Genomic profiling identifies somatic mutations predicting thromboembolic risk in patients with solid tumors

Area of Science:

• Oncology
• Genetics
• Hematology

Background:

• Cancer-associated thrombosis (CAT) is a significant cause of mortality in cancer patients.
• Understanding molecular drivers of CAT is crucial for risk stratification and management.

Purpose of the Study:

• To investigate associations between tumor-specific molecular signatures and the risk of developing cancer-associated venous thromboembolism (VTE).
• To evaluate the role of somatic mutations and clonal hematopoiesis in CAT development.

Main Methods:

• Analysis of deep-coverage targeted DNA sequencing data from over 14,000 solid tumor samples.
• Identification of somatic alterations using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets platform.
• Cause-specific Cox proportional hazards regression, adjusting for clinical covariates, to assess VTE risk.

Main Results:

• Tumor-specific mutations in STK11, KRAS, KEAP1, CTNNB1, CDKN2B, and MET were significantly associated with an increased risk of CAT, independent of tumor type.
• Mutations in SETD2 showed a decreased risk of CAT.
• The presence of clonal hematopoiesis was not associated with an increased VTE rate.

Conclusions:

• This large-scale study identifies specific tumor genomic alterations linked to CAT risk.
• Somatic mutations in STK11, KRAS, CTNNB1, KEAP1, CDKN2B, and MET are key molecular signatures associated with increased VTE risk in solid tumors.
• Further research is needed to validate these findings and explore tumor-type specific molecular signatures.