In ovarian cancer (OC), identifying key molecular players in disease escalation and chemoresistance remains critical. Our investigation elucidates the role of the DNA Polymerase Mu (POLM) , especially G312R mutation, in propelling oncogenesis through dual pathways. POLMG312R markedly augments the ribonucleotide insertion capability of POLM, precipitating genomic instability. Additionally, our research reveals that POLMG312R perturbs Collagen alpha-1 (XI) chain (COL11A1) expression-a gene plays a key role in oncogenesis-and modulates the NF-κB signaling pathway, alters the secretion of downstream inflammatory cytokines, and promotes tumor-macrophage interactions. We illustrate a bidirectional regulatory interaction between POLM, particularly its G312R variant, and COL11A1. This interaction regulates NF-κB signaling, culminating in heightened malignancy and resistance to chemotherapy in OC cells. These insights position the POLM as a potential molecular target for OC therapy, shedding light on the intricate pathways underpinning POLM variant disease progression.

BACKGROUND: The treatment of lung adenocarcinoma is difficult due to the limited therapeutic options. Cancer-associated fibroblasts play an important role in the development of cancers. This study aimed to identify a promising molecular target associated with cancer-associated fibroblasts for the treatment of lung adenocarcinoma.
METHODS: The Cancer Genome Atlas lung adenocarcinoma dataset was used to screen hub genes associated with cancer-associated fibroblasts via the EPIC algorithm and Weighted Gene Co-expression Network Analysis. Multiple databases were used together with our data to verify the differential expression and survival of COL11A1. Functional enrichment analysis and the single-cell TISCH database were used to elucidate the mechanisms underlying COL11A1 expression. The correlation between COL11A1 and immune checkpoint genes in human cancers was also evaluated.
RESULTS: Using the EPIC algorithm and Weighted Gene Co-expression Network Analysis, 13 hub genes associated with cancer-associated fibroblasts in lung adenocarcinoma were screened. Using the GEPIA database, Kaplan-Meier Plotter database, GSE72094, GSE75037, GSE32863, and our immunohistochemistry experiment data, we confirmed that COL11A1 overexpresses in lung adenocarcinoma and that high expression of COL11A1 is associated with a poor prognosis. COL11A1 has a genetic alteration frequency of 22% in patients with lung adenocarcinoma. COL11A1 is involved in the extracellular matrix activities of lung adenocarcinoma. Using the TISCH database, we found that COL11A1 is mainly expressed by cancer-associated fibroblasts in the tumor microenvironment rather than by lung adenocarcinoma cells. Finally, we found that COL11A1 is positively correlated with HAVCR2(TIM3), CD274 (PD-L1), CTLA4, and LAG3 in lung adenocarcinoma.
CONCLUSIONS: COL11A1 may be expressed and secreted by cancer-associated fibroblasts, and a high expression of COL11A1 may result in T cell exhaustion in the tumor microenvironment of lung adenocarcinoma. COL11A1 may serve as an attractive biomarker to provide new insights into cancer therapeutics.

UNASSIGNED: Stickler syndrome (STL) is a collagenopathy caused by pathogenic variants in collagen-coding genes, mainly COL2A1 or COL11A1 associated with Stickler syndrome type 1 (STL1) or type 2 (STL2), respectively. Affected individuals manifest ocular, auditory, articular, and craniofacial findings in varying degrees. Previous literature and case reports describe high variability in clinical findings for patients with STL. With this case report, we broaden the clinical spectrum of the phenotype.
UNASSIGNED: Case report on two members of a family (mother and son) including clinical examination and genetic testing using targeted trio whole exome sequencing (trio-WES).
UNASSIGNED: A boy and his mother presented with microphthalmia, congenital cataract, ptosis, and moderate-to-severe sensorineural hearing loss. Trio-WES found a novel heterozygote missense variant, c.4526A>G; p(Gln1509Arg) in COL11A1 in both affected individuals.
UNASSIGNED: We report a previously undescribed phenotype associated with a COL11A1-variant in a mother and son, expanding the spectrum for phenotype-genotype correlation in STL2, presenting with microphthalmia, congenital cataract, and ptosis not normally associated with Stickler syndrome.

UNASSIGNED: Developmental dysplasia of the hip (DDH) is a congenital condition affecting 2-3% of all infants. DDH increases the risk of osteoarthritis, is the cause of 30 ​% of all total hip arthroplasties (THAs) in adults <40 years of age and can result in loss of life quality. Our aim was to explore the genetic background of DDH in order to improve diagnosis, management and longterm outcome.
UNASSIGNED: We used the large, ongoing, longitudinal Trøndelag Health Study (HUNT) database. Case definition was based on ICD-9/-10 diagnoses of DDH, or osteoarthritis secondary to DDH. Analyses were performed using SAIGE software, with covariates including sex, batch, birth year and principal components. We included only single nucleotide polymorphisms (SNPs) with minor allele frequency (MAF) ≥ 0.01, R2≥ 0.8 and Hardy-Weinberg equilibrium (HWE) P-value ≥ 0.0001. Significance level was set at p ​< ​5 ​× ​10-8. Meta-analysis using data from DDH and primary osteoarthritis genome-wide association studies (GWASs) was done using METAL software. The study was approved by the regional ethical committee.
UNASSIGNED: Analysis included 69,500 individuals, of which 408 cases, and 8,531,386 SNPs. Two SNPs near COL11A1 were significantly associated with DDH; rs713162 (β ​= ​-0.43, SE ​= ​0.07, p ​= ​8.4 ​× ​10-9) and rs6577334 (β ​= ​-0.43, SE ​= ​0.08, p ​= ​8.9 ​× ​10-9). COL11A1 has previously been associated with acetabular dysplasia and osteoarthritis. Meta-analysis supported previous GWAS findings of both DDH and primary osteoarthritis.
UNASSIGNED: This large, genome-wide case-control study indicates an association between COL11A1 and DDH and is an important contribution to investigating the etiology of DDH, with further research needed.

OBJECTIVE: Collagen family genes (CFGs) play a significant role in the pathogenesis of cancers. This study aimed to evaluate changes in the expression levels (Els) of CFGs related to epithelial-mesenchymal transition (EMT) and metastasis in gastric (GC), breast (BC), and colorectal (CRC) cancers to introduce these genes as potential diagnostic biomarkers for these three types of cancer.
METHODS: The Cancer Genome Atlas (TCGA) examined ELS changes in CFGs associated with EMT and metastasis to determine their diagnostic value for GC, BC, and CRC. InteractiVenn was used to find genes shared by these three cancers. The biomarker role of CFGs was determined using the receiver operating characteristic (ROC) analysis. GC, BC, and CRC samples were analyzed using the RT-qPCR method to verify the bioinformatics results and evaluate the EL of the selected genes as biomarkers for these cancers.
RESULTS: The in-silico results showed a significant increase in the EL of several CFGs involved in EMT and metastasis in GC, BC, and CRC samples compared to healthy samples. Six common genes (COL11A1, COL12A1, COL1A1, COL1A2, COL5A1, and COL5A2) showed significantly increased in these three cancers, therebysupporting their oncogenic role. Furthermore, the biomarker-related analyses indicated that COL11A1 and COL1A1 were common diagnostic biomarkers for the three cancers. The RT-qPCR method confirmed that the ELs of COL11A1 and COL1A1 in the GC, BC, and CRC samples increased significantly compared to the adjacent normal samples.
CONCLUSIONS: CFGs in EMT and metastasis of GC, BC, and CRC are strong common diagnostic biomarkers for these cancers.

BACKGROUND: Determining the infiltration of carcinomas is essential for the proper follow-up and treatment of cancer patients. However, it continues to be a diagnostic challenge for pathologists in multiple types of tumors. In previous studies (carried out in surgical specimens), the protein COL11A1 has been postulated as an infiltration marker mainly expressed in the extracellular matrix (ECM). We hypothesized that a differential expression of COL11A1 may exist in the peritumoral stroma of tumors that have acquired infiltrating properties and that it may be detected in the small biopsies usually available in normal clinical practice.
METHODS: In our study, we performed immunohistochemical staining in more than 350 invasive and noninvasive small samples obtained via core needle biopsy (CNB), colonoscopy, or transurethral resection of bladder tumor (TURBT) of breast, colorectal, bladder, and ovarian cancer.
RESULTS: Our results revealed that COL11A1 immunostaining had a sensitivity to classify the samples into infiltrative vs. noninfiltrative tumors of 94% (breast), 97% (colorectal), >90% (bladder), and 74% (ovarian); and a specificity of 97% (breast), 100% (colorectal), and >90% (bladder). In ovarian cancer, the negative predictive value (0.59) did not present improvement over the usual histopathological markers. In all samples tested, the cumulative sensitivity was 86% and the specificity 96% (p < 0.0001).
CONCLUSIONS: COL11A1-positive immunostaining in small biopsies of breast, colon, bladder and ovarian cancer is an accurate predictive marker of tumor infiltration that can be easily implemented in daily clinical practice.

Adrenocortical carcinoma (ACC) is a rare but highly aggressive cancer with limited treatment options and poor survival for patients with advanced disease. An improved understanding of the transcriptional programs engaged in ACC will help direct rational, targeted therapies. Whereas activating mutations in Wnt/β-catenin signaling are frequently observed, the β-catenin-dependent transcriptional targets that promote tumor progression are poorly understood. To address this question, we analyzed ACC transcriptome data and identified a novel Wnt/β-catenin-associated signature in ACC enriched for the extracellular matrix (ECM) and predictive of poor survival. This suggested an oncogenic role for Wnt/β-catenin in regulating the ACC microenvironment. We further investigated the minor fibrillar collagen, collagen XI alpha 1 (COL11A1), and found that COL11A1 expression originates specifically from cancer cells and is strongly correlated with both Wnt/β-catenin activation and poor patient survival. Inhibition of constitutively active Wnt/β-catenin signaling in the human ACC cell line, NCI-H295R, significantly reduced the expression of COL11A1 and other ECM components and decreased cancer cell viability. To investigate the preclinical potential of Wnt/β-catenin inhibition in the adrenal microenvironment, we developed a minimally invasive orthotopic xenograft model of ACC and demonstrated that treatment with the newly developed Wnt/β-catenin:TBL1 inhibitor Tegavivint significantly reduced tumor growth. Together, our data support that the inhibition of aberrantly active Wnt/β-catenin disrupts transcriptional reprogramming of the microenvironment and reduces ACC growth and survival. Furthermore, this β-catenin-dependent oncogenic program can be therapeutically targeted with a newly developed Wnt/β-catenin inhibitor. These results show promise for the further clinical development of Wnt/β-catenin inhibitors in ACC and unveil a novel Wnt/β-catenin-regulated transcriptome.

Numerous studies have discovered that hsa_circ_0063526 (also known as circRANGAP1) is an oncogenic circular RNA (circRNA) in some human tumors, including non-small cell lung cancer (NSCLC). However, the concrete molecular mechanism of circRANGAP1 involved in NSCLC is not completely elucidated. CircRANGAP1, microRNA-653-5p (miR-653-5p), and Type XI collagen (COL11A1) contents were determined via real-time quantitative polymerase chain reaction (RT-qPCR). Cell proliferative ability, migration, and invasion were measured using 5-ethynyl-2\'-deoxyuridine (EdU), colony formation, wound healing, and transwell assays. E-cadherin, N-cadherin, Vimentin, and COL11A1 protein levels were detected via western blot assay. After Starbase software prediction, the binding between miR-653-5p and circRANGAP1 or COL11A1 was verified using a dual-luciferase reporter assay. Besides, the role of circRANGAP1 on tumor cell growth was analyzed using a xenograft tumor model in vivo. Increased circRANGAP1 and COL11A1, and reduced miR-653-5p were found in NSCLC tissues and cell lines. Furthermore, circRANGAP1 absence might hinder NSCLC cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) in vitro. Mechanically, circRANGAP1 functioned as a sponge of miR-653-5p to increase COL11A1 expression. In vivo experiments illustrated that circRANGAP1 knockdown repressed tumor growth. CircRANGAP1 silencing might suppress NSCLC cell malignant biological behaviors, at least in part, through the miR-653-5p/COL11A1 axis. These results provided a promising strategy for treating NSCLC malignancies.

The Stickler syndromes are the leading cause of inherited retinal detachment and the most common cause of rhegmatogenous retinal detachment in childhood. The clinical and molecular genetic spectrum of this connective tissue disorder is discussed in this article, emphasising the key role the ophthalmologist has to play in the identification, diagnosis and prevention of blindness in the increasingly widely recognised sub-groups with ocular-only (or minimal systemic) involvement. Without diagnosis and prophylaxis in such high-risk subgroups, these patients are at high risk of Giant Retinal Tear detachment and blindness, especially in the paediatric population, where late or second eye involvement is common. Initially considered a monogenic disorder, there are now known to be at least 11 distinct phenotypic subgroups in addition to allied connective tissue disorders that can present to the clinician as part of the differential diagnosis.
UNASSIGNED: Treatment and diagnostic advances in Stickler syndrome The Stickler syndromes are a group of related connective tissue disorders that are associated with short-sight and a very high risk of blindness from detachment of the retina - the light sensitive film at the back of the eye. Other features include cleft palate, deafness and premature arthritis. It is the most common cause of retinal detachment in children and the most common cause of familial or inherited retinal detachment. In contrast to most other forms of blinding genetic eye disease, blindness from retinal detachment in Stickler syndrome is largely avoidable with accurate diagnosis and prophylactic (preventive) surgery. Recent advances in the understanding of the genetic causes of Stickler syndrome mean that the diagnosis can now be confirmed in over 95% of cases and, most importantly, the patient\'s individual risk of retinal detachment can be graded. Preventative surgery is hugely effective in reducing the incidence of retinal detachment in those patients shown to be at high risk. NHS England have led the way in the multidisciplinary care for patients with Stickler syndrome by launching a highly specialist service that has been free at point of care to all NHS patients in England since 2011 (https://www.england.nhs.uk/commissioning/spec-services/highly-spec-services, www.vitreoretinalservice.org).

OBJECTIVE: Esophageal carcinoma (ESCA) is a common malignancy characterized by high morbidity and mortality. Our work managed to dissect the modulatory mechanism of E2F1/miR-29c-3p/COL11A1 in the malignant progression and sensitivity of ESCA cells to sorafenib.
METHODS: Via bioinformatics approaches, we identified the target miRNA. Subsequently, CCK-8, cell cycle analysis, and flow cytometry were used to check the biological influences of miR-29c-3p on ESCA cells. TransmiR, mirDIP, miRPathDB, and miRDB databases were used as tools for the prediction of upstream transcription factors and downstream genes of miR-29c-3p. The targeting relationship of genes was detected via RNA immunoprecipitation and chromatin immunoprecipitation, which was further validated by dual-luciferase assay. Finally, in vitro experiments revealed the way E2F1/miR-29c-3p/COL11A1 affected sorafenib\'s sensitivity, and in vivo experiments were used to verify the way E2F1 and sorafenib impacted ESCA tumor growth.
RESULTS: miR-29c-3p, downregulated in ESCA, could suppress ESCA cell viability, arrest the cell cycle in the G0/G1 phase, and impel apoptosis. E2F1 was found to be upregulated in ESCA and it could abate the transcriptional activity of miR-29c-3p. COL11A1 was found to be a downstream target of miR-29c-3p to enhance cell viability, induce cell cycle arrest in S phase, and constrain apoptosis. Cellular and animal experiments together demonstrated that E2F1 abated the sorafenib\'s sensitivity of ESCA cells via miR-29c-3p/COL11A1.
CONCLUSIONS: E2F1 affected the viability, cell cycle, and apoptosis of ESCA cells by modulating miR-29c-3p/COL11A1, and it attenuated the sensitivity of ESCA cells to sorafenib, shedding new light on the treatment of ESCA.