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. 2021 Apr 15;137(15):2103-2113.
doi: 10.1182/blood.2020007488.

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

Andrew Dunbar  1 , Kelly L Bolton  1 , Sean M Devlin  2 , Francisco Sanchez-Vega  2 , Jianjiong Gao  2 , Jodi V Mones  1 , Jonathan Wills  3 , Daniel Kelly  3 , Mirko Farina  4 , Keith B Cordner  4 , Young Park  4 , Sirish Kishore  5 , Krishna Juluru  5 , Neil M Iyengar  6 , Ross L Levine  1 , Ahmet Zehir  7 , Wungki Park  6 , Alok A Khorana  8 , Gerald A Soff  1 , Simon Mantha  1
Affiliations

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

Andrew Dunbar et al. Blood. .

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.

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Conflict of interest statement

Conflict-of-interest disclosure: S.K. serves as a consultant to Inari Medical. R.L.L. is on the supervisory board of Qiagen; is a scientific advisor to Loxo, Imago, C4 Therapeutics, and Isoplexis, each of which includes equity interest; receives research support from and consulted for Celgene and Roche; received research support from Prelude Therapeutics; has consulted for Lilly, Janssen, Incyte, Novartis, and Gilead; and has received honoraria from Lilly and Amgen for invited lectures. W.P. receives funding from Merck, Astellas, and Gossamer Bio; and is a consultant to Ipsen. A.A.K. received fees from Janssen, Bayer, Sanofi, Parexel, Halozyme, Pfizer, Seattle Genetics, Pharmacyclics, PharmaCyte, AngioDynamics, Leo Pharma, TriSalus, and Medscape; and grant support from Merck, Array, Bristol Myers Squibb, and Leap. S.M. is principal owner of Daboia Consulting LLC; and received speaking fees from MJH Associates and Physicians’ Education Resource. J.V.M. received fees from Sobi/Dova Pharmaceuticals. N.M.I. received consulting fees from Novartis and Seattle Genetics, along with grant support from Novartis. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Flow of CAT event assessment. *Patients who were followed up actively at the medical center for the years 2014 to 2016. VQ, ventilation–perfusion.
Figure 2.
Figure 2.
One-year incidence of CAT according to tumor type. Gyn, gynecologic.
Figure 3.
Figure 3.
One-year incidence of VTE according to cancer type, stratified by tumor mutational burden. Gyn, gynecologic.
Figure 4.
Figure 4.
One-year cumulative incidence of CAT according to mutation type.
Figure 5.
Figure 5.
HR of VTE for mutated vs unmutated genes, stratified according to tumor type. Results are shown for groups with at least 25 cases of mutations.
Figure 6.
Figure 6.
One-year cumulative incidence of CAT according to IDH1 mutation status for gliomas and hepatobiliary tumors. Gyn, gynecologic.
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Comment in

  • Cancer genes and blood clots.
    Rak J. Rak J. Blood. 2021 Apr 15;137(15):1996-1997. doi: 10.1182/blood.2020009967. Blood. 2021. PMID: 33856444 No abstract available.

References

    1. Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost. 2007;5(3):632-634. - PubMed
    1. Horsted F, West J, Grainge MJ. Risk of venous thromboembolism in patients with cancer: a systematic review and meta-analysis. PLoS Med. 2012;9(7):e1001275. - PMC - PubMed
    1. Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood. 2008;111(10):4902-4907. - PMC - PubMed
    1. Ay C, Dunkler D, Marosi C, et al. Prediction of venous thromboembolism in cancer patients. Blood. 2010;116(24):5377-5382. - PubMed
    1. Cronin-Fenton DP, Søndergaard F, Pedersen LA, et al. Hospitalisation for venous thromboembolism in cancer patients and the general population: a population-based cohort study in Denmark, 1997-2006. Br J Cancer. 2010;103(7):947-953. - PMC - PubMed

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