TY - JOUR
T1 - Genomic profiling identifies somatic mutations predicting thromboembolic risk in patients with solid tumors
AU - Dunbar, Andrew
AU - Bolton, Kelly L.
AU - Devlin, Sean M.
AU - Sanchez-Vega, Francisco
AU - Gao, Jianjiong
AU - Mones, Jodi V.
AU - Wills, Jonathan
AU - Kelly, Daniel
AU - Farina, Mirko
AU - Cordner, Keith B.
AU - Park, Young
AU - Kishore, Sirish
AU - Juluru, Krishna
AU - Iyengar, Neil M.
AU - Levine, Ross L.
AU - Zehir, Ahmet
AU - Park, Wungki
AU - Khorana, Alok A.
AU - Soff, Gerald A.
AU - Mantha, Simon
N1 - Funding Information:
Memorial Sloan Kettering research support was provided by the National Institutes of Health (NIH), National Cancer Institute (NCI) Cancer Center Support Grant (P30 CA008748). A.D. receives support from the American Association of Cancer Research (17-40-11-DUNB). A.A.K. acknowledges additional research support from the Sondra and Stephen Hardis Chair in Oncology Research and the NIH, National Heart, Lung, and Blood Institute (U01HL143402). Y.P. receives funding from the NIH, NCI (K12 CA184746 Paul Calabresi Award), the Parker Institute for Cancer Immunotherapy, and the Society for Immunotherapy of Cancer Sparkathon TimIOs project. N.M.I. receives research support from the NIH, NCI (R01CA235711), the Breast Cancer Research Foundation, and the American Cancer Society. J.G. was supported by the Marie-Josée and Henry R. Kravis Center for Molecular Oncology.
Publisher Copyright:
© 2021 American Society of Hematology
PY - 2021/4/15
Y1 - 2021/4/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85100900664&partnerID=8YFLogxK
U2 - 10.1182/blood.2020007488
DO - 10.1182/blood.2020007488
M3 - Article
C2 - 33270827
AN - SCOPUS:85100900664
SN - 0006-4971
VL - 137
SP - 2103
EP - 2113
JO - Blood
JF - Blood
IS - 15
ER -