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

Abstract

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.

Whole-genome and transcriptome analysis enhances precision cancer treatment options

“…38 Treatment with the chemotherapeutic 5-fluorouracil (5-FU) in patient 25317, with a primary of unknown origin, was based on low DPYD RNA expression [11th percentile compared to The Cancer Genome Atlas (TCGA) tumours overall, RPKM 0.7], and high TYMS:DPYD expression ratio (>35) previously associated with sensitivity to the 5-FU family of drugs. 39,40 Use of WGTA to select between standard therapies therefore included diverse treatments including both approved targeted agents and chemotherapies.…”

The Synergistic Antitumor Effect of 5-Fluorouracil Combined with Allicin against Lung and Colorectal Carcinoma Cells

“…Different synthesized chemical compounds are used for cancer therapy [4], and 5-fluorouracil (5-FU) is one of the most commonly used first-line anticancer drugs in clinical practice [5,6]. 5-FU is commonly prescribed for solid tumor types [7] and is widely used as an essential chemotherapeutic agent for colorectal cancer [6], gastric cancer [5], and hepatocellular carcinoma [8]. Moreover, 5-FU is most often used in combination with other specific cancer drugs to treat many types of cancer, including breast cancer, head and neck cancers, anal cancer, stomach cancer, colon cancer, and some skin cancers [9].…”

Immune Activation Following Irbesartan Treatment in a Colorectal Cancer Patient: A Case Study

“…The Personalized OncoGenomics (POG) program at BC Cancer utilises whole genome and transcriptome analysis (WGTA) to characterize patient tumours and identify clinically actionable alterations, seeking to use these data to align patients to treatment options [ 7 , 8 ], some of which are off-label [ 9 , 10 , 11 , 12 ]. We previously described a patient with advanced, pre-treated CRC [ 9 ].…”