Genetic polymorphisms in uridine diphospho-glucuronosyltransferase 1A1 and breast cancer risk in Africans

The UDP-glucuronosylatransferase 1A1 (UGT1A1) gene is involved in the metabolism of estrogen and detoxification of potential carcinogens. The number of TA repeats in the promoter region of UGT1A1 has been linked to breast cancer risk, but results varied by race. We performed a comprehensive assessment of genetic polymorphisms in the UGT1A1 gene, and examined these polymorphisms and TA repeats in relation to breast cancer risk in a case-control study in Nigeria. 512 breast cancer cases and 226 community controls were genotyped for UGT1A1. Compared with high-activity TA repeat genotypes, the odds ratios (OR) for low-activity and moderate-activity genotypes were 0.47 (95% confidence interval CI, 0.26-0.83) and 0.64 (95% CI, 0.39-1.06), respectively, in premenopausal women (P = 0.009 for trend), but no association was observed in postmenopausal women (P = 0.24). The effect of TA repeats was also differentiated by age: the OR was 0.39 (95% CI 0.21-0.71) for low-activity genotypes and 0.58 (95% CI 0.33-1.00) for moderate-activity genotypes in women <45 years old (P = 0.002 for trend), but no association was observed in women >/=45 years old (P = 0.15). Haplotype analysis showed that UGT1A1 haplotypes were highly diverse with blocked structures. We found a specific haplotype in block 2 that was significantly associated with a 2.1-fold elevated risk (95% CI 1.05-4.39; P = 0.04). In contrast with previous studies, we found low-activity TA repeat alleles were protective against breast cancer among premenopausal indigenous Africans, suggesting that the role of UGT1A1 in breast cancer development may vary by population, presumably due to different environmental and genetic modifier effects.     

Sulfotransferase 1A1 (SULT1A1) polymorphism,PAH-DNA adduct levels in breast tissue and breast cancer risk in a case-control study

Gene–environment interactions are hypothesized to be major contributors to susceptibility to environmental carcinogens and interindividual variability in cancer risk. We present findings on associations between genetic susceptibility due to inherited polymorphisms of the Phase II detoxification enzyme sulfotransferase 1A1 (SULT1A1), breast cancer risk, and polycyclic aromatic hydrocarbon (PAH)-DNA adducts. A hospital based case-control study was conducted at the New York-Presbyterian Medical Center (NYPMC). The study utilized two control groups: one comprised of women with benign breast disease (BBD) and the other comprised of women visiting NYPMC for routine gynecologic checkups (healthy controls). Blood samples were collected from cases and controls; and breast tissue from pathology blocks was collected from cases (tumor and non-tumor tissue) and BBD controls (benign tissue). PAH-DNA adduct levels were measured by immunohistochemistry in breast tissue samples, and the SULT1A1 (Arg/His) polymorphism at codon 213 was determined by PCR RFLP analyses using DNA from white blood cells. Increasing number of His alleles was modestly associated with breast cancer case-control status, when cases were compared to healthy controls (p for trend = 0.08), when cases were compared to BBD controls (p for trend = 0.08) and when cases were compared to both control groups combined (p for trend = 0.07). Contrary to our hypothesis PAH-DNA adduct levels in breast tissue were not associated with SULT1A1 genotype. Our findings are consistent with a prior report that the Arg/His polymorphism in SULT1A1 is associated with breast cancer risk.     

GSTM1 and GSTT1 polymorphisms and postmenopausal breast cancer risk

Glutathione S-transferases (GSTs) are a family of important enzymes involved in the detoxification of a wide variety of known and suspected carcinogens, including potential mammary carcinogens identified in charred meats and tobacco smoke. A substantial proportion of the Caucasian population has a homozygous deletion (null) of the GSTM1 or GSTT1 gene, which results in lack of production of these isoenzymes. We conducted a case-control study in a cohort of postmenopausal Iowa women who in 1986 completed a mailed questionnaire on lifestyle factors including information on cigarette smoking and breast cancer risk factors. DNA samples and information related to charred meat intake were obtained, in the case-control study, from breast cancer cases diagnosed during 1992–1994, and a random sample of cancer-free cohort members. Included in this study were 202 cases and 481 controls who were genotyped for GSTM1 or GSTT1 gene polymorphisms. Compared to women who had both GSTM1 and GSTT1 genes, a 60% elevated risk (95% CI = 1.0–2.5) was observed among those whose GSTM1 or GSTT1 gene was deleted. When stratified by meat eating habits, the risk of breast cancer associated with null GSTM1 or GSTT1 genotype was observed primarily among women who ate meats consistently well- or very well-done. Women who carried either one of the null genotypes and consumed meat consistently well- or very well-done had a 3.4-fold elevated risk of developing breast cancer (95% CI = 1.6–7.1). Cigarette smoking was not a risk factor for breast cancer among women who had either the GSTM1 or GSTT1 genes. Among those with the null GSTT1 genotype, however, a significantly elevated risk of breast cancer was associated with cigarette smoking (OR = 2.5, 95% CI = 1.1–5.4) and the association was stronger among former (OR = 4.4, 95% CI = 1.5–12.8) than current smokers (OR = 1.3, 95% CI = 0.4–4.1). This study suggests that certain null GST genotypes may be associated with an elevated risk of breast cancer and the association may be modified by charred meat intake and cigarette smoking.     

Cytochrome P4501A1 polymorphism as a susceptibility factor for breast cancer in postmenopausal Chinese women in Taiwan.

The incidence of breast cancer has been greatly increasing in Taiwan over the past two decades. Since cytochrome P4501A1 (CYP1A1) is involved in the metabolism of environmental carcinogens or oestrogen, we hypothesized that CYP1A1 genetic polymorphism may be a susceptibility factor for breast cancer. This hypothesis was evaluated in this case control study of 150 breast cancer patients and 150 healthy controls among Chinese women. Two CYP1A1 polymorphisms were studied, one containing a new Msp1 site and the other located in axon 7 and resulting in the replacement of an isoleucine (Ile) residue by a valine (Val). After simultaneously considering the known or significant risk factors for breast cancer, including the age of study participants, positive family history of breast cancer, early menarche (< or = 13 years), nulliparity and late first full-term pregnancy (> or = 30 years), hormone replacement therapy and smoking, the CYP1A1 Msp1 polymorphism was found to be a significant factor in determining the risk of breast cancer. The homozygous variant was the most susceptible genotype with an adjusted odds ratio of 1.98 (95% confidence interval (CI) = 1.01-3.99) compared with the non-homozygous variants (the homozygous wild-type and the heterozygous variant). In contrast, the CYP1A1 Ile/Val polymorphism was not significantly associated with breast cancer development (adjusted OR = 1.07, 95% CI = 0.64-1.78). Interestingly, the Msp1 polymorphism was especially significant in postmenopausal women, but not in premenopausal women. Further stratification analysis in postmenopausal women who were non-smokers and with no history of hormone replacement therapy showed the cancer risk due to the Msp1 variant to be more significant in women with early menarche. We conclude that CYP1A1 polymorphism is a susceptibility factor for breast cancer in postmenopausal Chinese women in Taiwan. Further study with a large sample size should be considered to address issues of interactions between CYP1A1 and other risk factors.     

Association between polymorphisms in UDP-glucuronosyltransferase 1A6 and 1A7 and colorectal cancer risk

Genetic polymorphisms of uridine diphosphate-glucuronosyltransferases 1A6 (UGT1A6) and 1A7 (UGT1A7) may lead to genetic instability and colorectal cancer carcinogenesis. Our objective was to measure the interaction between polymorphisms of these repair genes and tobacco smoking in colorectal cancer (CRC). A total of 68 individuals with CRC and 112 non-cancer controls were divided into non-smoker and smoker groups according to pack-years of smoking. Genetic polymorphisms of UGT1A6 and UGT1A7 were examined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). We found a weak association of UGT1A6 polymorphisms with CRC risk (crude odds ratio [OR], 1.65; 95% confidence interval [95%CI], 0.9-3.1, P=0.107; adjusted OR 1.95, 95%CI 1.0-3.8, P=0.051). The ORs for the UGT1A7 polymorphisms were statistically significant (crude OR: 26.40, 95%CI: 3.5-198.4, P=0.001; adjusted OR: 21.52, 95%CI: 2.8-164.1, P=0.003). The joint effect of tobacco exposure and UGT1A6 polymorphisms was significantly associated with colorectal cancer risk in non-smokers (crude OR, 2.11; 95%CI, 0.9-5.0, P=0.092; adjusted OR 2.63, 95%CI 1.0-6.7, P=0.042). In conclusion, our findings suggest that UGT1A6 and UGT1A7 gene polymorphisms are associated with CRC risk in the Japanese population. In particular, UGT1A6 polymorphisms may strongly increase CRC risk through the formation of carcinogens not associated with smoking.     

Increased UGT1A3 and UGT1A7 Expression is Associated with Pancreatic Cancer

UGT1A play important roles in the glucuronidation of a variety of endogenous and exogenous compounds.UGT1A isoforms are expressed tissue specifically. The aim of this study was to examine the relationship betweenUGT1A3 and UGT1A7 mRNA expression and pancreatic cancer. Paired healthy and tumor tissue samples of43 patients with pancreatic cancer were included in this study. UGT1A3 and UGT1A7 mRNA expressions wereanalyzed by real time-PCR. In the result of study, UGT1A3 and UGT1A7 mRNA expressions were significantlyhigher in tumor tissue than normal tissue of pancreatic cancer patients (p<0.05). In addition, high mRNAexpression of UGT1A3 and UGT1A7 was significantly associated with larger tumor size (p<0.05). The datasuggested that UGT1A3 and UGT1A7 may play roles in the progression of pancreatic cancer. Consequently,UGT1A3 and UGT1A7 are potential prognostic indicators.     

UGT1A1基因多态性与伊立替康治疗结直肠癌不良反应的关系

背景与目的：尿苷二磷酸葡萄糖醛酸转移酶1A1(uridine diphosphoglucu-ronosyltransferase 1A1,UGTlA1)是伊立替康代谢关键酶,其活性受基因多态性影响显著。本研究探讨结直肠癌患者中,UGT1A1*28和UGT1A1*6基因多态性与伊立替康治疗相关不良反应之间的关系。方法：入组2013年4月—2013年12月于复旦大学附属中山医院肿瘤内科接受治疗的消化道恶性肿瘤患者160例。抽提外周血中基因组DNA,分别采用STR方法和Sanger测序法,检测UGT1A1*28和UGT1A1*6基因型,分析UGT1A1基因多态性分布情况。对其中82例化疗方案中含伊立替康的结直肠癌患者进行随访,记录不良反应发生情况和严重程度,比较不同基因型患者之间的差异。结果：160例消化道肿瘤患者中,UTG1A1*28(启动子TATA盒区域TA重复次数)野生型TA6/6124例(77.5%);杂合子TA6/7 33例(20.5%);纯合子TA7/7 3例(2.0%)。UGT1A1*6位点(211G>A)野生型GG 105例(65.6%),杂合子GA 48例(30.0%);纯合子AA 7例(4.4%)。82例化疗方案中含伊立替康的结直肠癌患者中,*28基因型(TA6/7和TA7/7)显著增加发生3级以上中性粒细胞减少的风险(58.3% vs 0.0%,P<0.001),并增加整体不良反应发生率(76.0% vs 45.6%,P<0.001);*6基因型(GA和AA)、年龄、性别、化疗方案和伊立替康相关不良反应发生无显著相关性。结论：接受伊立替康化疗的结直肠癌患者,UGT1A1*28位点多态性显著增加中性粒细胞减少发生的风险,可预测伊立替康引起的骨髓抑制性不良反应,辅助临床选择合适的化疗方案。     

纺锤体检查点功能复合物基因MAD1L1遗传变异与潮汕地区女性乳腺癌易感性研究

目的：研究纺锤体检查点功能复合物基因MAD1L1基因变异与潮汕地区女性乳腺癌易感性的关系。方法：采用病例-对照研究,收集2015年12月—2017年12月在汕头大学医学院附属肿瘤医院住院的乳腺癌新发病例191例及同期社区健康对照225例,采用TaqMan荧光双标记探针法对MAD1L1基因位点rs1801368进行基因分型。同时收集其人口学特征、女性生理生育相关信息、生活方式、既往病史及乳腺癌患者临床病理指标。结果：MAD1L1 rs1801368位点基因型CC、CT、TT的频率分布在病例组中分别为20.63%、42.86%、36.51%,在对照组中分别为30.14%、41.15%、28.71%,两组中分布的差异无统计学意义（P > 0.05）。多因素分析表明,调整了年龄、初潮年龄、绝经状态等混杂因素后,相较于野生型纯合子CC,突变型纯合子TT增加乳腺癌患病风险（OR=3.399,95% CI：1.288~8.973,P=0.013）。结论：MAD1L1基因位点rs1801368多态性与潮汕地区女性乳腺癌易感性可能相关,携带TT基因型的较携带CC或CT基因型的女性患乳腺癌的风险高。     

Genetic polymorphisms of interleukin-1 beta (IL-1B) and IL-1 receptor antagonist (IL-1RN) and breast cancer risk in Korean women

Objective To evaluate the potential role of genetic polymorphisms of interleukin-1 beta (IL-1B) and IL-1 receptor antagonist (IL-1RN) on breast cancer development, a hospital-based case-control study was conducted in Korea. Methods Histologically confirmed breast cancer cases (n = 560) and controls (n = 509) without cancer history were recruited from three teaching hospitals in Seoul between September 1998 and January 2002. Information on risk factors of breast cancer were collected by interviewed questionnaire. Genotypes of IL-1B (-31C/T) and IL-1RN (86 bp variable number tandom repeats in intron 2) were determined by PCR-CTPP (confronting two-pair primers) and PCR, respectively. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by unconditional logistic regression model. Results The IL-1RN *2-allele was associated with decreased breast cancer risk with marginal significance (OR = 0.7, 95% CI = 0.48–1.05). The IL-1B CC or TC genotype was not associated with decreased risk of breast cancer (OR = 0.9, 95% CI = 0.65–1.16). However, combination of IL-1B C-allele (CT or CC) and IL-1RN *2-allele containing genotypes significantly decreased the risk of breast cancer (OR = 0.6, 95% CI = 0.39–0.99). A moderately decreasing trend of risk was observed as the number of ‘putative low risk’ allele increased (p for trend = 0.07). Suggestive combined effect on breast cancer risk was also observed between body mass index (BMI) and IL-1RN non-*2 allele: women with higher BMI and IL-1RN non-*2 allele had 1.7-fold higher risk than women with lower BMI and IL-1RN*2 genotypes. Conclusion Our results suggest that genetic polymorphisms of interleukin-1 may play a role in the individual susceptibility for breast cancer development in Korean women.     

Genetic polymorphism in the conjugating enzyme UGT1A1 and the risk of head and neck cancer

UDP-glucuronosyltransferase 1A1 (UGT1A1) is an enzyme which catalyses not only the glucuronidation of tobacco smoke carcinogens like benzopyrene, but also of the endogenous substrate bilirubin. Bilirubin for a long time was considered to be only a toxic waste product of hemoglobin degradation, but recent findings have shown that bilirubin is a potent antioxidant, which may play a protective role against cancer. We investigated whether a genetic polymorphism in UGT1A1 (UGT1A1*28), associated with a reduced UGT1A1 enzyme activity, may have a risk-modifying effect on head and neck carcinogenesis. Blood samples from 421 patients with oral, pharyngeal or laryngeal carcinoma, and 417 healthy controls were investigated for the UGT1A1*28 polymorphism. On the basis of the occurrence of this polymorphism, patients and controls were divided according to predicted UGT1A1 enzyme activity (low, intermediate, high). Logistic regression analysis showed a significant increased distribution of predicted high activity UGT1A1*1 polymorphisms among the patients (OR: 1.37; 95% CI: 1.02-1.83). Stratified analyses demonstrated that predicted high activity UGT1A1 polymorphisms were present even more significantly in patients with laryngeal cancer, older patients, heavy smokers and heavy drinkers. In conclusion, the predicted high activity UGT1A1*1 polymorphism, which results in lower serum levels of the endogenous antioxidant bilirubin, was associated with an increased risk of head and neck cancer.     

Genetic polymorphisms and esophageal cancer risk

The aim of this paper is to review and evaluate, in a comprehensive manner, the published data regarding the contribution of genetic polymorphisms to risk of esophageal cancer, including squamous cell carcinoma (SCC) and adenocarcinoma, in humans. All relevant studies available in MEDLINE and published before February 2007 were identified. Studies carried out in humans and that compared esophageal cancer patients with at least 1 standard control group were considered for analysis. One-hundred studies and 3 meta-analyses were identified. Eighty (80%) studies were conducted in Asian countries, particularly China including Taiwan (60 (60%) studies). The most intensively examined genes were those encoding carcinogen metabolic enzymes. The most widely studied gene was GSTM1 (15 studies), followed by ALDH2 (11 studies). ALDH2, MTHFR C677T, CYP1A1 Ile/Val, CYP1A1MspI, CYP2E1, GSTP1, GSTM1 and GSTT1 were examined by meta-analyses and significant relations were found between ALDH2*1*2 and the CYP1A1 Val allele and increased risk of esophageal cancer. In addition, increased risk of esophageal SCC was consistently associated with the ADH2*1*2 and the p53 codon 72 Pro/Pro genotypes. Cohort studies that simultaneously consider multiple genetic and environmental factors possibly involved in esophageal carcinogenesis are needed to ascertain not only the relative contribution of these factors to tumor development but also the contributions of their putative interactions.     

Association of FGFR3 and FGFR4 gene polymorphisms with breast cancer in Chinese women of Heilongjiang province

Background

The fibroblast growth factor (FGF) receptor pathway is activated in many tumors. FGFR2 has been identified as a breast cancer susceptibility gene. Common variation in other FGF receptors might also affect breast cancer risk. We carried out a case-control study to investigate associations of variants in FGFR3 and FGFR4 with breast cancer in women from Heilongjiang Province.

Methods

SNP rs2234909 and rs3135848 in FGFR3 and rs1966265 and rs351855 in FGFR4 were successfully genotyped in 747 breast cancer patients and 716 healthy controls using the SNaPshot method. The associations between SNPs and breast cancer were examined by logistic regression. The associations between SNPs and disease characteristics were examined by chi-square tests or one-way ANOVA as needed.

Results

The minor alleles of rs1966265 and rs351855 in FGFR4 were strongly associated with breast cancer in the population, with odds ratios of 1.335 (95%CI = 1.154-1.545) and 1.364 (95%CI = 1.177-1.580), respectively. However, no significant associations were detected between other SNPs and breast cancer. Analyses of the disease characteristics showed that SNP rs351855 was associated with lymph-node-positive breast cancer with a dose-dependent effect of the minor allele (P = 0.008).

Conclusions

SNPs rs1966265 and rs351855 in FGFR4 were associated with breast cancer in a northern Chinese population.     

Cytochrome P4501A1 genetic polymorphisms and breast cancer risk in Nigerian women

Summary In this case-control study based on 250 women with breast cancer and 250 age-matched controls, we sought to evaluate the role of four polymorphic variants in the CYP1A1 gene in breast cancer susceptibility in Nigerian women. Heterozygosity for the CYP1A1 M1 genotype (CYP1A1 M1 [T/C]) was associated with a 21% reduced risk of breast cancer (OR=0.79, 95% CI 0.46–1.40) while homozygosity for the genotype (CYP1A1 M1 [C/C]) conferred a non-significant 9% reduced risk of breast cancer. These risk profiles were not significantly altered in subgroup analysis by menopausal status. While heterozygosity for the CYP1A1 M3 genotype (T/C) conferred a non-significant 24% reduced risk of breast cancer (OR=0.76, 95% CI 0.47–1.22), homozygosity for the variant was associated a non-significant 1.95-fold increased risk of breast cancer (OR=1.95, 95% CI 0.24–6.01). Subgroup analysis showed a non-significant 11% reduced risk in premenopausal heterozygous carriers (OR=0.89, 95% CI 0.45–1.44) and a non-significant 6% increased risk of postmenopausal breast cancer for carriers of the CYP1A1 M3 (T/C) genotype. The CYP1A1 M2 (isoleucine to valine) polymorphism in exon 7 and CYP1A1 M4 (threonine to asparagine) variant in codon 461 of the CYP1A1 gene were found to be very rare in our study subjects. This study has shown that while the CYP1A1 M1 polymorphism conferred reduced risk of breast cancer, homozygosity for the CYP1A1 M3 (C/C) was associated with increased risk of breast cancer although these risks did not attain statistical significance.     

Association between WT1 polymorphisms and susceptibility to breast cancer: results from a case-control study in a southwestern Chinese population

Wilms’ tumor gene 1 (WT1) single nucleotide polymorphism (SNP), rs16754, has been considered as an independent prognostic factor in patients with acute myeloid leukemia and renal cell carcinoma. However, its biological role in breast cancer has not been reported. To test whether WT1 SNPs can be used as a molecular marker in order to improve the risk stratification of breast cancer, we performed a case-control study including 709 female sporadic breast cancer patients and 749 female healthy control subjects in the Southeast China. Five WT1 SNPs (rs16754, rs3930513, rs5030141, rs5030317, rs5030320) were selected and determined by polymerase chain reaction-ligase detection reaction to assess their associations with breast cancer risk. Results showed the distributions of the alleles of these WT1 SNPs were consistent with data from Chinese population as suggested by the International HapMap Project. Individuals with the minor alleles of rs16754, rs5030317 and rs5030320 showed a significant decrease of breast cancer risk in codominant model (OR = 0.6370, 95% CI: 0.4260-0.9520 for rs16754; OR = 0.5940, 95% CI: 0.3890-0.9070 for rs5030317; OR = 0.5870, 95% CI: 0.3850-0.8960 for 5030320, respectively) and recessive model. Stratified analyses showed the protective effects were more evident in the subjects with age ≤ 50 years or in pre-menopausal status. To explore the potential mechanism, we conducted bioinformatics genotype-phenotype correlation analysis, and found that the mRNA expression level for homozygous rare allele of WT1 gene was lower than that in wild-type and heterozygous group (P = 0.0021) in Chinese population. In summary, our findings indicated that minor alleles of rs16754, rs5030317 and rs5030320 are associated with reduced risk of breast cancer, suggesting that WT1 SNPs may be a potential biomarker of individualized prediction of susceptibility to breast cancer. However, large prospective and molecular epidemiology studies are needed to verify this correlation and clarify its underlying mechanisms.     

XPC polymorphisms and lung cancer risk

Polymorphisms in DNA repair genes may be associated with differences in the capacity to repair DNA damage and thereby influence an individual's susceptibility to smoking-related cancer. To test this hypothesis, we investigated the potential association of 7 XPC polymorphisms (-449G-->C, -371G-->A, -27G-->C, Val499Arg, PAT-/+, IVS11-5C-->A and Lys939Gln) and their haplotypes with lung cancer risk in a Korean population. XPC genotypes were determined in 432 lung cancer patients and 432 healthy controls frequency-matched for age and sex. XPC haplotypes were predicted using a Bayesian algorithm in the Phase program. The combined -27CG+CC genotype was associated with a significantly increased risk for overall lung cancer compared to the -27GG genotype (adjusted OR = 1.97, 95% CI 1.22-3.17, p = 0.005). The other 6 polymorphisms were not significantly associated with overall risk of lung cancer. When lung cancer cases were categorized by tumor histology, the -371AA genotype was associated with a significantly increased risk of squamous cell carcinoma compared to the combined -371GG and GA genotype (adjusted OR = 2.08, 95% CI 1.09-4.00, p = 0.03). The PAT-/+, IVS11-5C-->A and Lys939Gln polymorphisms were associated with a significantly decreased risk of small cell carcinoma (SM) under a dominant model for the polymorphic allele (adjusted OR = 0.49, 95% CI 0.29-0.82, p = 0.006; adjusted OR = 0.60, 95% CI 0.36-1.00, p = 0.05; and adjusted OR = 0.58, 95% CI 0.35-0.97, p = 0.04, respectively). Consistent with genotyping analyses, haplotype 4 (1112222) containing the PAT+/IVS11-5A/939Gln alleles was associated with a significantly decreased risk of SM (adjusted OR = 0.56, 95% CI 0.37-0.85, p = 0.007 and Bonferroni-corrected p = 0.049), whereas haplotype 5 (1122111) containing the -27C allele was associated with a significantly increased risk of SM (adjusted OR = 2.88, 95% CI 1.41-5.87, p = 0.004 and Bonferroni-corrected p = 0.028). These results suggest that XPC polymorphisms/haplotypes may contribute to genetic susceptibility for lung cancer.     

Clinical implications of UGT1A1*28 genotype testing in colorectal cancer patients

BACKGROUND:

Metastatic colorectal cancer is frequently treated with irinotecan, a topoisomerase‐I inhibitor. The UGT1A1 gene encodes for an enzyme that metabolizes irinotecan, and its genetic variants were shown to be associated with increased drug toxicity. We evaluated clinical outcomes associated with the UGT1A1*28 variant.

METHODS:

The study included 329 colorectal cancer patients from the Israeli population‐based Molecular Epidemiology of Colorectal Cancer study who were treated with a chemotherapy regimen that included irinotecan. Patients with metastases or disease recurrence were followed up for a median period of 2 years after occurrence of the event. Study end points were appearance of grade 3‐4 hematological and gastroenterological toxicity, hospitalization due to toxic events (mostly neutropenia, fever, diarrhea, or vomiting), length of hospitalization, and overall survival. UGT1A1*28 was genotyped from peripheral blood DNA by fragment analysis and reported as number of TATA sequence repeats in the promoter of the gene.

RESULTS:

The 7/7 variant of UGT1A1*28 was detected in 11.9% of the 329 participants. Grade 3‐4 hematological toxicity was significantly higher in 7/7 carriers compared with 6/7 and 6/6 carriers (48.0%,10.2%, and 7.7% respectively; P < .001), as was the risk of toxicity‐related hospitalization (45.8%, 25.3%, and 14.4% respectively; P = .001). Both short‐term death within 2 months of treatment start (12.8%, 5.2%, and 2.9%, respectively) and median overall survival (1.6, 2.0, and 2.4 years, respectively; P = .01) were significantly worse in the 7/7 carriers. The age/stage‐adjusted hazard ratio for patients with the 7/7 genotype compared with 6/6 was 1.7 (95% confidence interval, 1.1‐2.3).

CONCLUSIONS:

The UGT1A1*28 7/7 genotype is strongly associated with severe hematological toxicity and higher hospitalization rate and predicts lower survival of colorectal cancer in users of irinotecan. Cancer 2011. © 2011 American Cancer Society.