According to the World Cancer Report given by the World Health Organization, the global cancer rate could increase by an alarming 50% causing 15 million cancer cases to appear in the year 2020.1 With this in mind and the heavy reliance on chemotherapeutic drugs, an issue is now starting to materialize with the reactions patients are having with chemotherapy drugs based on mutations in the genes that these drugs rely so heavily on to be effective. A study done in 2013 was conducted to evaluate just that: how the use of chemotherapy drugs to save lives is actually causing more harm than good to some patients. 

              Muhammad Wasif Saif from the Tufts University School of Medicine has been focusing on the specific gene Dihydropyrimidine Dehydrogenase (DPYD) that, when mutated, can cause significant and life threatening toxicities to chemotherapy patients.3 DPD is the enzyme that is controlled by the DPYD gene and focuses on breaking down the pyrimidine bases as well as the breakdown of specific drugs used in cancer patients.4 

Figure 1 shows the structure of DPD unmutated. The DPD mutation is more specific to the chemotherapeutic drugs that use the 5- FU/capecitabine-based therapies. Saif focused his research on sample of patients on which he performed full sequencing of the DYPD gene and DNA sequencing. This included the 23 coding exons of the gene as well as around 690 adjacent intronic base pairs of the DPYD gene. Most of the patients being tested (about 75%) had either breast or colon cancer and the majority of the identified patients were Caucasian.3 






Figure 2 shows the breakdown of the patients’ information used in the study. Results contributed to the statistic that of all toxicities experienced with the 5-FU/Capecitabine drugs, 60% were related to a DPD deficiency. 








Figure 3 shows Saif’s findings of these mutations that have the potential to cause harmful damage to patients using specific drugs.3 






             This finding suggests that patients with DPD deficiency who receive this chemotherapy treatment need to be observed with extreme caution or avoid the drug all together avoid life-threatening adverse effects. Saif sates that mutations in the DPD are frequent in Caucasian patients who experience these toxicities with drug therapies involving 5-FU/capecitabine. DPD deficiency is also an autosomal recessive disorder which means that individuals should take extra caution if a family experiences issues the therapies such as 5-FU/capecitabine.5 Saif suggests that testing for deficiencies prior to the use of the drugs onpatients require the use of 5-FU/Capecitabine treatment could be extremely helpful to identify those patients that are more susceptible to the adverse effects that he is seeing. What is even more shocking is that mutations of the DPYD gene are assumed to be present in 3%-5% of the current population. 
Muhammad Wasif Saif
      
           Thus, Saif ends with the encouragement to test every patient for this mutation prior to the use of 5- FU/capecitabine as a cancer therapeutic agent. Currently there are studies and research being done to find alternate therapies for patients with DPD deficiencies. These currently include the idea recombinant human DPD which would benefit and be used for in vivo studies leading to further development of cancer drugs.5 However, development of new treatments are always time consuming and costly so immediate results and drugs are not likely. Testing for DPD deficiency and DPYD mutations should always be a priority prior to usage of 5-FU and capecitabine based drugs.


REFERENCES 
1. "Global Cancer Rates Could Increase by 50% to 15 Million by 2020." WHO. World Health
Organization, 2013. Web. 7 Apr. 2014.
2. "RCSB PDB - Jmol Viewer - 1H7W 3D View Report." RCSB PDB - Jmol Viewer - 1H7W 3D View
Report. RCSB Protein Data Bank, 2014. Web. 5 Mar. 2014.
3. Saif, Muhammad W. "Dihydropyrimidine Dehydrogenase Gene (DPYD) Polymorphism among
Caucasian and Non-Caucasian Patients with 5-FU- and Capecitabine-related Toxicity Using Full
Sequencing of DPYD." Dihydropyrimidine Dehydrogenase Gene (DPYD) Polymorphism among
Caucasian and Non-Caucasian Patients with 5-FU- and Capecitabine-related Toxicity Using Full
Sequencing of DPYD. Cancer Genomics & Proteomics, 2013. Web. 3 Feb. 2014.
4. "Dihydropyrimidine Dehydrogenase Deficiency." - Genetics Home Reference. National Institute
of Health, Nov. 2011. Web. 10 Apr. 2014.
5. "Dihydropyrimidine Dehydrogenase Deficiency." National Center for Advancing Translational
Sciences. US Department of Health and Human Services, 20 Aug. 2012. Web. 12 Mar. 2014
6. "DPD Deficiency Foundation Raising Awareness. Supporting Families. Working towards a
Cure." DPD Deficiency. DPD Deficiency Foundation, 2012. Web. 10 Apr. 2014.



Written by Lauren Manke