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Cold Spring Harb Mol Case Stud. 2020 Feb 3;6(1). pii: a004713. doi: 10.1101/mcs.a004713. Print 2020 Feb.

Fluorouracil sensitivity in a head and neck squamous cell carcinoma with a somatic DPYD structural variant.

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Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 4S6, Canada.
Department of Medical Oncology, BC Cancer, Vancouver, British Columbia V5Z 4E6, Canada.
Pancreas Centre BC, Vancouver, British Columbia V5Z 1L8, Canada.
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada.
Department of Molecular Biology and Biochemistry, Simon Fraser University, Vancouver, British Columbia V5A 1S6, Canada.
Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6H 3N1, Canada.


Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers worldwide and represents a heterogeneous group of tumors, the majority of which are treated with a combination of surgery, radiation, and chemotherapy. Fluoropyrimidine (5-FU) and its oral prodrug, capecitabine, are commonly prescribed treatments for several solid tumor types including HNSCC. 5-FU-associated toxicity is observed in ∼30% of treated patients and is largely caused by germline polymorphisms in DPYD, which encodes dihydropyrimidine dehydrogenase, 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 tumor 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 wk, with subsequent relapse due to unknown resistance mechanisms. This suggests that somatic alterations present in this tumor may serve as markers for tumor sensitivity to 5-FU, aiding in the selection of personalized treatment strategies.


squamous cell carcinoma of the skin

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