Lung adenocarcinoma is the most common primary lung cancer seen in the world, and identifying genetic markers is essential for predicting the prognosis of lung adenocarcinoma and improving treatment outcomes. It is well known that alterations in circadian rhythms are associated with a higher risk of cancer. Moreover, circadian rhythms play a regulatory role in the human body. Therefore, studying the changes in circadian rhythms in cancer patients is crucial for optimizing treatment. The gene expression data and clinical data were sourced from TCGA database, and we identified the circadian clock-related genes. We used the obtained TCGA-LUAD data set to build the model, and the other 647 lung adenocarcinoma patients’ data were collected from two GEO data sets for external verification. A risk score model for circadian clock-related genes was constructed, based on the identification of 8 genetically significant genes. Based on ROC analyses, the risk model demonstrated a high level of accuracy in predicting the overall survival times of lung adenocarcinoma patients in training folds, as well as external data sets. This study has successfully constructed a risk model for lung adenocarcinoma prognosis, utilizing circadian rhythm as its foundation. This model demonstrates a dependable capacity to forecast the outcome of the disease, which can further guide the relevant mechanism of lung adenocarcinoma and combine behavioral therapy with treatment to optimize treatment decision-making.

Background: More and more ground glass opacity associated lung adenocarcinoma (GGO-LUAD) have been diagnosed in young patients nowadays. Our study aims to investigate the clinical features and surgical outcomes of young patients with GGO-LUAD.Methods: Patients aged ≤ 40 years who were diagnosed as lung adenocarcinoma and who underwent video assisted thoracoscopic surgery (VATS) were retrospectively reviewed from January 2017 to December 2018. According to radiological appearance of the patient’s lesions, they were divided into a solid nodule (SN) group and GGO group. The pathological subtypes, surgical procedures and nodules size were analyzed, and the clinical features and prognosis were evaluated between these patients.Results: A total of 165 patients were included, of which 133 were in the GGO group and 32 in the SN group. Both the GGO group and the SN group had a higher proportion of females and non-smokers. Compared with patients (15.63%) in the SN group, there are more patients (27.8%) under the age of 30 in the GGO group. Pathological findings showed 83.5% of lesions were pre-invasive lesions in the GGO group, although 16.5% of lesions were invasive adenocarcinoma, whereas in the SN group, 96.9% were invasive adenocarcinoma. The GGO group had significantly better histological characteristics and prognosis than the SN group. Perioperative complications occurred in only 6 patients, including pneumonia in one patient, pneumothorax in two patients, and prolonged air leak in three patients. No other serious complications or deaths occurred. After a median follow-up time of 41.2 ± 7.2 months (32-56), the 3-year recurrence free survival (RFS) (100%) and overall survival (OS) (100%) of the GGO group were significantly higher than those (93.42% and 96.88%) in the SN group.Conclusions: Young patients with GGO-LUAD are mainly non-smokers and female. Most of these patients were early-stage with good prognosis after surgery.

Keratin 6 A (KRT6A) is a member of the keratin family and can participate in the occurrence and development of some tumors. However, there is still a lack of pan-cancer analysis of KRT6A in humans. We studied the pan-cancer role of KRT6A with the help of a variety of external public databases (mainly including TCGA, GTEx, HPA, TIMER2.0, UALCAN, TISIDB, GEPIA2, Kaplan-Meier Plotter, cBioPortal and TISCH2, etc.). We performed immunohistochemistry detection of KRT6A protein expression in lung adenocarcinoma (LUAD) and its adjacent normal tissues. The results showed that KRT6A mRNA and protein were differentially expressed in most tumors, and its expression and function may be regulated by DNA methylation, RNA methylation and protein phosphorylation, and were related to the prognosis and clinical subtypes of patients with different tumors. KRT6A has multiple genetic and epigenetic characteristics in different cancers, and the main type of its genetic variation is mutation. At the same time, KRT6A is closely related to tumor mutation burden (TMB), microsatellite instability (MSI), tumor stemness score (TSC), immune checkpoints, immunomodulatory genes, and tumor immune microenvironment (TIME) in different human tumors. Secondly, the expression level of KRT6A is associated with immunotherapy and drug sensitivity. In addition, bioinformatics analysis and immunohistochemistry experiments verified that KRT6A mRNA and protein were up-regulated in LUAD, and could promote the development process of LUAD by promoting processes such as epidermis development, intermediate filament cytoskeleton and cornified envelope. This is the first pan-cancer analysis of KRT6A, which provides a comprehensive and systematic understanding of its role in various human tumors, and also reveals that KRT6A is expected to become a potential prognostic biomarker and a new target for cancer immunotherapy.

Chronic alcohol consumption is an established risk factor for esophageal squamous cell carcinoma (ESCC). Elucidating the underlying mechanisms linking metabolic stress to esophageal carcinogenesis could help identify prevention and treatment strategies. Through a trans-ancestry meta-analysis encompassing more than 200,000 individuals from East Asia, we identified a germline variant (rs1051921 C>T) at the MLXIPL locus (encoding ChREBP) that markedly elevated ESCC risk among alcohol drinkers. Functionally, the risk allele facilitated N6-methyladenosine (m6A) modification of ChREBP transcripts, enhancing their stability through recognition by the m6A reader YTHDF1. Alcohol further potentiated this regulatory axis by promoting ACSS2-driven acetyl-CoA synthesis and increasing H3K27ac enrichment at promoters of key m6A regulators. Increased ChREBP expression activated the transcription factor ATF3, which triggered endoplasmic reticulum stress and epithelial-mesenchymal transition, thereby conferring anoikis resistance. In parallel, ATF3 promoted an immunosuppressive tumor microenvironment through upregulation of PD-L1 and VEGFA, leading to exclusion of CD8+ T cells and expansion of granulocytic myeloid-derived suppressor cells. In vivo intervention via ATF3 knockdown, anti-PD-L1 treatment, or pharmacological perturbation of ChREBP-related metabolism with metformin or an ACSS2 inhibitor significantly suppressed ESCC progression and restored intratumoral CD8+ T-cell infiltration. These findings establish ChREBP as an alcohol-sensitive metabolic-epitranscriptomic switch that integrates genetic susceptibility with immune evasion to drive esophageal carcinogenesis.

Endogenous expression level of Gas1 in six colon cancer cells demonstrated by Western blot (A) and RT-PCR (B).