present a negative impact on survival in Non-small Cell Lung Cancer (NSCLC) patients, however, its relationship with immune related genes remains unclear. This study is to unveil whether overexpressed- and mutated-STK11 impact survival in NSCLC and to explore whether immune related genes (IRGs) are involved in STK11 mutations. Methods: 188 NSCLC patients with intact formalin-fixed paraffin-embedded (FFPE) tissue available for detecting STK11 protein expression were included in the analysis. After immunohistochemical detection of STK11 protein, patients were divided into high STK11 expression group (STK11High) and low STK11 expression group (STK11Low), and then Kaplan-Meier survival analysis and COX proportional hazards model were used to compare the overall survival (OS) and progression-free survival (PFS) of the two groups of patients. In addition, the mutation data from the TCGA database was used to categorize the NSCLC population, namely STK11 Mutated (STK11Mut) and wild-type (STK11Wt) subgroups. The difference in OS between STK11Mut and STK11Wt was compared. Finally, bioinformatics analysis was used to compare the differences in IRGs expression between STK11Mut and STK11Wt populations. Results: The median follow-up time was 51.0 months (range 3.0 - 120.0 months) for real-life cohort. At the end of follow-up, 64.36% (121/188) of patients experienced recurrence or metastasis. 64.89% (122/188) of patients ended up in cancer-related death. High expression of STK11 was a significant protective factor for NSCLC patients, both in terms of PFS [HR=0.42, 95% CI= (0.29-0.61), P<0.001] and OS [HR=0.36, 95% CI= (0.25, 0.53), P<0.001], which was consistent with the finding in TCGA cohorts [HR=0.76, 95%CI= (0.65, 0.88), P<0.001 HR=0.76, 95%CI= (0.65, 0.88), P<0.001]. In TCGA cohort, STK11 mutation was a significant risk factor for NSCLC in both lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) histology in terms of OS [HR=6.81, 95%CI= (2.16, 21.53), P<0.001; HR=1.50, 95%CI= (1.00, 2.26), P=0.051, respectively]. Furthermore, 7 IRGs, namely CALCA, BMP6, S100P, THPO, CGA, PCSK1 and MUC5AC, were found significantly overexpressed in STK11-mutated NSCLC in both LUSC and LUAD histology. Conclusions: Low STK11 expression at protein level and presence of STK11 mutation were associated with poor prognosis in NSCLC, and mutated STK11 might probably alter the expression IRGs profiling.

Genome-wide CRISPR screens in spheroid culture reveal that the tumor suppressor LKB1 inhibits growth via the PIKFYVE lipid kinase.

The tumor suppressor LKB1 is a serine/threonine protein kinase that is frequently mutated in human lung adenocarcinoma (LUAD). LKB1 regulates a complex signaling network that is known to control cell polarity and metabolism; however, the pathways that mediate the tumor-suppressive activity of LKB1 are incompletely defined. To identify mechanisms of LKB1-mediated growth suppression, we developed a spheroid-based cell culture assay to study LKB1-dependent growth. We then performed genome-wide CRISPR screens in spheroidal culture and found that LKB1 suppresses growth, in part, by activating the PIKFYVE lipid kinase. Finally, we used chemical inhibitors and a pH-sensitive reporter to determine that LKB1 impairs growth by promoting the internalization of wild-type EGFR in a PIKFYVE-dependent manner.

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

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.