Background: Fluoropyrimidine (FP) based adjuvant chemotherapy (5-Fluorouracil and Capecitabine) increases survival of patients with colorectal and breast cancers. However, 1-5 % of patients experience cardiovascular toxicity, which is not explained by variants in the gene encoding dihydropyrimidine dehydrogenase. Methods: We sought genetic determinants of FP-induced cardiovascular toxicity by performing a genome wide association study of NCI-CTCAE graded cardiovascular toxicity using samples from the QUASAR 2 trial (n=759 patients with colorectal cancer (CRC)). Validation studies (n= 5438 patients with CRC and 1478 patients with breast cancer) were performed in the SCOT, COIN and TACT2 trials. The most commonly reported symptoms were chest pain, angina and arrhythmias with 6 patients experiencing myocardial infarctions. Results: rs4904753, mapping to an intron of D-glutamate cyclase (DGLUCY) was genome wide significant in QUASAR 2 (P =4.38 x 10^-16) and validated in SCOT, COIN and TACT2 (P<0.0002 in all studies. rs4904753 was associated with levels of expression of DGLUCY in multiple tissues including the atrial appendage. Under a recessive model, 45.3% (61/137) of patients with cardiac toxicity as compared to 10.2% (691/6786) of controls carried both minor alleles (meta-analysis: OR=7.72, 95% CI 5.31-11.22, P=1.03 x 10^-26). Conclusions: The sensitivity, specificity, positive predictive value and negative predictive values of testing for two copies of the toxicity associated allele of rs4904753 were 48%, 90%, 8% and 99% respectively. Clinical implementation of testing for this variant has the potential to identify almost half of those at risk of FP-induced cardiovascular toxicity with high specificity, thereby enabling changes to their clinical management.

XELOX: Oxaliplatin and Capecitabine; OxMDG/FOLFOX: leucovorin, 5-FU, oxaliplatin; CMF: cyclophosphamide, methotrexate, 5-FU.