Refining theUGT1AHaplotype Associated with Irinotecan-Induced Hematological Toxicity in Metastatic Colorectal Cancer Patients Treated with 5-Fluorouracil/Irinotecan-Based Regimens

Abstract

Despite the importance of UDP-glucuronosyltransferase (UGT) 1A1*28 in irinotecan pharmacogenetics, our capability to predict drug-induced severe toxicity remains limited. We aimed at identifying novel genetic markers that would improve prediction of irinotecan toxicity and response in advanced colorectal cancer patients treated with folic acid (leucovorin), fluorouracil (5-FU), and irinotecan (camptosar)-based regimens. The relationships between UGT1A candidate markers across the gene (n 5 21) and toxicity were prospectively evaluated in 167 patients. We included variants in the 39untranscribed region (39UTR) of the UGT1A locus, not studied in this context yet. These genetic markers were further investigated in 250 Italian FOLFIRI-treated patients. Several functional UGT1A variants, including UGT1A1*28, significantly influenced risk of severe hematologic toxicity. As previously reported in the Italian cohort, a 5-marker risk haplotype [haplotype II (HII); UGTs 1A9/1A7/1A1] was associated with severe neutropenia in our cohort [odds ratio (OR) 5 2.43; P 5 0.004]. The inclusion of a 39UTR singlenucleotide polymorphism (SNP) permitted refinement of the previously defined HI, in which HIa was associated with the absence of severe neutropenia in combined cohorts (OR 5 0.55; P 5 0.038). Among all tested UGT1A variations and upon multivariate analyses, no UGT1A1 SNPs remained significant, whereas three SNPs located in the central region of UGT1A were linked to neutropenia grade 3-4. Haplotype analyses of these markers with the 39UTR SNP allowed the identification of a protective HI (OR 5 0.50; P 5 0.048) and two risk haplotypes, HII and HIII, characterized by 2 and 3 unfavorable alleles, respectively, revealing a dosage effect (ORs of 2.15 and 5.28; P # 0.030). Our results suggest that specific SNPs in UGT1A, other than UGT1A1*28, may influence irinotecan toxicity and should be considered to refine pharmacogenetic testing.

A novel UGT1 marker associated with better tolerance against irinotecan-induced severe neutropenia in metastatic colorectal cancer patients

“…2, 13–15 More recently, it was established that UGT1 haplotypes, e.g., combination of variants in UGT1A1, UGT1A6 , UGT1A7 , and UGT1A9 , are also associated with an increased risk of severe neutropenia. 11, 16, 17 These findings demonstrate that in addition to the well-established UGT1A1 rs8175347 TATA box promoter variant, other UGT1 variants might be involved in irinotecan-induced toxicities. Through haplotyping, our group recently found that the presence of the variant rs8330 in the 3’–untranslated region (3’UTR) of the UGT1 locus improves the ability to predict the risk of severe irinotecan-induced neutropenia, which suggests variance in this region common to all UGT1A transcripts, may also participate in the toxic effect of irinotecan.…”

ABCC5 and ABCG1 polymorphisms predict irinotecan-induced severe toxicity in metastatic colorectal cancer patients

“…A similar Transporter genes and irinotecan toxicity Chen et al 577 finding was obtained for the minor ABCC5 rs2292997A allele, whereas their co-occurrence further increased the risk, suggesting that increased exposure to the toxic metabolite SN-38 is coupled to neutropenia. The assessment of these new transporter gene markers along with relevant UGT1 variants (UGT1A1*28 and rs11563250) [15,29,30], which have been proven to affect the risk of severe neutropenia in the studied populations, significantly improved risk prediction, suggesting that both metabolic and transport pathways cooperate to determine drug exposure and the subsequent risk of neutropenia.…”

“…All patients received a 180 mg/m 2 intravenous dose of irinotecan every 2 weeks and 75 patients also received cotreatments such as bevacizumab. Detailed treatment modalities, eligibility, recruitment criteria, and isolation of DNA from wholeblood samples were documented previously [29]. Table 2 summarizes patient demographics (age, sex) and clinical information (treatment, toxicity, tumor site).…”

“…Finally, a combined analysis of genetic markers in UGT1, ABCG1, and ABCC5 was carried out in relation to grade 3-4 neutropenia because two genetic variants in UGT1 (rs8175347 and rs11563250) were previously linked to severe neutropenia in the same two mCRC patient cohorts [15,29,30]. The markers associated with increased risk were ABCG1 rs225440T, ABCC5 rs2292997A, and UGT1A1*28, whereas inversely, the UGT1 rs11563250G variant has been associated with a decreased risk of severe neutropenia in both populations [15].…”

Cytochrome P450 in Cancer Susceptibility and Treatment

“…Only a small percentage, however, is converted to active SN-38 (<3%) due to low CES substrate affinity [288,289] (Fig. 8).…”