Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers worldwide and represents a heterogeneous group of tumours, the majority of which are treated with a combination of surgery, radiation and chemotherapy. Fluoropyrimidine (5-FU) and its oral pro-drug, capecitabine, are commonly prescribed treatments for several solid tumour types including HNSCC. 5-FU-associated toxicity is observed in approximately 30% of treated patients and is largely caused by germline polymorphisms in DPYD which encodes dihydropyrimidine dehydrogenase (DPD), a key enzyme of 5-FU catabolism and deactivation. Although the association of germline DPYD alterations with toxicity is well-described, the potential contribution of somatic DPYD alterations to 5-FU sensitivity has not been explored. In a patient with metastatic HNSCC, in-depth genomic and transcriptomic integrative analysis on a biopsy from a metastatic neck lesion revealed alterations in genes that are associated with 5-FU uptake and metabolism. These included a novel somatic structural variant resulting in a partial deletion affecting DPYD, a variant of unknown significance affecting SLC29A1 and homozygous deletion of MTAP. There was no evidence of deleterious germline polymorphisms that have been associated with 5-FU toxicity, indicating a potential vulnerability of the tumour to 5-FU therapy. The discovery of the novel DPYD variant led to the initiation of 5-FU treatment that resulted in a rapid response lasting 17 weeks, with subsequent relapse due to unknown resistance mechanisms. This suggests that somatic alterations present in this tumour may serve as markers for tumour sensitivity to 5-FU, aiding in selection of personalized treatment strategies.
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