Novel genome-wide significant germline genetic variants associated with venous thrombo-embolism (VTE) and arterial embolism (ATE) risk in patients with ALK and ROS1 fusion non-small cell lung cancer (NSCLC).
Authors: Khan Sam , Jimenez Beatriz , Hueniken Katrina , Hou Tianzhichao , Patel Devalben , Stockley Tracy , Tsao Ming-Sound , Zer Alona , Moskovitz Mor , Rosenberg Yehuda , Bradbury Penelope Ann , Eng Lawson , Leighl Natasha B. , Sacher Adrian G. , Liu Geoffrey , Shepherd Frances A. 
Published: June 2024

12092 Background: In a recent meta-analysis, non small cell lung cancers (NSCLC) with ALK or ROS1 fusions had higher rates of VTE compared to KRAS or EGFR mutant NSCLC, and were associated with increased ATE risk, particularly around diagnosis. The underlying mechanisms of how these somatic fusions affect thrombosis remain unclear. We examined clinico-demographic and germline genetic factors associated with VTE and ATE in NSCLC patients with ALK/ROS1 fusions in this first comprehensive genome wide association analysis (GWAS). Methods: In this prospective cohort, germline DNA from whole blood was obtained from 150 patients with ALK fusions and 32 with ROS1 fusions at Princess Margaret Cancer Centre (recruited 2014- 2023). Clinico-demographic, treatment and outcome data were collected from electronic medical charts. Overall survival (OS) by VTE or ATE status was assessed via Cox regression, treating ATE and VTE as time-varying covariates. Genotyping utilized the Infinium Global Screening Array (v3.0 Illumina); quality-control removed 3 patients from final analysis. Using linear regression, outcomes were weighted; no VTE/ATE events (0), one VTE/ATE event (1), or multiple ATE/VTEs (>2). Global significance was set at p < 5 x10-8 and adjusted for age, sex, body mass index (BMI), and ethnic/population stratification (top 3 principal components). Results: There were 97 females (54%) and 82 males (46%), mean age was 57.4 years, 70% had stage 4 disease, 96% adenocarcinoma; 35% experienced VTE/ATE at any time; 13% had 2+ VTE/ATE events. For those with VTE, 32 scored 1, 22 scored 2 and 6 scored 3 on Khorana score. Higher BMI was a significant risk factor for VTE/ATE (adjusted odds ratio 1.59 per 5-unit increase, p=0.01). Shorter OS was observed in patients with VTE (Hazard ratio (HR)=3.15, p<0.001) and ATE (HR=2.51, p=0.036), compared to those without. Two novel GWAS gene peaks on the Manhattan plot (previously not reported to be associated with VTE/ATE) had globally significant associations with risk of VTE/ATE: at Chromosome 6q15 (intergenic region between RNGTT and LOC101928936; 5/10 top variants with top risk-allele p=3.594E-09) and at 15p22 ( TLN2 gene; 2/10 top variants p=1.095E-08). TLN2 is a cytoskeletal protein involved in the assembly of actin filaments and linkages with extracellular matrices. Additional identified variants potentially associated with VTE/ATE in ALK/ROS1 fusion patients were found in: CTBP2, NALCN, WDR7, PAX7, ZNF385D, SORBS2, and CSMD1. Conclusions: Two novel globally significant variants, associated with VTE/ATE, are unique to patients with ALK/ROS1 fusion NSCLC. If validated, these biomarkers may help identify ALK/ROS1 patients who are at highest risk of VTE/ATE who may benefit from prophylactic anticoagulation. Further investigation and clinical evaluation are warranted.