UGT1A1 is the gene that encodes the UDP-glucuronosyltransferase 1 enzyme. That means that the UGT1A1 gene gives your cells the instructions to make the UGT1A1 enzyme. The UGT1A1 enzyme is needed to break down and clear irinotecan chemotherapy in your body.
Irinotecan (Camptosar) is a topoisomerase I inhibitor chemotherapy drug used to treat stage IV / metastatic colorectal cancer (mCRC). It may be used alone or in combination with 5-fluorouracil and leucovorin in the FOLFIRI regimen.
If you have a mutation (genetic variant) leading to decreased UGT1A1 enzyme level or function, your body does not break down irinotecan properly. This leads to increased levels of the irinotecan active metabolite (breakdown product) which may cause severe toxic effects, like severe neutropenia.
UGT1A1 is a predictive biomarker. It predicts severe irinotecan-induced toxicity. Mutations in genes that affect drug metabolism and toxicity are called pharmacogenetic mutations or pharmacogenetic variants.
5-10% of people have a decreased level or function of UGT1A1 due to a mutation. UGT1A1 mutations are not the cause or result of your colorectal cancer, but they are relevant to your cancer treatment and treatment side effects. Mutations in the UGT1A1 gene are hereditary.
There are several different mutations that may be present in the UGT1A1 gene. The most common UGT1A1 variants that are relevant to your risk of severe irinotecan toxic effects are called UGT1A1*28, UGT1A1*93, and UGT1A1*6. The wild-type (WT) non-mutated version is called UGT1A1*1.
The UGT1A1*28 mutation is commonly found in people of African (43%) or European (39%) ancestry, and is less common in those of East Asian ancestry (16%). The UGT1A1*93 mutation is also common in those of African (34%) and European (27%) ancestry, and less common in people of East Asian ancestry (13%). The UGT1A1*6 mutation is most common in those of East Asian ancestry (15%), and uncommon in people of African (0.1%) and European (1%) ancestry.
When testing for UGT1A1, your medical team is looking specifically at your genes, not your tumor’s genes. UGT1A1 is tested in a blood sample or in cells collected from your mouth or saliva.
Sometimes, UGT1A1 is first tested by phenotyping, in this case measuring unconjugated bilirubin in blood. People with decreased UGT1A1 enzyme level or function have low unconjugated bilirubin.
If phenotyping results are normal, no genotype testing is needed, you are not at increased risk of severe irinotecan toxicity. If phenotyping results indicate decreased UGT1A1 enzyme, you are at higher risk of severe irinotecan toxicity, and genotyping will be done to determine your UGT1A1 mutation and more specific level of risk. Both phenotyping and genotyping are good ways to determine whether your UGT1A1 status puts you at high risk for severe irinotecan related toxicity.
If you have no mutation in UGT1A1 (wild-type)
If you have one mutated copy of UGT1A1 and one normal wild-type copy
If you have two mutated copies of UGT1A1
Colorectal cancer patients who experience severe toxic effects of irinotecan chemotherapy should be tested for UGT1A1. Recommendations for pre-treatment UGT1A1 testing are different around the world. Talk to your oncology team about whether pre-treatment testing would benefit you.
A biomarker is a piece of information about your health. Biomarkers include your blood pressure, your blood type, and cholesterol or blood sugar levels measured in a blood test. The biomarkers of cancer are also known as tumor markers.
