Long Survival and Severe Toxicity Under 5-Fluorouracil-Based Therapy in a Patient With Colorectal Cancer Who Harbors a Germline Codon-Stop Mutation in TYMS.

We report the first clinical description of a patient with cancer with a heterozygous germline codon-stop mutation in the TYMS gene. The mutation g.657795_657826del, c.53_84del (NM_001071.2), p.Gln18Argfs*42 causes loss of function of one of the TYMS alleles, resulting in a truncated protein. This gene codifies for the target enzyme of 5-fluorouracil (5-FU), the basic treatment in colorectal cancer. The patient, diagnosed with metastatic colorectal cancer, had diarrhea and neutropenia grade 4 and mucositis and neurological toxicity grade 3 under 5-FU-based therapy and exceeded by more than 50% the average survival after metastasectomy. On the basis of the patient's characteristics and the key role of TYMS in 5-FU activity, we hypothesize that this mutation may contribute to the drug response and toxicities suffered by the patient.