Clinical and molecular impacts of tumor mutational burden in histological and cytological specimens from cancer patients.

Background: The tumor mutational burden (TMB) is a promising biomarker for immune checkpoint inhibitor (ICI). However, its relationships with clinical parameters have not been fully explored. We aimed to assess potential factors including age, microsatellite instability (MSI) state, tumor types, and gene mutations that might influence TMB value through analyzing 1,504 tissue samples and 496 blood samples from cancer patients. Methods: The TMB value of individual samples was calculated by whole-exome sequencing (WES) analysis and major cancer-related gene mutations were evaluated using panel sequencing. MSI was detected with MSI analysis system. Results: The results showed that for blood samples, compared to age 1 (age ≤56 years old) or age 2 (56< age <68 years old) groups, the TMB value in the age 3 group (age ≥68 years old) was significantly higher. The MSI ratio (%) had no linear correlation with TMB, and a significant difference of TMB between Kirsten rat sarcoma viral oncogene homologue (KRAS) other alterations and p.G12 alteration was identified. For tissue samples, compared to age 1 (age ≤53 years old), TMB was higher in the age 2 (53< age <65 years old) group and lower in the age 3 (age ≥65 years old) group. MSI ratio (%) had no linear correlation with TMB. Significant differences in TMB were discovered between adenosquamous carcinoma (ASC), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), non-small cell lung cancer (NSCLC), and small cell lung cancer (SCLC) samples. TMB among KRAS p.G12A, p.G12C, p.G12D, p.G12R, p.G12S, p.G12V, and other KRAS alterations were observed in tissue samples. Conclusions: In conclusion, analysis of age, tumor types, and KRAS mutations may provide a relative effectivity for estimating TMB.

High expression of NFAT2 contributes to carboplatin resistance in lung cancer.

Carboplatin is a platinum-based chemotherapy drug in lung cancer treatment. However, its efficacy is frequently limited by intrinsic and acquired drug resistance. Recently, nucleus factor of activated T cells, cytoplasmic 1 (NFAT2) has been recognized as an oncogene and involved in disease progression and drug resistance in various cancers. In the current study, we found that overexpression of NFAT2 was associated with poor prognosis in lung cancer patients, and is observed in a carboplatin resistant lung cancer cell line, indicative of its role in regulating drug response. We further showed that NFAT2 played a critical role in promoting cell proliferation and overcome carboplatin-induced DNA damage and cell cycle arrest. NFAT2 knockdown or inhibition of its nucleus translation via cyclosporine A largely restored the sensitivity to carboplatin in the resistant line by inducing DNA damage, blocking cell cycle progression and activating apoptotic cell death. We thus suggest that NFAT2 is a putative therapeutic target to overcome carboplatin resistance in lung cancers.

Glutathione S-transferase T1 and M1 polymorphisms are associated with lung cancer risk in a gender-specific manner.

BACKGROUND: Glutathione S-transferase (GST) T1 and M1 are detoxification enzymes which neutralize various carcinogenic compounds. Polymorphisms of the GSTT1 and GSTM1 genes which encode the enzymes could be associated with cancer risk. PATIENTS AND METHODS: We investigated the association of GSTT1 and GSTM1 null polymorphisms with lung cancer risk in a tightly matched, considerably large sample in China. Genotyping was performed utilizing polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis and DNA sequencing, and associations were measured by using logistic regression analysis. RESULTS: We found that the null genotypes of both polymorphisms resulted in an increased lung cancer risk, with an odds ratio (OR) of 1.57 (95% confidence interval (CI) 1.23-2.00) for GSTT1 and OR 1.87 (95% CI 1.46-2.39) for GSTM1 (p < 0.01). Significant associations remained after stratification by histopathology (p < 0.01) and smoking status (p < 0.05). When gender-stratified association was performed, we found that the GSTT1 null genotype resulted in an increased risk among males (adjusted OR 2.95, 95% CI 2.07-4.20; p < 0.01) but not females (p > 0.05), while the GSTM1 null genotype resulted in an increased risk among females (adjusted OR 2.18, 95% CI 1.54-3.10; p < 0.01) but not males (p < 0.05). CONCLUSION: Polymorphisms in GSTT1 and GSTM1 are associated with the risk of lung cancer in a gender-specific manner.