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Mutagenicity and potential carcinogenicity of thiopurine treatment in patients with inflammatory bowel disease.

ABSTRACT: The thiopurines azathioprine and 6-mercaptopurine (6-MP) are effective immune modulators and cytotoxic agents extensively used in the treatment of autoimmune diseases, graft rejection, and cancer. There is compelling epidemiologic evidence that thiopurine treatment increases the risk for a variety of tumors by mechanisms that are unclear. We investigated the in vivo mutagenicity of long-term thiopurine treatment by determining the frequency and spectra of somatic mutation events at the hypoxanthine phosphoribosyltransferase (HPRT) locus in peripheral T lymphocytes as well as the prevalence of mutant clonal proliferation in a cross-sectional analysis of data from 119 children and adults with inflammatory bowel disease (IBD). ANOVA and regression were performed to assess relationships among the frequency and spectra of HPRT mutations with disease, duration of illness, duration of treatment, and total therapeutic dose of azathioprine and 6-MP. We observed a significant increase in the frequency of somatic mutations in 56 subjects treated with thiopurines for IBD compared with 63 subjects not treated with thiopurines. This increase was related to both total dose (P < 0.001) and duration of treatment (P < 0.001). Comparative mutation spectra analysis of 1,020 mutant isolates revealed a significant increase in the proportion of all transitions (P < 0.001), particularly G:C to A:T transitions (P < 0.001). Combined analyses of two signatures for mutant clonality, HPRT mutation, and T-cell receptor beta CDR3 region unique gene sequence also showed a significant thiopurine-dependent increase in mutant cell clonal proliferation (P < 0.001). These findings provide in vivo evidence for mutation induction as a potential carcinogenic mechanism associated with chronic thiopurine intervention.

SUBMITTER: Nguyen T

PROVIDER: S-EPMC2749269 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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Mutagenicity and potential carcinogenicity of thiopurine treatment in patients with inflammatory bowel disease.

Nguyen Truc T Vacek Pamela M PM O'Neill Patrick P Colletti Richard B RB Finette Barry A BA

Cancer research 20090825 17

The thiopurines azathioprine and 6-mercaptopurine (6-MP) are effective immune modulators and cytotoxic agents extensively used in the treatment of autoimmune diseases, graft rejection, and cancer. There is compelling epidemiologic evidence that thiopurine treatment increases the risk for a variety of tumors by mechanisms that are unclear. We investigated the in vivo mutagenicity of long-term thiopurine treatment by determining the frequency and spectra of somatic mutation events at the hypoxanth ...[more]

PMID: 19706768

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Project description:PurposeThiopurine drugs are well established treatments in the management of inflammatory bowel disease (IBD), but their use is limited by significant adverse drug reactions (ADRs). Thiopurine S-methyltransferase (TPMT) is an important enzyme involved in thiopurine metabolism. Several clinical guidelines recommend determining TPMT genotype or phenotype before initiating thiopurine therapy. Although several studies have investigated the association between TPMT polymorphisms and thiopurine-induced ADRs, the results are inconsistent. The purpose of this study is to evaluate whether there is an association between TPMT polymorphisms and thiopurine-induced ADRs using meta-analysis.MethodsWe explored PubMed, Web of Science and Embase for articles on TPMT polymorphisms and thiopurine-induced ADRs. Studies that compared TPMT polymorphisms with-ADRs and without-ADRs in IBD patients were included. Relevant outcome data from all the included articles were extracted and the pooled odds ratio (OR) with corresponding 95% confidence intervals were calculated using Revman 5.3 software.ResultsFourteen published studies, with a total of 2,206 IBD patients, which investigated associations between TPMT polymorphisms and thiopurine-induced ADRs were included this meta-analysis. Our meta-analysis demonstrated that TPMT polymorphisms were significantly associated with thiopurine-induced overall ADRs and bone marrow toxicity; pooled ORs were 3.36 (95%CI: 1.82-6.19) and 6.67 (95%CI: 3.88-11.47), respectively. TPMT polymorphisms were not associated with the development of other ADRs including hepatotoxicity, pancreatitis, gastric intolerance, flu-like symptoms and skin reactions; the corresponding pooled ORs were 1.27 (95%CI: 0.60-2.71), 0.97 (95%CI: 0.38-2.48), 1.82 (95%CI: 0.93-3.53), 1.28 (95%CI: 0.47-3.46) and 2.32 (95%CI: 0.86-6.25), respectively.ConclusionsOur meta-analysis demonstrated an association of TPMT polymorphisms with overall thiopurine-induced ADRs and bone marrow toxicity, but not with hepatotoxicity, pancreatitis, flu-like symptoms, gastric intolerance and skin reactions. These findings suggest that pretesting the TPMT genotype could be helpful in clinical practice before initiating thiopurine therapy. However, white blood cell count analysis should be the mainstay for follow-up.

Project description:Inflammatory Bowel Disease (IBD), mainly comprising Crohn's disease (CD) and ulcerative colitis (UC), is a chronic condition that primarily affects the intestine and is characterized by leukocytic infiltration. Blocking the migration of leukocytes from the circulation is therefore a reasonable therapeutic goal. Recent clinical trials using this approach have shown promise, with the monoclonal antibody to ?4?7 integrin, vedolizumab, and previously with the monoclonal antibody to the ?4 subunit, natalizumab. Directly targeting the subset of ?4?7 expressing cells that co-express CC chemokine receptor 9 (CCR9), using the orally administered antagonist, CCX282-B, also known as vercirnon, has also been evaluated in Phase II and III trials that have produced mixed results. Although CCX282-B showed efficacy in inducing response in active CD in early studies, this was not confirmed in a Phase III study. CCX282-B was also more effective than placebo in maintaining remission, and this result has yet to be confirmed in Phase III. The efficacy of blocking CCR9 in UC, where vedolizumab was effective, has not been tested. The prospect of targeting CCR9 in IBD remains attractive. Much of the local accumulation of inflammatory cells in the intestine arises from migration rather than local proliferation and genetic and pharmacological targeting of CCR9 or its ligand in preclinical models that mimic UC and CD ameliorate inflammation in some cases. Furthermore, binding of chemokine ligands to receptor is a critical step in activating integrin binding, so there is a potential for synergistic action between integrin and chemokine antagonists. CCR9 is expressed on a smaller proportion of circulating cells than ?4?7 integrin, which may offer greater specificity of effect, particularly in long term use. Furthermore, while ?4?7 is widely expressed on T and B cell subsets, CCR9 is mainly expressed on effector memory Th1 cells. Indications for the use of intestine-specific integrin and chemokine receptor targeting may also extend beyond IBD, to include, for example, postoperative ileus, and primary sclerosing cholangitis.

Project description:ImportanceUse of thiopurines may be limited by myelosuppression. TPMT pharmacogenetic testing identifies only 25% of at-risk patients of European ancestry. Among patients of East Asian ancestry, NUDT15 variants are associated with thiopurine-induced myelosuppression (TIM).ObjectiveTo identify genetic variants associated with TIM among patients of European ancestry with inflammatory bowel disease (IBD).Design, setting, and participantsCase-control study of 491 patients affected by TIM and 679 thiopurine-tolerant unaffected patients who were recruited from 89 international sites between March 2012 and November 2015. Genome-wide association studies (GWAS) and exome-wide association studies (EWAS) were conducted in patients of European ancestry. The replication cohort comprised 73 patients affected by TIM and 840 thiopurine-tolerant unaffected patients.ExposuresGenetic variants associated with TIM.Main outcomes and measuresThiopurine-induced myelosuppression, defined as a decline in absolute white blood cell count to 2.5 × 109/L or less or a decline in absolute neutrophil cell count to 1.0 × 109/L or less leading to a dose reduction or drug withdrawal.ResultsAmong 1077 patients (398 affected and 679 unaffected; median age at IBD diagnosis, 31.0 years [interquartile range, 21.2 to 44.1 years]; 540 [50%] women; 602 [56%] diagnosed as having Crohn disease), 919 (311 affected and 608 unaffected) were included in the GWAS analysis and 961 (328 affected and 633 unaffected) in the EWAS analysis. The GWAS analysis confirmed association of TPMT (chromosome 6, rs11969064) with TIM (30.5% [95/311] affected vs 16.4% [100/608] unaffected patients; odds ratio [OR], 2.3 [95% CI, 1.7 to 3.1], P = 5.2 × 10-9). The EWAS analysis demonstrated an association with an in-frame deletion in NUDT15 (chromosome 13, rs746071566) and TIM (5.8% [19/328] affected vs 0.2% [1/633] unaffected patients; OR, 38.2 [95% CI, 5.1 to 286.1], P = 1.3 × 10-8), which was replicated in a different cohort (2.7% [2/73] affected vs 0.2% [2/840] unaffected patients; OR, 11.8 [95% CI, 1.6 to 85.0], P = .03). Carriage of any of 3 coding NUDT15 variants was associated with an increased risk (OR, 27.3 [95% CI, 9.3 to 116.7], P = 1.1 × 10-7) of TIM, independent of TPMT genotype and thiopurine dose.Conclusions and relevanceAmong patients of European ancestry with IBD, variants in NUDT15 were associated with increased risk of TIM. These findings suggest that NUDT15 genotyping may be considered prior to initiation of thiopurine therapy; however, further study including additional validation in independent cohorts is required.

Dataset Information

Mutagenicity and potential carcinogenicity of thiopurine treatment in patients with inflammatory bowel disease.

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Mutagenicity and potential carcinogenicity of thiopurine treatment in patients with inflammatory bowel disease.

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