Clinical importance of risk variants in the dihydropyrimidine dehydrogenase gene for the prediction of early-onset fluoropyrimidine toxicity

We investigated the clinical relevance of dihydropyrimidine dehydrogenase gene (DPYD) variants to predict severe early onset fluoropyrimidine (FP) toxicity in particular of a recently discovered haplotype hapB3 and a linked deep intronic splice site mutation c.1129 5923C>G. Selected regions of DPYD were sequenced in prospectively collected germline DNA of 500 patients receiving FP based chemotherapy. Associations of DPYD variants and haplotypes with hematologic gastrointestinal infectious and dermatologic toxicity in therapy cycles 1 2 and resulting FP dose interventions (dose reduction therapy delay or cessation) were analyzed accounting for clinical and demographic covariates. Fifteen additional cases with toxicity related therapy delay or cessation were retrospectively examined for risk variants. The association of c.1129 5923C>G/hapB3 (4.6\ carrier frequency) with severe toxicity was replicated in an independent prospective cohort. Overall c.1129 5923G/hapB3 carriers showed a relative risk of 3.74 (RR 95\ CI=2.30 6.09 p=2 x 10( 5)) for severe toxicity (grades 3 5). Of 31 risk variant carriers (c.1129 5923C>G/hapB3 c.1679T>G c.1905+1G>A or c.2846A>T) 11 (all with c.1129 5923C>G/hapB3) experienced severe toxicity (15\ of 72 cases RR=2.73 95\ CI=1.61 4.63 p=5 x 10( 6)) and 16 carriers (55\) required FP dose interventions. Seven of the 15 (47\) retrospective cases carried a risk variant. The c.1129 5923C>G/hapB3 variant is a major contributor to severe early onset FP toxicity in Caucasian patients. This variant may substantially improve the identification of patients at risk of FP toxicity compared to established DPYD risk variants (c.1905+1G>A c.1679T>G and c.2846A>T). Pre therapeutic DPYD testing may prevent 20 30\ of life threatening or lethal episodes of FP toxicity in Caucasian patients. What's New? Fluorouracil (5FU) is effective against a variety of cancers and is one of the most commonly prescribed chemotherapy drugs. But 5FU causes severe toxicity in some patients with their susceptibility determined largely by variations in the rate limiting enzyme dihydropyrimidine dehydrogenase (DPD) which catabolizes 5FU. This study shows that a relatively common haplotype hapB3 which is linked to an intronic splice site mutation (c.1129 5923C>G) in the DPD encoding gene DPYD is a major contributor to early onset severe fluoropyrimidine toxicity in Caucasian carriers. Inclusion of the c.1129 5923C>G variant in DPYD genetic testing could help prevent severe toxicity associated with fluoropyrimidine based therapies.