Patients diagnosed with advanced colon cancer have few treatment options besides surgery and aggressive chemotherapy. All chemotherapies are designed to block cell growth. Since all multiplying cells need to replicate their DNA, blocking DNA synthesis stops cell growth. The 5-Fluorouracil (5FU) drug is a modified nucleotide that blocks DNA replication. 5FU is commonly used in combination with other drugs for patients with breast, colorectal, lung, and other malignancies. Patients with mutations in the DPYD gene are at a high risk of drug-induced toxicity with 5FU, thus genetic testing for the DPYD gene is an important aspect of colon cancer treatment.

5FU-induced toxicity depends on the effective drug dose. Some patients cannot metabolize the drug effectively due to a deficiency in the dihydropyrimidine dehydrogenase (DPD) enzyme, which is encoded by the DPYD gene. DPD is the key enzyme required for the metabolism of pyrimidines like 5FU, clearing more than 80% of 5FU. It is also required for clearing of the oral 5FU prodrug, capecitabine.

Pyrimidines include uracil, thymine and cytosine, components used for DNA synthesis, as well as compounds that resemble them like 5FU. More than 50 mutations in the DPYD gene have been identified and these mutations interfere with the breakdown of uracil and thymine. Excess uracil and thymine in the blood, urine, and the fluid that surrounds the brain and spinal cord (cerebrospinal fluid) largely goes unnoticed in healthy people but some DPD deficient individuals present with neurological symptoms of toxicity.

Cancer patients with DPYD mutations are at a very high risk of severe drug-induced toxicity that can make the treatment intolerable. For DPD-deficient patients, substantial dose reduction is required. A lower drug dose does not compromise the efficiency of treatment, as the effective drug concentration in the blood of DPC-deficient patients is sufficient.

DPD deficiency affects approximately 5% of the overall population, and even mutation carriers (contain only one mutant copy of the gene) may experience severe adverse side effects. Genetic testing is the most effective way to assess DPYD mutations and metabolic status. Unfortunately, DPYD genetic testing is not used in clinical practice, and physicians typically find out that a patient cannot tolerate the standard dose of drug after the first chemo treatment. Dose reduction in subsequent chemo cycles improves tolerability of treatment.

When is it a good time for DPYD genetic testing?

Unlike regular blood testing, genetic tests take a bit more time – sample shipping time to special laboratories, need for sample batching, data analysis and communication back to a physician all prolong the turn around times. It is imperative to get the test results before the first chemo round, which is the harshest for DPD deficient patients. Confirmatory genetic testing in the middle of chemotherapy does not yield any clinical benefits. Therefore, patients diagnosed with colon cancer have to request DPYD genetic testing right away.

Patients with a strong family history of colon cancer need to be aware of their risks and undergo genetic testing for mutations in genes predisposing to colon cancer including MLH1, MSH2, MYH, APC, and other genes, as well as DPYD, TPMT and UGT1A1 genes that pay a role in the metabolism of various chemotherapeutic drugs including 5-FU, cisplatin and irinotecan. Patients at a high risk of colon cancer have to undergo regular colonoscopies to remove polyps, and also have the genetic test results for DPYD, TPMTand UGT1A1 genes on their file, just in case they will require chemo treatment. Getting genetic testing in time ensures your health and improves your chances of a full recovery.

“Knowledge is a weapon. I intend to be formidably armed.” -Terry Goodkind