Non-small cell lung cancer (NSCLC) is known to carry heavy mutation load. Besides smoking, cytidine deaminase APOBEC3B plays a key role in the mutation process of NSCLC. APOBEC3B is also reported to ...be upregulated and predicts bad prognosis in NSCLC. However, targeting APOBEC3B high NSCLC is still a big challenge. Here we show that APOBEC3B upregulation is significantly associated with immune gene expression, and APOBEC3B expression positively correlates with known immunotherapy response biomarkers, including: PD-L1 expression and T-cell infiltration in NSCLC. Importantly, APOBEC mutational signature is specifically enriched in NSCLC patients with durable clinical benefit after immunotherapy and APOBEC mutation count can be better than total mutation in predicting immunotherapy response. In together, this work provides evidence that APOBEC3B upregulation and APOBEC mutation count can be used as novel predictive markers in guiding NSCLC checkpoint blockade immunotherapy.
Immunotherapy, represented by immune checkpoint inhibitors (ICI), is transforming the treatment of cancer. However, only a small percentage of patients show response to ICI, and there is an unmet ...need for biomarkers that will identify patients who are more likely to respond to immunotherapy. The fundamental basis for ICI response is the immunogenicity of a tumor, which is primarily determined by tumor antigenicity and antigen presentation efficiency. Here, we propose a method to measure tumor immunogenicity score (TIGS), which combines tumor mutational burden (TMB) and an expression signature of the antigen processing and presenting machinery (APM). In both correlation with pan-cancer ICI objective response rates (ORR) and ICI clinical response prediction for individual patients, TIGS consistently showed improved performance compared to TMB and other known prediction biomarkers for ICI response. This study suggests that TIGS is an effective tumor-inherent biomarker for ICI-response prediction.
Genome alteration signatures reflect recurring patterns caused by distinct endogenous or exogenous mutational events during the evolution of cancer. Signatures of single base substitution (SBS) have ...been extensively studied in different types of cancer. Copy number alterations are important drivers for the progression of multiple cancer. However, practical tools for studying the signatures of copy number alterations are still lacking. Here, a user-friendly open source bioinformatics tool "sigminer" has been constructed for copy number signature extraction, analysis and visualization. This tool has been applied in prostate cancer (PC), which is particularly driven by complex genome alterations. Five copy number signatures are identified from human PC genome with this tool. The underlying mutational processes for each copy number signature have been illustrated. Sample clustering based on copy number signature exposure reveals considerable heterogeneity of PC, and copy number signatures show improved PC clinical outcome association when compared with SBS signatures. This copy number signature analysis in PC provides distinct insight into the etiology of PC, and potential biomarkers for PC stratification and prognosis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Lymph nodes metastases are common in patients with lung cancer. Additionally, those patients are often at a higher risk for death from lung tumor than those with tumor-free lymph nodes. Somatic DNA ...alterations are key drivers of cancer, and copy number alterations (CNAs) are major types of DNA alteration that promote lung cancer progression. Here, we performed genome-wide DNA copy number analysis, and identified a novel lung-cancer-metastasis-related gene, EFNA4. The EFNA4 genome locus was significantly amplified, and EFNA4 mRNA expression was significantly up-regulated in lung cancer compared with normal lung tissue, and also in lung cancer with lymph node metastases compared with lung cancer without metastasis. EFNA4 encodes Ephrin A4, which is the ligand for Eph receptors. The function of EFNA4 in human lung cancer remains largely unknown. Through cell line experiments we showed that EFNA4 overexpression contributes to lung tumor cells growth, migration and adhesion. Conversely, EFNA4 knockdown or knockout led to the growth suppression of cells and tumor xenografts in mice. Lung cancer patients with EFNA4 overexpression have poor prognosis. Together, by elucidating a new layer of the role of EFNA4 in tumor proliferation and migration, our study demonstrates a better understanding of the function of the significantly amplified and overexpressed gene EFNA4 in lung tumor metastasis, and suggests EFNA4 as a potential target in metastatic lung cancer therapy.
How cells adapt to oncogenic transformation-associated cellular stress and become fully transformed is still unknown. Here we identified a novel GGCT-regulated glutathione (GSH)-reactive oxygen ...species (ROS) metabolic pathway in oncogenic stress alleviation. We identified GGCT as a target of oncogenic Ras and that it is required for oncogenic Ras-induced primary mouse cell proliferation and transformation and in vivo lung cancer formation in the LSL-Kras G12D mouse model. However, GGCT deficiency is compatible with normal mouse development, suggesting that GGCT can be a cancer-specific therapeutic target. Genetically amplified GGCT locus further supports the oncogenic driving function of GGCT. In summary, our study not only identifies an oncogenic function of GGCT but also identifies a novel regulator of GSH metabolism, with implications for further understanding of oncogenic stress and cancer treatment.
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•GGCT is a target of Ras and is required for Ras-induced cancer formation•GGCT deletion is compatible with normal mouse development and tissue function•GGCT genomic locus is amplified in multiple human cancer types•GGCT could alleviate oncogenic stress by regulating GSH-ROS metabolism
Biological Sciences; Cell Biology; Cancer
Noncoding DNA sequences occupy more than 98% of the human genome; however, few cancer noncoding drivers have been identified compared with cancer coding drivers, probably because cancer noncoding ...drivers have a distinct mutation pattern due to the distinct function of noncoding DNA. Here we performed pan-cancer whole genome mutation analysis to screen for functional noncoding mutations that influence protein factor binding. Recurrent mutations were identified in the promoter of CDC20 gene. These CDC20 promoter hotspot mutations disrupt the binding of ELK4 transcription repressor, lead to the up-regulation of CDC20 transcription. Physiologically ELK4 binds to the unmutated hotspot sites and is involved in DNA damage-induced CDC20 transcriptional repression. Overall, our study not only identifies a detailed mechanism for CDC20 gene deregulation in human cancers but also finds functional noncoding genetic alterations, with implications for the further development of function-based noncoding driver discovery pipelines.
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•Pan-cancer noncoding analysis for mutations that influence protein factor binding•Recurrent mutations were identified in the promoter of CDC20 gene•Promoter hotspot mutations disrupt ELK4 binding, up-regulate CDC20 transcription•Promoter hotspot mutation site is involved in DNA damage-induced CDC20 repression
Genetics; Genomics; Cancer Systems Biology; Cancer
Immunotherapy, represented by immune checkpoint inhibitors (ICI), is transforming the treatment of cancer. However, only a fraction of patients show response to ICI, and there is an unmet need for ...biomarkers that will identify patients more likely to respond to ICI. Here we report that the ICI response prediction biomarker tumor mutational burden (TMB) shows significant sex differences. TMB's predictive power is significantly better for female than for male lung cancer patients. Receiver operating characteristic curve analysis was performed and the area under the curve (AUC) was reported to evaluate the predictive power of TMB in lung cancer ICI response. Hazard ratios (HR) of TMB‐high vs. TMB‐low patients were compared between male and female patients. Both AUC and HR differences between female and male are significant in all available independent lung cancer datasets. However, the AUC of programmed death ligand 1 (PD‐L1) expression does not show a difference between female and male, suggesting TMB, but not PD‐L1 expression has a better predictive power for female than for male lung cancer patients. Our study suggests significant sex differences in the performance of TMB in ICI response prediction. Future development of ICI biomarker should consider sex differences and special efforts should be paid to improve the performance of ICI predictive biomarkers for male lung cancer patients.
What's new?
Only a fraction of cancer patients show response to immune checkpoint inhibitors (ICI), and there remains an unmet need for biomarkers to select patients most likely to benefit. Inherent sex differences in immune response could potentially influence the performance of predictive biomarkers. Here, the authors report that the emerging biomarker tumor mutational burden (TMB) shows significant sex differences, with TMB's predictive power being significantly better for female than for male lung cancer patients. Future development of predictive biomarkers for ICI response should consider sex differences, and the performance of biomarkers for male lung cancer patients should also be improved.
Summary
The expression of GGCT (γ‐glutamyl cyclotransferase) is upregulated in various human cancers. γ‐glutamyl cyclotransferase enzyme activity was originally purified from human red blood cells ...(RBCs), but the physiological function of GGCT in RBCs is still not clear. Here we reported that Ggct deletion in mice leads to splenomegaly and progressive anaemia phenotypes, due to elevated oxidative damage and the shortened life span of Ggct−/− RBCs. Ggct−/− RBCs have increased reactive oxygen species (ROS), and are more sensitive to H2O2‐induced damage compared to control RBCs. Glutathione (GSH) and GSH synthesis precursor l‐cysteine are decreased in Ggct−/− RBCs. Our study suggests a critical function of Ggct in RBC redox balance and life span maintenance through regulating GSH metabolism.
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