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

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

Authors:	Dunbar, A.; Bolton, K. L.; Devlin, S. M.; Sanchez-Vega, F.; Gao, J.; Mones, J. V.; Wills, J.; Kelly, D.; Farina, M.; Cordner, K. B.; Park, Y.; Kishore, S.; Juluru, K.; Iyengar, N. M.; Levine, R. L.; Zehir, A.; Park, W.; Khorana, A. A.; Soff, G. A.; Mantha, S.
Article Title:	Genomic profiling identifies somatic mutations predicting thromboembolic risk in patients with solid tumors
Abstract:	Venous thromboembolism (VTE) associated with cancer (CAT) is a well-described complication of cancer and a leading cause of death in patients with cancer. 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 Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets platform to identify somatic alterations associated with VTE. End point 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 analysis. Tumor-specific mutations in KRAS (hazard ratio [HR], 1.34; 95% confidence interval (CI), 1.09-1.64; adjusted P = .08), STK11 (HR, 2.12; 95% CI, 1.55-2.89; adjusted P<.001), KEAP1 (HR, 1.84; 95% CI, 1.21-2.79; adjusted P=.07), CTNNB1 (HR, 1.73; 95% CI, 1.15-2.60; adjusted P=.09), CDKN2B (HR, 1.45; 95% CI, 1.13-1.85; adjusted P=.07), and MET (HR, 1.83; 95% CI, 1.15-2.92; adjusted P=.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; 95% CI, 0.16-0.79; adjusted P=.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 patients with solid tumors. Further analysis is needed to validate these findings and identify additional molecular signatures unique to individual tumor types.
Keywords:	chemotherapy; adenocarcinoma; thrombosis; population; grade; venous thromboembolism; cancer-patients; idh1; metaanalysis; pulmonary-embolism
Journal Title:	Blood
Volume:	137
Issue:	15
ISSN:	0006-4971
Publisher:	American Society of Hematology
Date Published:	2021-04-15
Start Page:	2103
End Page:	2113
Language:	English
ACCESSION:	WOS:000646132800018
DOI:	10.1182/blood.2020007488
PROVIDER:	wos
PMCID:	PMC8057259
PUBMED:	33270827
Notes:	Article -- Source: Wos