Key result
Somatic STK11 mutations linked to ~112% higher cancer-associated VTE risk across solid tumors.
Why the study?
Cancer-associated venous thromboembolism is a leading cause of death in cancer patients, but potential associations of molecular signatures with CAT remain to be assessed.
Does the presence of specific somatic tumor mutations predict the risk of cancer-associated venous thromboembolism in patients with solid tumors?
Cohort (n=11,695)
No
Does the presence of specific somatic tumor mutations predict the risk of cancer-associated venous thromboembolism in patients with solid tumors?
Specific somatic tumor mutations, such as STK11 and KRAS, are associated with an increased risk of venous thromboembolism in patients with solid tumors, suggesting a role for genomic profiling in VTE risk stratification.
Answers are grounded in this paper and cite their sources.
STK11 mutations may refine CAT risk assessment in solid tumors; hypothesis-generating and requires prospective validation before clinical use.
Cancer-associated venous thromboembolism (CAT) is a well-described complication of cancer and a leading cause of death in cancer patients. The purpose of this study was to assess potential associations of molecular signatures with CAT, including tumor-specific mutations and the presence of clonal hematopoiesis. We analyzed deep-coverage targeted DNA-sequencing data of >14,000 solid tumor samples using the MSK-IMPACT™ platform to identify somatic alterations associated with VTE. Endpoint was defined as the first instance of cancer-associated pulmonary embolism and/or proximal/distal lower extremity deep vein thrombosis. Cause-specific Cox proportional hazards regression was used, adjusting for pertinent clinical covariates. Of 11,695 evaluable individuals, 72% had metastatic disease at time of IMPACT. Tumor-specific mutations in KRAS (HR=1.34 [1.09-1.64]; adjusted p =0.08), STK11 (HR=2.12 [1.55-2.89]; adjusted p <0.001), KEAP1 (HR=1.84 [1.21-2.79]; adjusted p =0.07), CTNNB1 (HR=1.73 [1.15-2.60]; adjusted p =0.09), CDKN2B (HR= 1.45 [1.13-1.85], adjusted p=0.07) and MET (HR=1.83 [1.15-2.92]; adjusted p =0.09) were associated with a significantly increased risk of CAT independent of tumor type. Mutations in SETD2 were associated with a decreased risk of CAT (HR=0.35 [0.16-0.79], adjusted p=0.09). The presence of clonal hematopoiesis was not associated with an increased VTE rate. This is the first large-scale analysis to elucidate tumor-specific genomic events associated with CAT. Somatic tumor mutations of STK11, KRAS, CTNNB1, KEAP1, CDKN2B and MET were associated with an increased risk of VTE in solid tumor patients. Further analysis is needed to validate these findings and identify additional molecular signatures unique to individual tumor types. Key Points Tumor mutations in STK11, KRAS, CTNNB1, KEAP1, CDKN2B, MET and SETD2 modulate the risk of cancer-associated thrombosis. The presence of clonal hematopoiesis does not affect the risk of cancer-associated thrombosis.
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Dunbar et al. (2020) conducted a cohort in Solid Tumors (n=11,695). STK11 somatic mutation vs. Unmutated STK11 was evaluated on Time to first instance of cancer-associated pulmonary embolism and/or proximal/distal lower extremity deep vein thrombosis (HR 2.12, 95% CI 1.55-2.89, p=<0.001). Somatic tumor mutations in STK11 increased the risk of cancer-associated venous thromboembolism independent of tumor type in patients with solid tumors.
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