Genetic Polymorphisms In UGT1A1and Risk Of Breast Cancer

Breast cancer is one of the most prevalent type of cancer in women and isthe main disease in cancer related deaths. Breast cancer is associated withhormones, and the exposure to high levels of endogenous and exogenousestrogens during life has been proven to play an important role incarcinogenesis. Estrogens are associated with proliferation and maturation ofbreast tissue, acting through intracellular receptors that promote the activationof transcription factors, the transcription of mitochondrial DNA and theproduction of secondary messengers such as camp, TGF alpha and EGF.However, it has been recently discovered that the degradation products ofestrogens also have a proliferative action and, in some cases, cause damage toDNA. Genetic variation in genes involved in estrogen synthesis, metabolismand signal transduction have been suggested to play a role. Inherited variationsin genes involved in the metabolism of estrogens, in addition to those ofcarcinogens, are suggested to be associated with an increased risk of breastcancer. This hypothesis was tested in a number of epidemiological studies thathave focused on polymorphisms present in different enzymatic pathwaysincluding cytochrome P450enzymes, catechol-O-methyltransferaseglutathione S-transferases, and N-acetyltransferases. UGTs catalyze theglucuronidation reaction, which represents a major pathway in phase II drugmetabolism. They play a major role in the detoxification of a diverse range ofmolecules, including carcinogens and biologically active endogenouscompounds, such as steroid hormones. UGT1A1have shown glucuronidationactivity for estrogens and their metabolites, catechol estrogens. Mutations ofUGT1A1gene can lead to the estrogen metabolic disorder, which increasesthe risk of breast cancer. The domestic and foreign research proved thatUGT1A1*28was closely related to breast cancer，but the relationshipbetween UGT1A1*6and Chinese women’s breast cancer risk has not been reported in literature.Objective: We investigated the association of UGT1A1*28, UT1A1*6with the risk of breast cancer for guidance in the early diagnosis andprevention of breast cancer.Methods: we enrolled46women with breast cancer as the experimentalgroup,15patients with gastrointestinal cancer and13healthy women as acontrol group in this trial. All of the subjects were Han Chinese and the controlgroup of healthy women without malignant family history. Genomic DNA wasobtained from peripheral blood, using the blood genomic DNA extraction kit.Two pairs of primers was designed according target gene the UGT1A1*28and UGT1A1*6. PCR was performed to amplify the extracted DNA withprimers. PCR products was determined in comparison with external sizemarkers by an automated DNA sequencer and analyzed using the FragmentAnalysis Software. We determined the genotype of sample according to thesequencing peak diagram and sequence. The genotype of sample was dividedinto three types: wild-type, heterozygous mutant, and homozygous mutant.Immunohistochemical staining method was used to stain the pathologicaltissue of patients with breast cancer after operation.Finally, we ascertained relationship between the UGT1A1genepolymorphism and breast cancer risk after the application of statisticalmethods to compare the genotype distribution of breast cancer patients and thecontrol group.Results:1The experimental group and the control group of UGT1A1*28andUGT1A1*6gene frequency distribution1.1UGT1A1*28gene frequency distribution among breast cancer patients:89%(n=41) for the wild-type (*1/*1),11%(n=5) were heterozygousmutant (*1/*28), no homozygous mutant (*28/*28) were found.UGT1A1*6gene frequency distribution among breast cancer patients:67%(n=31) for the wild-type (G/G),26%(n=12) were heterozygous mutant (G/A) and7%(n=3) for the homozygous mutant (A/A). 1.2UGT1A1*28gene frequency distribution among gastrointestinal cancerpatients:87%(n=13) for the wild-type (*1/*1),13%(n=2) wereheterozygous mutant (*1/*28) and no homozygous mutant (*28/*28)were found. UGT1A1*6gene frequency distribution among Gastrointestinalcancer patients:60%(n=9) for the wild type (G/G),40%(n=6) wereheterozygous mutant (G/A) and no homozygous mutant-type (A/A) werefound.1.3UGT1A1*28gene frequency distribution among healthy women:61%(n=8) for the wild-type (*1/*1),39%(n=5) were heterozygous mutant (*1/*28), no homozygous mutant (*28/*28) were found. UGT1A1*6genefrequency distribution among healthy women:100%(n=13) for the wild-type(G/G), heterozygous mutant (G/A) and homozygous mutant (A/A) werenot found.2UGT1A1*28and UGT1A1*6gene frequency distribution comparisonbetween breast cancer patients and normal healthy female: UGT1A1*28genedistribution was no significant difference (χ2=3.679, P=0.055). UGT1A1*6gene distribution was significantly higher than normal women (χ~2=4.095, P=0.043).3UGT1A1*28and UGT1A1*6gene frequency distribution comparisonbetween gastrointestinal cancer patients and normal healthy female: UGT1A1*28gene frequency distribution was no significant difference (P=0.198).UGT1A1*6gene distribution was significantly higher than normal women (P=0.018).4No significant difference was observed between breast cancer patients andgastrointestinal cancer patients for the UGT1A1*28and UGT1A1*6genefrequency distribution (P>0.05).5UGT1A1*6gene frequency distribution of clinically relevant factors5.1UGT1A1*6gene frequency distribution of breast cancer patients was notsignificantly different in different ER, PR and HER-2expression status(P>0.05).5.2UGT1A1*6gene frequency distribution of breast cancer patients was not significantly whether patients in postmenopausal (P>0.05).5.3UGT1A1*6gene frequency distribution of breast cancer patients was notsignificantly in the presence of distant metastasis and primary tumor size(P>0.05).Conclusions:1No significant association was observed with UGT1A1*28allele andbreast cancer.2The UGT1A1*6allele may be associated with an increased risk forbreast cancer among Han Chinese women in Asia. There was no directcorrelation between UGT1A1*6and ER, PR, HER-2expression status,whether menopause, the presence of distant metastasis and primary tumor sizebecause of the relatively small number of cases. Further large sample test isrequired to reveal the relationship.