Coagulation-related genes and tumor location linked to lung cancer survival

“Thrombophilia genes contribute to tumorigenesis and thrombotic events in lung cancer, yet current treatments do not incorporate gene-specific strategies for F2, F5, PROS1, and SERPINC1.”

BUFFALO, NY - November 4, 2026 – A new research paper was published in Volume 17 of Oncotarget on November 2, 2026, titled “Survival factors in lung cancer patients with mutations in the PROS1, SERPINC1, F2, and F5 genes.”

The study identified associations between genes involved in blood coagulation and survival outcomes in patients with lung cancer. Analyzing genetic and clinical data from 1,419 patients, the researchers found that the prognostic significance of four coagulation-related genes varied according to mutation status, tumor location and other clinical characteristics. The findings suggest that these genes may provide additional information for understanding lung cancer prognosis, although their clinical usefulness remains to be established.

The research was led by first and corresponding author Ryan Brownlee, affiliated with the Medical College of Georgia at Augusta University.

Lung cancer remains a leading cause of cancer-related death worldwide. Although advances in targeted therapies, immunotherapy and molecular diagnostics have improved outcomes for some patients, survival varies considerably depending on disease stage, tumor characteristics and treatment response. Identifying additional biological factors associated with prognosis could help researchers better understand these differences.

One area of growing interest is the relationship between cancer and blood coagulation. Patients with malignancies are at increased risk of abnormal blood clots, known as cancer-associated thrombosis. Beyond causing potentially serious complications, coagulation-related proteins can influence inflammation, tumor growth and interactions between malignant cells and their surrounding tissues.

The researchers focused on four genes associated with thrombophilia, an increased tendency to develop blood clots: PROS1, SERPINC1, F2 and F5. These genes encode proteins involved in regulating the coagulation cascade, and alterations in their function have been linked to thrombotic disorders.

The F2 gene encodes prothrombin, the precursor of thrombin, an enzyme essential for blood clot formation. Thrombin also participates in signaling pathways associated with inflammation, cellular proliferation and tumor progression, including pathways involving EGFR, AKT and mTOR. The F5 gene encodes coagulation factor V, which supports thrombin generation. Certain inherited variants, including Factor V Leiden, increase susceptibility to venous thromboembolism.

In contrast, PROS1 and SERPINC1 encode proteins that help limit excessive coagulation. PROS1 produces protein S, which supports the anticoagulant activity of activated protein C, while SERPINC1 encodes antithrombin, an important inhibitor of thrombin and other clotting enzymes. Both proteins have also been implicated in biological signaling that may influence cancer-cell survival and the tumor microenvironment.

To investigate their prognostic significance, the researchers analyzed data from The Cancer Genome Atlas (TCGA), using the lung adenocarcinoma (TCGA-LUAD) and lung squamous cell carcinoma (TCGA-LUSC) datasets. These represent two major types of non-small cell lung cancer.

The analysis included 569 patients with mutations involving the studied genes and 850 patients in a comparison group without these mutations. The researchers examined RNA sequencing data to measure gene expression and evaluated its relationship with overall survival.

Using Cox proportional hazards models, the team assessed survival associations while accounting for age at diagnosis, race, cancer stage, primary tumor location, laterality and treatment type. This approach allowed them to examine whether gene expression and clinical characteristics were associated with survival after statistical adjustment.

One of the main findings was that gene expression showed different relationships with survival depending on mutation status. In the comparison group, higher PROS1 expression was associated with improved overall survival (hazard ratio [HR] 0.94; p = 0.025), as was higher SERPINC1 expression (HR 0.81; p = 0.002).

However, higher expression of F2 and F5 showed the opposite pattern. In adjusted analyses, F2 expression was associated with worse overall survival (HR 1.16; p < 0.001), while higher F5 expression was also linked to increased mortality hazard (HR 1.04; p = 0.032).

Importantly, these associations were observed in patients without mutations in the respective genes. Among patients carrying the studied mutations, none of the four gene-expression measurements remained statistically significant after adjustment for clinical variables. Although F2 and F5 showed trends toward worse survival, their adjusted associations did not reach conventional statistical significance.

These findings suggest that mutation status may influence the relationship between coagulation-related gene expression and prognosis. However, the study does not establish that particular mutations directly cause changes in survival or that these genes can already serve as reliable clinical biomarkers.

Beyond gene expression, cancer stage emerged as one of the strongest predictors of survival. Patients with more advanced disease generally had worse outcomes than those diagnosed at stage I, reinforcing the importance of tumor progression in determining prognosis.

Tumor location was another important factor. Across several adjusted analyses, cancers involving the upper or middle lobes of the lung, as well as cases categorized by pleural location, were associated with poorer survival compared with reference tumor sites.

Among patients with F5 mutations, middle-lobe tumor location was associated with worse survival (HR 1.49; p = 0.028). Similar associations were observed for pleural sites (HR 1.33; p = 0.006) and upper-lobe tumors (HR 1.20; p = 0.025). These results indicate that anatomical location may provide additional prognostic information in patients carrying F5 alterations.

The researchers also examined differences between tumors located in the right and left lungs. Right-sided tumors were associated with worse survival in several adjusted models, although this relationship was not statistically significant in every subgroup.

The authors propose that differences in pulmonary oxygenation, blood flow and local tissue conditions could help explain some of these findings. Altered coagulation activity may interact with these factors, potentially influencing oxidative stress and tumor behavior. However, these mechanisms were not directly investigated and remain hypothetical.

An additional finding involved age and race among patients with F5 mutations. Increasing age at diagnosis was associated with a higher mortality hazard (HR 1.01; p = 0.015). Black or African American patients also showed worse survival than White patients within this subgroup (HR 1.33; p = 0.024).

These results require cautious interpretation. The analysis could not determine whether the observed differences reflected genetic factors, clinical characteristics, treatment access, socioeconomic influences or other unmeasured variables. Further investigation in larger and more diverse populations will be necessary.

“Pathologic stage was consistently and strongly associated with worse survival in every gene.”

The findings highlight the complex relationship between coagulation biology and cancer progression. Blood clotting proteins can influence inflammatory signaling, immune-cell activity, blood vessel formation and the tumor microenvironment. These processes may contribute to differences in cancer outcomes, although the present study did not establish the biological mechanisms underlying the observed associations.

The researchers suggest that integrating coagulation-related genetic information with established prognostic factors, including disease stage and tumor location, could eventually help identify patients with different survival risks. However, the findings do not demonstrate that anticoagulant treatment or therapies targeting these genes would improve lung cancer survival.

The study has several limitations. Its retrospective design relied on publicly available datasets, limiting control over treatment selection, timing and other clinical variables. Gene-expression measurements represented individual time points and may not reflect changes during cancer progression.

Additionally, the analysis did not distinguish between gain-of-function and loss-of-function mutations, which may produce different biological effects. The dataset also lacked detailed information about thromboembolic events and specific metastatic sites, preventing direct assessment of whether clotting complications contributed to the survival differences.

Future research will need to investigate individual mutation types, validate the findings in independent patient populations and examine how coagulation-related signaling influences tumor biology. Studies incorporating longitudinal gene-expression measurements, thrombosis outcomes and detailed treatment information may help clarify the clinical relevance of these associations.

Overall, the study identifies relationships between coagulation-related gene expression, tumor characteristics and survival in lung cancer. While advanced disease stage remained a dominant prognostic factor, findings involving PROS1, SERPINC1, F2 and F5 suggest that coagulation biology may provide additional insights into cancer outcomes. The results offer a foundation for investigating these genes as potential prognostic biomarkers and exploring their relevance to future personalized lung cancer care.

DOI: https://doi.org/10.18632/oncotarget.28914

Correspondence to: Ryan Brownlee - Rbrownlee@augusta.edu

Abstract video: https://www.youtube.com/watch?v=3leoNrmo3Ag

Keywords: cancer, F5, PROS1, SERPINC1, lung cancer, thrombophilia

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