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TP53 Status, Patient Sex, and the Immune Response as Determinants of Lung Cancer Patient Survival.

ABSTRACT: Lung cancer poses the greatest cancer-related death risk and males have poorer outcomes than females, for unknown reasons. Patient sex is not a biological variable considered in lung cancer standard of care. Correlating patient genetics with outcomes is predicted to open avenues for improved management. Using a bioinformatics approach across non-small cell lung cancer (NSCLC) subtypes, we identified where patient sex, mutation of the major tumor suppressor gene, Tumour protein P53 (TP53), and immune signatures stratified outcomes in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), among datasets of The Cancer Genome Atlas (TCGA). We exposed sex and TP53 gene mutations as prognostic for LUAD survival. Longest survival in LUAD occurred among females with wild-type (wt) TP53 genes, high levels of immune infiltration and enrichment for pathway signatures of Interferon Gamma (INF-?), Tumour Necrosis Factor (TNF) and macrophages-monocytes. In contrast, poor survival in men with LUAD and wt TP53 genes corresponded with enrichment of Transforming Growth Factor Beta 1 (TGFB1, hereafter TGF-?) and wound healing signatures. In LUAD with wt TP53 genes, elevated gene expression of immune checkpoint CD274 (hereafter: PD-L1) and also protein 53 (p53) negative-regulators of the Mouse Double Minute (MDM)-family predict novel avenues for combined immunotherapies. LUSC is dominated by male smokers with TP53 gene mutations, while a minor population of TCGA LC patients with wt TP53 genes unexpectedly had the poorest survival, suggestive of a separate etiology. We conclude that advanced approaches to LUAD and LUSC therapy lie in the consideration of patient sex, TP53 gene mutation status and immune signatures.

SUBMITTER: Freudenstein D

PROVIDER: S-EPMC7352604 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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TP53 Status, Patient Sex, and the Immune Response as Determinants of Lung Cancer Patient Survival.

Freudenstein Donald D Litchfield Cassandra C Caramia Franco F Wright Gavin G Solomon Benjamin J BJ Ball David D Keam Simon P SP Neeson Paul P Haupt Ygal Y Haupt Sue S

Cancers 20200611 6

Lung cancer poses the greatest cancer-related death risk and males have poorer outcomes than females, for unknown reasons. Patient sex is not a biological variable considered in lung cancer standard of care. Correlating patient genetics with outcomes is predicted to open avenues for improved management. Using a bioinformatics approach across non-small cell lung cancer (NSCLC) subtypes, we identified where patient sex, mutation of the major tumor suppressor gene, Tumour protein P53 (TP53), and im ...[more]

PMID: 32545367

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Project description:ObjectiveLow dose computed tomography (LDCT) became the standard method for lung cancer (LC) screening in 2013. However, it is unclear whether there are differences in survival rates based on sex and whether the differences depend on screening status. We aimed to evaluate the LC survival rates between females and males based on screening.Material and methodsThis retrospective cohort study examined data from the Boston LC Study (BLCS) between 2013 and 2021. LC screening depends on patients' demographics (age and smoking history) to determine whether a person is a high-risk individual and, therefore, undergo LDCT. Descriptive statistics were calculated for race, age, histology, smoking history, stage, and treatment. These variables' distributions were compared between sex and screening status using t-test and chi-square, respectively. Cox proportional hazards model and Kaplan-Meier curves were used to compare survival between sex and screening. Propensity score matching was applied to account for selection bias in screening when evaluating the association between screening and stage.ResultsA total of 1,216 LC patients were identified with a screening incidence of 9.4 %, among whom 56 % were female. Unscreened males had 1.59 times higher risk of mortality than unscreened females (P=.0002) and had a worse 5-year survival (male 50 %; 95 %CI, 0.38,0.6 vs female 70 %; 95 %CI,0.62,0.76). In contrast, there were no significant differences in survival between sexes among screened. In a balanced cohort of screened and unscreened, the odds of being diagnosed at late stages for females and smokers were 1.33 and 2.51 times that of males and nonsmokers; however, there were no statistical significance.ConclusionUnscreened females had a lower risk of mortality and better survival than unscreened males, while among the screened population, there was no difference in the overall survival. These observations demonstrate the influence of sex on survival prognosis in LC when screening is not performed.

Project description:TP53 mutation is a critical driver mutation that affects the carcinogenesis and prognosis of patients with pancreatic cancer (PC). Currently, there is no driver mutation-derived signature based on TP53 mutational status for prognosis and predicting therapeutic response in PC. In the present study, we characterized the TP53 mutational phenotypes in multiple patient cohorts and developed a prognostic TP53-associated signature based on differentially expressed genes between PC samples with mutated TP53 and wild-type TP53. Comprehensive investigations were carried out in prognostic stratification, genetic variation, immune cell infiltration, and efficacy prediction of chemotherapy and targeted therapy. We found that TP53 mutation commonly occurred as a survival-related driver mutation in PC. In total, 1,154 differentially expressed genes were found between two distinct TP53 mutational phenotypes. A five-gene TP53-associated signature was constructed in The Cancer Genome Atlas (TCGA) cohort by least absolute shrinkage and selection operator (LASSO)-Cox analysis and proven to be a robust prognostic predictor, which performed well in three independent Gene Expression Omnibus (GEO) validating cohorts. Remarkably, patients in the low-risk group were characterized with decreased tumor mutation burden and activity of immunity, with favorable prognosis. Higher fractions of macrophages M0 and impaired CD8 + T cells were observed in patients in the high-risk group, suggesting immunosuppression with poor survival. Patients in the high-risk group also demonstrated enhanced response to specific chemotherapeutic agents, including gemcitabine and paclitaxel. Several targeted inhibitors, like histamine receptor inhibitor, were screened out as promising drugs for PC treatment. Collectively, the TP53-associated signature is a novel prognostic biomarker and predictive indicator of PC. The signature could contribute to optimizing prognostic stratification and guide effective PC treatments.

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TP53 Status, Patient Sex, and the Immune Response as Determinants of Lung Cancer Patient Survival.

Publications

TP53 Status, Patient Sex, and the Immune Response as Determinants of Lung Cancer Patient Survival.

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