| Background and Objection:Breast cancer is one of the most common cancers among women. Compared with western countries, China has lower incidence of breast cancer. With the development of industry and the change of lifestyle, however, the incidence of Breast cancer in China is increasing, and patients with breast cancer are being much younger now than in the past. According to the investigation in 2005, the incidence of breast cancer in cities of China has been ranked as 1st. Moreover, the incidence of breast cancer among Chinese women is expected to reach 85.3/100,000 in 2021. Therefore, taking effective measures to control the incidence of breast cancer is becoming more and more important in our country. It is necessary for us to screen out high risk population by some efficient assessment based on the risk factors of breast cancer to facilitate the individualized treatment and the first-grade prevention.As we know, the development of breast cancer is a complicated process with interactions of multiple factors and stages. Its associated risk factors can be divided into two groups, endogenous and exogenous, in term of their sources, characteristics and functional ways. Endogenous factors mainly include the immune status, genetic background, the level of hormone and so on. Of these factors, different genetic background could explain, to a certain extent, that not all of women suffered from breast cancer when they live in the same environment. A lot of susceptibility genes that are closely associated with various cancers have been found so far. Except well-known breast cancer genes, BRCA1 and 2, other genes, such as HER-2/neu,CyclinDl,COX,FGFR-2, have been identified as breast cancer susceptibility genes. In addition, another important reason for the development of breast cancer is single nucleotide polymorphism (SNP) which is the third generation of genetic marker following RFLP, SSCP, and defined as base changes (transition, transversion, insertion and deletion) in gene sequence with a higher density of once every 300-1000 bases. Additionally, a large amount of studies have found that SNP is a crucial genetic basis for individual differences in many biological traits such as disease susceptibility and drug sensitivity etc. Therefore, the studies based on SNPs will provide theoretical evidences and data bases for individualized medicine including disease diagnosis, treatment and precaution. Exogenous factors also have close relationship with environment and lifestyle. At present, it is admitted that exogenous risk factors of breast cancer involve breast feeding history, oral contraceptive, living environment, diet, etc.In some western countries with high incidence of breast cancer, more and more breast cancer risk assessment tools have been built based on these risk factors mentioned above. In America, for example, the first breast cancer risk assessment tool-Gail Model was developed in 1898, and then BRCAPRO Model, Claus Model, Tyrer-Cuzick Model, BOADICE Model, and some online assessment tools appeared gradually. In some Asian countries, Japan and Korea, for examples, have built appropriate breast cancer risk assessment tools as well. However, China is still in the stage of exploration. Besides, it is fortunate that more and more people are turning their eyes on the use of breast cancer susceptive SNPs for population risk prediction and subsequently this kind of detection has its own market recently. Therefore, there is no doubt that an ideal assessment tool will be beneficial for us to find high risk individuals earlier and make reasonable strategy to use medical resource.With the incidence of breast cancer is increasing recently in our country, it is necessary and vital to develop a breast cancer assessment model fit to Chinese women, which will be useful for screening high risk population and taking more reasonable measures to control breast cancer. Currently, we are still in the exploratory stage in this matter, and related studies and SNP data are limited compared to foreign countries.In the present study, we collected and analyzed two parts data; one is from the validation of SNPs that were picked out from other genome-wide association studies and related studies with a large amount of samples, and another is from the Meta-analysis of common breast cancer risk factors, so as to lay a foundation for the next stage study building breast cancer assessment model.Methods:Chapter 1 Screening the breast cancer susceptive SNPs1. Collection of study subjects Blood samples from Breast cancer female patients and healthy females were collected according to case-control design. Meanwhile, clinical data were organized2. Selection of SNPs SNPs were picked out from some published genome-wide association studies and studies with a large amount of samples.3. Detection and analysis of SNPs Genotyping of SNPs were performed for all blood samples on Sequenom MassARRAY-IPLEX platform. Statistical analysis was done with SPSS13.0.Chapter 2 Meta-analysis on breast cancer risk factors in Chinese women1. Collection of related papers Related papers published from 2000 to 2010 were collected according to certain picking principles and searching strategies.2. Extraction and analysis of data Data were extracted from the collected papers and subsequent Meta analysis was made via Stata11.0.ResultsChapter 1 Screening the breast cancer susceptive SNPs31 SNPs were picked out at last. After the test and statistical analysis of these SNPs in Chinese Han women, we found that, of all SNPs, three (rs999737, rs10995190, rs7895767) had no polymorphism, Six show statistically significant;.1) rs2046210 is fit in dominant genetic model. Compared with CC genotype, CT-TT genotype is risk genotype with 1.602 of OR (95%CI:1.206-2.127, P=0.001); 2) rs3757318 is fit in dominant genetic model. Compared with AA genotype, AG-GG genotype is risk genotype with 3.082 of OR (95%CI:2.273-4.181, P＜0.0001) 3) rs2981579 is fit in dominant genetic model. Compared with CC genotype, CT-TT genotype is risk genotype with 1.374 of OR (95%CI:1.017-1.855, P=0.038); 4) rs16886165 is fit in recessive genetic model. Compared with TT-TG genotype, GG genotype is risk genotype with 1.573of OR (95%CI:1.069-2.315, P=0.022); 5) rs4784227 is fit in dominant genetic model. Compared with CC genotype, CT-TT genotype is risk genotype with 1.519 of OR (95%CI:1.160-1.990, P=0.002); 6) rs8051542 is fit in dominant genetic model. Compared with CC genotype, CT-TT genotype is risk genotype with 1.352 of OR (95%CI:1.015-1.800, P=0.039). The result of cumulative risk calculation shows that the OR value and 95% CI in individuals with 3,4, and more than 5 risk genotypes are 1.933(1.322-2.862, P=0.001),1.881(1.244-2.864, P=0.003),3.313(2.094-5.242, P＜0.0001) respectively, compared with individuals carried with 2 risk genotypes.Chapter 2 Meta-analysis on breast cancer risk factors in Chinese women27 studies were enrolled in our Meta-analysis in which 8 well-known breast cancer risk factors were chosen and used. Of these factors, six have statistically significant associations with breast cancer.1) the combined OR for the age at menarche<13y is 1.461 (95%CI:1.254-1.730); 2) the combined OR for having breast cancer family history is 2.252 (95%CI:1.792-2.829) 3) the combined OR for no breast feeding history is 1.440 (95%CI:1.182-1.756); 4) the combined OR for age at menopause≥50y is 1.272 (95%CI:1.075-1.506); 5) the combined OR for having benign breast disease history is 2.404 (95%CI:1.636-3.533); 6) the combined OR for age at fist live birth>30y is 1.420 (95%CI:1.291-1.562). Two have no statistically significant associations with breast cancer; 1) the combined OR for having oral contraceptive is 1.038 (95%CI:0.881-1.224); 2) the combined OR for birth number<2is 0.924 (95%CI:0.693-1.243).Conclusion31 SNPs were picked out at last. Six of these SNPs were validated as susceptive SNPs possibly associated breast cancer in Han Chinese women. The risk of breast cancer was significantly increased with increasing number of risk genotypes. In Meta-analysis on the common risk factors of breast cancer, we found that six risk factor-were statistically significant; they were age at menarche<13y, breast cancer family history, no breast feeding history, age at menopause≥50y, benign breast disease history, fist live birth≥30y. Other two risk factors, oral contraceptive and birth number<2, were not statistically significant in the Meta-analysis. Our results lay a good foundation for the preliminary study on breast cancer assessment model for Chinese women. |
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