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Mutations in colorectal epithelium drive ulcerative colitis progression

Ulcerative colitis (UC) is a complex chronic disease of the gastrointestinal tract. Multiple factors are known to influence predisposition to UC, including genetics, gut microbiota composition, and diet. A recent genetic analysis of gut epithelial cells in UC patients revealed unique patterns of mutation that drive disease progression. Mutations in stem cells, which in turn give rise to epithelial cells, occur more frequently in genes controlling the immune response. Since each epithelial cell derived from a mutated stem cell has a unique mutation profile, it can be quite challenging to select the right treatment strategy. Although several treatment options are in use today, including antibiotics, corticosteroids and immunosuppressive agents, these provide only partial relief to most patients. Precision medicine tools can help to select the appropriate immunosuppressant dose to reduce the risk of severe side effects.

The colorectal epithelium is composed of single-layer cells that protect the body from bacteria in the gut and absorb nutrients. Structurally, the layer consists of many protuberances, called villi, and depressions, called crypts. Epithelial cells are generated by stem cells located at the bottom of the crypts. The new epithelial cells expand to the villi tips to repair any damage. It is estimated that 50,000 crypts are lost annually and replaced by new ones through crypt fissions. In patients with UC, the rate of crypt fission is accelerated to compensate for crypt defects. Genetic analysis of epithelial cells demonstrated that the mutation rate in UC patients is three times higher than in crypts of healthy individuals. Furthermore, mutations in three genes – NFKBIZ, PIGR and ARID1A – lead to the dominance of cells that carry them.

Epidemiological studies have compared the incidence and lethality of colorectal cancer (CRC) in patients with UC to those without. Patients with UC have a significantly higher rate of CRC and significantly higher mortality risk compared to individuals without UC, despite early diagnosis and treatment. Patients with extensive colitis, liver complications (primary sclerosing cholangitis), childhood-onset of disease, and family history of CRC are at particularly high risk of developing CRC.

Analysis of mutations in colon cancer epithelial cells also showed an increased mutation rate, but in different genes compared to UC. This indicates that different mutations affect inflammatory response and cancer risk. The studies also provide additional insights regarding how low doses of chemotherapeutic agents, such as 6-mercaptopurine (Purinethol), azathioprine (Imuran), and cyclosporine, work.

A low dose of these agents reduces the epithelial cell proliferation rate and slows down the growth of mutated cells, thereby reducing inflammation and, potentially, the risk of cancer as well. However, at higher doses, mercaptopurine and azathioprine also suppress bone marrow function (myelosuppression), leading to low production of red and white blood cells and platelets. To reduce the risk of suppression, the drug dose must be adjusted based on the patient’s metabolism.

TPMT is an enzyme responsible for the clearance of azathioprine, thioguanine and mercaptopurine. The Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline indicates that people who carry a mutation in the TPMT gene should start treatment with reduced doses (30-80% of a normal dose). Further gradual dose increase should take into consideration the extent of myelosuppression. People with drastically reduced TPMT activity, called Poor Metabolizers, should be treated with alternative non-thiopurine immunosuppressant therapy. If mercaptopurine treatment is still required for TPMT Poor Metabolizers, the staring dose must be reduced tenfold.

Clearance of 6-mercaptopurine and azathioprine is also affected by NUDT15 gene mutations, which are common in Asians and Hispanics. Carriers of these mutations have reduced breakdown of thiopurine and are at a higher risk of myelosuppression.

People with reduced TMPT or NUDT15 activity may receive treatment with other immunosuppressants, such as sirolimus, also known as rapamycin, or tacrolimus. The liver enzyme CYP3A5 metabolizes both sirolimus and tacrolimus. Most Caucasians do not express the CYP3A5 enzyme. Hence, the typical starting drug dose is calculated to account for low drug clearance. However, people of African origin do express CYP3A5, and regular sirolimus and tacrolimus will not be effective. Pharmacogenetic testing can provide insights into an individual’s CYP3A5 function.

For patients suffering from UC, physicians should consider pharmacogenetic testing, such as Pillcheck, before prescribing 6-mercaptopurine, azathioprine, sirolimus or tacrolimus. Pillcheck analyzes TPMT, CYP3A5 and many other drug-metabolism genes. The test can deliver critical insights on the individual’s anticipated drug response to help you and your patient select appropriate treatment options.


Kakiuchi N. et al., Frequent mutations that converge on the NFKBIZ pathway in ulcerative colitis Nature (2020):577, 260–265

Olén O. et al., Colorectal cancer in ulcerative colitis: A Scandinavian population-based cohort study. The Lancet, online January, 2020.

Reiling MV. et al., Clinical Pharmacogenetics Implementation Consortium Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2018 Update clinical pharmacology & therapeutics (2019):105(5), 1095-1105

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