染色体不稳定性与乳腺癌易感性及预后关系的分子流行病学研究
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摘要
第一部分博莱霉素诱导的突变敏感性与女性乳腺癌危险性关系的病例对照研究
目的：遗传变异和环境因素共同参与了乳腺癌罹患风险的调控,DNA修复能力不足也与患乳腺癌相关。本研究的主要目的是：(1)评估可间接反映DNA修复能力的“突变敏感性”和乳腺癌罹患风险之间的相关性；(2)评估中国女性被动吸烟史与其罹患乳腺癌的风险之间的相关性。
方法：本研究样本由196名中国女性乳腺癌患者(病例组)及211名无癌症家族史的健康对照组成。以博莱霉素作为诱变剂,本研究探讨了博莱霉素突变敏感性与乳腺癌罹患风险之间的关系。通过检测博莱霉素诱导短期体外培养的上述两组个体的外周血淋巴细胞染色体断裂数,估计博莱霉素诱导的个体突变敏感性。通过非参数检验和Fisher确切概率法比较病例对照组间差异性,并采用多因素Logistic回归(调整相关协变量)分析突变敏感性与乳腺癌危险性的关系。
结果：与对照组相比,病例组博莱霉素诱导的平均每细胞染色体断裂数显著增加(0.81vs.0.73,P=0.016)。随着博莱霉素诱导的平均每细胞染色体断裂数增加,乳腺癌的罹患风险增加,校正后的OR值为1.82(95%可信区间：1.00-3.35,P<0.01)。对于绝经前和被动吸烟的女性而言,博莱霉素突变敏感性和乳腺癌罹患风险之间关系更为密切。既有博莱霉素突变敏感性又有被动吸烟史的女性患乳腺癌的风险更大,有被动吸烟史的乳腺癌的罹患风险增加了2.77倍(95%可信区间：1.33-5.80,P<0.01),长期被动吸烟者(>20年)乳腺癌罹患风险增加了5.02倍(95%可信区间：1.99-9.97,P<0.01)。
结论：本研究结果表明,博莱霉素诱导的突变敏感性与中国女性乳腺癌的罹患风险呈正相关,随着博来霉素突变敏感性增加,中国女性患乳腺癌的可能性显著增加。有被动吸烟史也增加了乳腺癌的罹患风险,既有被动吸烟史又有博莱霉素高敏感性的中国女性患乳腺癌的风险更大。
第二部分外周血粒细胞DNA特异性端粒长度与乳腺癌危险性关系的病例对照研究
目的：导致染色体不稳定性的端粒异常在乳腺癌的发生发展中可能具有非常重要的作用,外周血粒细胞端粒缩短作为乳腺癌发生发展过程中的一个事件,可望成为乳腺癌的诊断和预后评价指标之一,但是目前它与肿瘤风险相关性报道结果不尽一致。为此。本研究探讨了乳腺癌外周血中性粒细胞DNA端粒长度与乳腺癌危险性的关系,并分析了其与乳腺癌病理组织学分级,病理分期,激素受体状态的关系。
方法：本研究以213名女性乳腺癌患者及230名无癌症家族史的健康对照为研究对象,采用特殊设计的实时定量PCR技术测定研究对象外周血中性粒细胞染色体DNA端粒长度。Fisher确切概率、多因素Logistic回归和线性趋势性分析评价外周血中性粒细胞DNA端粒长度与乳腺癌危险性的关系。
结果：乳腺癌患者外周血中性粒细胞染色体DNA端粒长度较对照组明显缩短(8.47vs.9.02,P=0.06)。随着端粒的变短,乳腺癌的危险性增大,线性趋势性检验P<0.01。这种端粒缩短的趋势在绝经前妇女中尤为明显(调整OR=1.95,95%CI：1.02-3.73,并且存在显著的剂量-效应关系(调整OR=3.41,95%CI：1.29-9.05,趋势性P<0.01)。乳腺癌病例的端粒长度与病理组织分级以及分期有关。分级高者和分期晚者端粒长度分别低于分级低者和分期早者。在分级高者和分期晚者中,其调整OR分别为1.72(95%CI：1.00-2.96)和1.65(95%CI：1.17-2.57)。而激素受体状态与染色体DNA端粒长度无相关性。
结论：外周血中性粒细胞端粒长度缩短与乳腺癌发生风险密切正相关,而且与肿瘤的临床病理特征,如肿瘤的分化程度、肿瘤分期等密切相关,它可能是反映乳腺癌发生及预后相关的生物标志物之一。
第三部分乳腺癌组织特异性端粒长度、肿瘤细胞端粒衰减与乳腺癌危险因素与预后因素的关系研究
目的：端粒长度的维护在乳腺癌发生发展中起着重要的作用,端粒缩短见于乳腺癌前病变由导管增生到导管原位癌转化过程的细胞中。端粒长度的检测不仅作为重要的肿瘤发生生物标记,而且可以作为重要的临床预后指标。本研究检测了213例原发性乳腺癌病例组织中多种类型的细胞的端粒长度,通过对不同类型细胞端粒长度进行比较,探讨端粒长度与乳腺癌已知危险因素和预后因素的关系,为寻找可靠的乳腺癌生物标记来判断预后提供依据。
方法：采用改进的端粒特异性定量荧光原位杂交技术,以及数字化端粒荧光信号的定量用软件ImageJ。检测219例原发性乳腺癌病例组中,213例收集到明确的临床病理资料和完整病理切片病例的多种类型细胞端粒长度。
结果：乳腺癌细胞平均相对端粒长度(0.54±0.43)显著低于肿瘤浸润淋巴细胞(1.344±0.96,P<0.001)和邻近正常上皮细胞(0.88±0.56,P<0.001)。肿瘤相对端粒长度(端粒衰减)与乳腺癌相关危险因素的关系分析显示有主动吸烟史、长期饮酒者、无女性乳腺癌家族史病例与端粒衰减危险性有关,OR (95%CI)分别为1.83(0.52-6.11),1.02(0.39-2.48)和1.23(0.26-5.43),但无统计学意义。端粒衰减与乳腺癌临床病理特征关系分析结果显示,肿瘤大于1.5厘米病例的肿瘤相对端粒长度(0.43+0.41)显著低于肿瘤小于1.5厘米者(0.56±0.34,P=0.019)。肿瘤分期为Ⅲ和Ⅳ期病例的肿瘤相对端粒长度(0.45±0.52)显著低于肿瘤分期为Ⅰ和Ⅱ期者(0.59±0.56,P=0.05)。肿瘤组织分级为Ⅲ级者的肿瘤相对端粒长度(0.39±0.52)显著低于肿瘤分级为Ⅰ和Ⅱ级者(0.48±0.57,P=0.043)。多因素Logistic回归分析显示端粒衰减与肿瘤大小、肿瘤分期以及肿癌分级显著相关,调整后的OR值(95%CI)分别为1.71(1.12-2.79),1.97(1.06-3.25)和2.06(1.17-3.45)。而肿瘤端粒衰减与肿瘤组织学类型、ER和PR状态的未见具有统计学意义的相关性。
结论：肿瘤细胞端粒长度显著短于肿瘤基质细胞和周围正常上皮细胞。肿瘤细胞端粒缩短与肿瘤大小,肿瘤分期,病理组织学分级显著相关。较大肿瘤、高分级和高分期者肿瘤端粒衰减程度增大。肿瘤组织端粒长度以及端粒衰减有望作为乳腺癌预后因素的生物学标记物之一。
Part1The Association Between Bleomycin-induced Mutagen Sensitivity and the Risk of Breast Cancer:A Case-Control Study
Objective It is well recognized that genetic variation as well as environmental factors modulate breast cancer risk. Deficiencies in DNA repair capacity are thought to associate with breast cancer risk. The main aim of this study was to use the mutagen sensitivity assay (MSA) as an indirect measure of DNA repair capacity to assess breast cancer risk, and the relationship between passive smoking and breast cancer risk among women in China.
Methods We carried out a case-control study, involving196Chinese patients with breast cancer and211controls without the disease and with no history of cancer. We investigated the association between mutagen sensitivity and breast cancer risk using bleomycin as the mutagen. Mutagen sensitivity was measured by quantifying the chromatid breaks induced by mutagens in short-term cultures of peripheral blood lymphocytes. Non-parametric tests and the Fisher's exact test were used to determine the statistical significance of the crude case-control comparisons, followed by logistic regression to adjust for important covariates.
Results The mean number of bleomycin-induced breaks per cell was0.81for cases compared with0.73for the controls (P=0.016). A greater number of bleomycin-induced chromosomal breaks per cell was associated with an increased risk of breast cancer (adjusted odds ratio of1.82, P trend <0.01). The association between bleomycin sensitivity and breast cancer risk was greater for women who were premenopausal and exposed to tobacco smoke (passive smokers). The combination of bleomycin sensitivity and exposure to tobacco smoke increased risk further; women passive smokers with high sensitivity to bleomycin had a2.77-fold increased risk of breast cancer. Of these women, those who were exposed to tobacco smoke for>20hour-year had a5.02-fold increased risk of breast cancer.
Conclusions Our data indicate that increased bleomycin-induced mutagen sensitivity is significantly associated with an increased risk of breast cancer among Chinese women. Exposure to passive smoke is also associated with increased breast cancer risk, and the correlation is even greater for women with both longer passive exposure to tobacco smoke and high sensitivity to bleomycin.
Part2The case-control study of relationship between telomere length from blood cells and the risk of breat cancer
Objective Telomere dysfunction, which leads to genomic instability, maybe played an important role in the development of breast cancer. Although the telomere in tumors was considered to be a potential promising biomarker for early diagnosis and indicator for prognostic judgment in breast cancer, current results in the research of the peripheral leukocyte telomere length are not consistent in breast cancer risk assessment. Thus, we examined telomere length in peripheral leukocyte DNA in breasts cancer patients and explore the association among telomere length and breast cancer risk as well as clinicopathological features such as tumor stage, grade of differential status.
Method In this case-control study of breast cancer conducted in a Chinese population, we measured telomere length of peripheral leukocyte DNA in213breast cancer cases and230age-matched controls using telomere specific quantitative real-time PCR. The Fisher's exact test, multivariate Logstic regression and linear trend test were used to analysis the association between telomere length and breast cancer risk.
Result It is showen that shorter telomere length in breast cancer cases (mean telomere length,8.47Kb) when compared with controls (9.02Kb; P=0.06). With the telomere length became shorter, the breast cancer risk increased (P for trend <0.01). Especially in premenopausal women, the adjusted OR was1.95(95%CI:1.02-3.73). There also showed a dose-dependent (adjusted OR was3.41,95%CI:1.29-9.05, P for treand<0.01). There is an association between telomere length and clinicopathological features such as tumor stage, grade of differential status. The letomere length in advanced TNM stage and higher tumor grade were shorter than those in earlier TNM stage and lower tumor grade respectively. Among advanced TNM stage and higher tumor grade, their adjusted OR was1.72(95%CI:1.00-2.96) and1.65(95%CI:1.17-2.57), respectively. Our data does not show that telomere length change in peripheral leukocyte DNA was associated with hormone receptors status.
Conclusion Our results suggest that telomere length in peripheral leukocyte DNA was associated with breast cancer risk. Shortened telomeres not only increased breast cancer risk in Chinese women, but also are closely associated with clinicopathological features such as tumor stage, grade of differential status in cases. The peripheral leukocyte telomere length shorten could be an important screening marker for early diagnosis and indicator for prognosis in breast cancer.
Part3The study of the relationship among telomere length, telomere attrition from tumor tissue and the risk and prognosis in breast cancer
Objective Maintenance of telomere length is critical in tumorigenesis of breast cancer. Shortness of telomere attrition is frequently presented in the process of pre-cancer development of breast cancer from ductal hyperplasia to carcinoma in situ. Examination of telomere length can be used as bio-marker of tumorigenesis and provide pivotal prognostics in clinic. In this study, telomere length of multiple cell types from primary breast cancer samples of213from219patients, which were have clinicopathological data and tumor tissue slides, were examined and telomere length of different cell type was analyzed to correlate them with breast cancer risk factors and prognosis. Therefore, this study will provide evidence to finding reliable bio-markers for clinical prognosis.
Methods A modified protocol for quantitative telomere-specific fluorescent-in-situ-hybridization (FISH) was used in this study. Image J was employed to quantify the data. Telomere length of multiple cell types from primary breast cancer samples of213patients was examined.213of219samples have complete clinical pathology data as well as slides.
Results The average telomere attrition of tumor cells (0.54±0.43) is significantly shorter than that of tumor infiltrated lymphatic cells (1.34±0.96, P<0.001) and adjacent normal epithelial cells (0.88±0.56, P<0.001). The correlation analysis of tumor relative telomere length and breast cancer risk factors suggests that active smoker, long-term drinker, and females with no family history of breast cancer are highly related to the shortness of telomere. OR scores (95%CI) are1.83(0.52-6.11),1.02(0.39-2.48), and1.23(0.26-5.43), respectively. There is no statistically significant difference.The relationship between telomere attrition of tumor cells and breast cancer clinical pathological characteristics:telomere attrition of tumors larger than1.5cm (0.43±0.41) is significantly shorter than that of tumors smaller than1.5cm (0.56±0.34, P=0.019). Telomere attrition of tumors at stage Ⅲ and Ⅳ (0.45±0.52) is significantly shorter than that of tumors at stage I and II (0.59±0.56, P=0.05). Telomere attrition of tumors graded as Ⅲ (0.39±0.52) is significantly shorter than that of tumors graded as Ⅰ and Ⅱ (0.48±0.57, P=0.043). Logistic analysis shows that telomere attrition of tumor cells is closely related to tumor size, clinical tumor stage, and pathological tumor grade. The adjusted OR (95%CI) are1.71(1.12-2.79),1.97(1.06-3.25), and2.06(1.17-3.45), respectively. There is no significant correlation between telomere attrition of tumor cells and tumor histology type, ER and PR status.
Conclusions The telomere attrition of tumor cells is significantly shorter than that of tumor stroma cells and adjacent normal epithelial cells. It is closely related to the size, clinical stage, and pathological grade of tumors. Tumors have large size, higher clinical stage, and pathological grade tend to have shorter telomeres. Both telomere length and telomere attrition are potential bio-markers for breast cancer prognosis.
目的：遗传变异和环境因素共同参与了乳腺癌罹患风险的调控,DNA修复能力不足也与患乳腺癌相关。本研究的主要目的是：(1)评估可间接反映DNA修复能力的“突变敏感性”和乳腺癌罹患风险之间的相关性；(2)评估中国女性被动吸烟史与其罹患乳腺癌的风险之间的相关性。
方法：本研究样本由196名中国女性乳腺癌患者(病例组)及211名无癌症家族史的健康对照组成。以博莱霉素作为诱变剂,本研究探讨了博莱霉素突变敏感性与乳腺癌罹患风险之间的关系。通过检测博莱霉素诱导短期体外培养的上述两组个体的外周血淋巴细胞染色体断裂数,估计博莱霉素诱导的个体突变敏感性。通过非参数检验和Fisher确切概率法比较病例对照组间差异性,并采用多因素Logistic回归(调整相关协变量)分析突变敏感性与乳腺癌危险性的关系。
结果：与对照组相比,病例组博莱霉素诱导的平均每细胞染色体断裂数显著增加(0.81vs.0.73,P=0.016)。随着博莱霉素诱导的平均每细胞染色体断裂数增加,乳腺癌的罹患风险增加,校正后的OR值为1.82(95%可信区间：1.00-3.35,P<0.01)。对于绝经前和被动吸烟的女性而言,博莱霉素突变敏感性和乳腺癌罹患风险之间关系更为密切。既有博莱霉素突变敏感性又有被动吸烟史的女性患乳腺癌的风险更大,有被动吸烟史的乳腺癌的罹患风险增加了2.77倍(95%可信区间：1.33-5.80,P<0.01),长期被动吸烟者(>20年)乳腺癌罹患风险增加了5.02倍(95%可信区间：1.99-9.97,P<0.01)。
结论：本研究结果表明,博莱霉素诱导的突变敏感性与中国女性乳腺癌的罹患风险呈正相关,随着博来霉素突变敏感性增加,中国女性患乳腺癌的可能性显著增加。有被动吸烟史也增加了乳腺癌的罹患风险,既有被动吸烟史又有博莱霉素高敏感性的中国女性患乳腺癌的风险更大。
第二部分外周血粒细胞DNA特异性端粒长度与乳腺癌危险性关系的病例对照研究
目的：导致染色体不稳定性的端粒异常在乳腺癌的发生发展中可能具有非常重要的作用,外周血粒细胞端粒缩短作为乳腺癌发生发展过程中的一个事件,可望成为乳腺癌的诊断和预后评价指标之一,但是目前它与肿瘤风险相关性报道结果不尽一致。为此。本研究探讨了乳腺癌外周血中性粒细胞DNA端粒长度与乳腺癌危险性的关系,并分析了其与乳腺癌病理组织学分级,病理分期,激素受体状态的关系。
方法：本研究以213名女性乳腺癌患者及230名无癌症家族史的健康对照为研究对象,采用特殊设计的实时定量PCR技术测定研究对象外周血中性粒细胞染色体DNA端粒长度。Fisher确切概率、多因素Logistic回归和线性趋势性分析评价外周血中性粒细胞DNA端粒长度与乳腺癌危险性的关系。
结果：乳腺癌患者外周血中性粒细胞染色体DNA端粒长度较对照组明显缩短(8.47vs.9.02,P=0.06)。随着端粒的变短,乳腺癌的危险性增大,线性趋势性检验P<0.01。这种端粒缩短的趋势在绝经前妇女中尤为明显(调整OR=1.95,95%CI：1.02-3.73,并且存在显著的剂量-效应关系(调整OR=3.41,95%CI：1.29-9.05,趋势性P<0.01)。乳腺癌病例的端粒长度与病理组织分级以及分期有关。分级高者和分期晚者端粒长度分别低于分级低者和分期早者。在分级高者和分期晚者中,其调整OR分别为1.72(95%CI：1.00-2.96)和1.65(95%CI：1.17-2.57)。而激素受体状态与染色体DNA端粒长度无相关性。
结论：外周血中性粒细胞端粒长度缩短与乳腺癌发生风险密切正相关,而且与肿瘤的临床病理特征,如肿瘤的分化程度、肿瘤分期等密切相关,它可能是反映乳腺癌发生及预后相关的生物标志物之一。
第三部分乳腺癌组织特异性端粒长度、肿瘤细胞端粒衰减与乳腺癌危险因素与预后因素的关系研究
目的：端粒长度的维护在乳腺癌发生发展中起着重要的作用,端粒缩短见于乳腺癌前病变由导管增生到导管原位癌转化过程的细胞中。端粒长度的检测不仅作为重要的肿瘤发生生物标记,而且可以作为重要的临床预后指标。本研究检测了213例原发性乳腺癌病例组织中多种类型的细胞的端粒长度,通过对不同类型细胞端粒长度进行比较,探讨端粒长度与乳腺癌已知危险因素和预后因素的关系,为寻找可靠的乳腺癌生物标记来判断预后提供依据。
方法：采用改进的端粒特异性定量荧光原位杂交技术,以及数字化端粒荧光信号的定量用软件ImageJ。检测219例原发性乳腺癌病例组中,213例收集到明确的临床病理资料和完整病理切片病例的多种类型细胞端粒长度。
结果：乳腺癌细胞平均相对端粒长度(0.54±0.43)显著低于肿瘤浸润淋巴细胞(1.344±0.96,P<0.001)和邻近正常上皮细胞(0.88±0.56,P<0.001)。肿瘤相对端粒长度(端粒衰减)与乳腺癌相关危险因素的关系分析显示有主动吸烟史、长期饮酒者、无女性乳腺癌家族史病例与端粒衰减危险性有关,OR (95%CI)分别为1.83(0.52-6.11),1.02(0.39-2.48)和1.23(0.26-5.43),但无统计学意义。端粒衰减与乳腺癌临床病理特征关系分析结果显示,肿瘤大于1.5厘米病例的肿瘤相对端粒长度(0.43+0.41)显著低于肿瘤小于1.5厘米者(0.56±0.34,P=0.019)。肿瘤分期为Ⅲ和Ⅳ期病例的肿瘤相对端粒长度(0.45±0.52)显著低于肿瘤分期为Ⅰ和Ⅱ期者(0.59±0.56,P=0.05)。肿瘤组织分级为Ⅲ级者的肿瘤相对端粒长度(0.39±0.52)显著低于肿瘤分级为Ⅰ和Ⅱ级者(0.48±0.57,P=0.043)。多因素Logistic回归分析显示端粒衰减与肿瘤大小、肿瘤分期以及肿癌分级显著相关,调整后的OR值(95%CI)分别为1.71(1.12-2.79),1.97(1.06-3.25)和2.06(1.17-3.45)。而肿瘤端粒衰减与肿瘤组织学类型、ER和PR状态的未见具有统计学意义的相关性。
结论：肿瘤细胞端粒长度显著短于肿瘤基质细胞和周围正常上皮细胞。肿瘤细胞端粒缩短与肿瘤大小,肿瘤分期,病理组织学分级显著相关。较大肿瘤、高分级和高分期者肿瘤端粒衰减程度增大。肿瘤组织端粒长度以及端粒衰减有望作为乳腺癌预后因素的生物学标记物之一。
Part1The Association Between Bleomycin-induced Mutagen Sensitivity and the Risk of Breast Cancer:A Case-Control Study
Objective It is well recognized that genetic variation as well as environmental factors modulate breast cancer risk. Deficiencies in DNA repair capacity are thought to associate with breast cancer risk. The main aim of this study was to use the mutagen sensitivity assay (MSA) as an indirect measure of DNA repair capacity to assess breast cancer risk, and the relationship between passive smoking and breast cancer risk among women in China.
Methods We carried out a case-control study, involving196Chinese patients with breast cancer and211controls without the disease and with no history of cancer. We investigated the association between mutagen sensitivity and breast cancer risk using bleomycin as the mutagen. Mutagen sensitivity was measured by quantifying the chromatid breaks induced by mutagens in short-term cultures of peripheral blood lymphocytes. Non-parametric tests and the Fisher's exact test were used to determine the statistical significance of the crude case-control comparisons, followed by logistic regression to adjust for important covariates.
Results The mean number of bleomycin-induced breaks per cell was0.81for cases compared with0.73for the controls (P=0.016). A greater number of bleomycin-induced chromosomal breaks per cell was associated with an increased risk of breast cancer (adjusted odds ratio of1.82, P trend <0.01). The association between bleomycin sensitivity and breast cancer risk was greater for women who were premenopausal and exposed to tobacco smoke (passive smokers). The combination of bleomycin sensitivity and exposure to tobacco smoke increased risk further; women passive smokers with high sensitivity to bleomycin had a2.77-fold increased risk of breast cancer. Of these women, those who were exposed to tobacco smoke for>20hour-year had a5.02-fold increased risk of breast cancer.
Conclusions Our data indicate that increased bleomycin-induced mutagen sensitivity is significantly associated with an increased risk of breast cancer among Chinese women. Exposure to passive smoke is also associated with increased breast cancer risk, and the correlation is even greater for women with both longer passive exposure to tobacco smoke and high sensitivity to bleomycin.
Part2The case-control study of relationship between telomere length from blood cells and the risk of breat cancer
Objective Telomere dysfunction, which leads to genomic instability, maybe played an important role in the development of breast cancer. Although the telomere in tumors was considered to be a potential promising biomarker for early diagnosis and indicator for prognostic judgment in breast cancer, current results in the research of the peripheral leukocyte telomere length are not consistent in breast cancer risk assessment. Thus, we examined telomere length in peripheral leukocyte DNA in breasts cancer patients and explore the association among telomere length and breast cancer risk as well as clinicopathological features such as tumor stage, grade of differential status.
Method In this case-control study of breast cancer conducted in a Chinese population, we measured telomere length of peripheral leukocyte DNA in213breast cancer cases and230age-matched controls using telomere specific quantitative real-time PCR. The Fisher's exact test, multivariate Logstic regression and linear trend test were used to analysis the association between telomere length and breast cancer risk.
Result It is showen that shorter telomere length in breast cancer cases (mean telomere length,8.47Kb) when compared with controls (9.02Kb; P=0.06). With the telomere length became shorter, the breast cancer risk increased (P for trend <0.01). Especially in premenopausal women, the adjusted OR was1.95(95%CI:1.02-3.73). There also showed a dose-dependent (adjusted OR was3.41,95%CI:1.29-9.05, P for treand<0.01). There is an association between telomere length and clinicopathological features such as tumor stage, grade of differential status. The letomere length in advanced TNM stage and higher tumor grade were shorter than those in earlier TNM stage and lower tumor grade respectively. Among advanced TNM stage and higher tumor grade, their adjusted OR was1.72(95%CI:1.00-2.96) and1.65(95%CI:1.17-2.57), respectively. Our data does not show that telomere length change in peripheral leukocyte DNA was associated with hormone receptors status.
Conclusion Our results suggest that telomere length in peripheral leukocyte DNA was associated with breast cancer risk. Shortened telomeres not only increased breast cancer risk in Chinese women, but also are closely associated with clinicopathological features such as tumor stage, grade of differential status in cases. The peripheral leukocyte telomere length shorten could be an important screening marker for early diagnosis and indicator for prognosis in breast cancer.
Part3The study of the relationship among telomere length, telomere attrition from tumor tissue and the risk and prognosis in breast cancer
Objective Maintenance of telomere length is critical in tumorigenesis of breast cancer. Shortness of telomere attrition is frequently presented in the process of pre-cancer development of breast cancer from ductal hyperplasia to carcinoma in situ. Examination of telomere length can be used as bio-marker of tumorigenesis and provide pivotal prognostics in clinic. In this study, telomere length of multiple cell types from primary breast cancer samples of213from219patients, which were have clinicopathological data and tumor tissue slides, were examined and telomere length of different cell type was analyzed to correlate them with breast cancer risk factors and prognosis. Therefore, this study will provide evidence to finding reliable bio-markers for clinical prognosis.
Methods A modified protocol for quantitative telomere-specific fluorescent-in-situ-hybridization (FISH) was used in this study. Image J was employed to quantify the data. Telomere length of multiple cell types from primary breast cancer samples of213patients was examined.213of219samples have complete clinical pathology data as well as slides.
Results The average telomere attrition of tumor cells (0.54±0.43) is significantly shorter than that of tumor infiltrated lymphatic cells (1.34±0.96, P<0.001) and adjacent normal epithelial cells (0.88±0.56, P<0.001). The correlation analysis of tumor relative telomere length and breast cancer risk factors suggests that active smoker, long-term drinker, and females with no family history of breast cancer are highly related to the shortness of telomere. OR scores (95%CI) are1.83(0.52-6.11),1.02(0.39-2.48), and1.23(0.26-5.43), respectively. There is no statistically significant difference.The relationship between telomere attrition of tumor cells and breast cancer clinical pathological characteristics:telomere attrition of tumors larger than1.5cm (0.43±0.41) is significantly shorter than that of tumors smaller than1.5cm (0.56±0.34, P=0.019). Telomere attrition of tumors at stage Ⅲ and Ⅳ (0.45±0.52) is significantly shorter than that of tumors at stage I and II (0.59±0.56, P=0.05). Telomere attrition of tumors graded as Ⅲ (0.39±0.52) is significantly shorter than that of tumors graded as Ⅰ and Ⅱ (0.48±0.57, P=0.043). Logistic analysis shows that telomere attrition of tumor cells is closely related to tumor size, clinical tumor stage, and pathological tumor grade. The adjusted OR (95%CI) are1.71(1.12-2.79),1.97(1.06-3.25), and2.06(1.17-3.45), respectively. There is no significant correlation between telomere attrition of tumor cells and tumor histology type, ER and PR status.
Conclusions The telomere attrition of tumor cells is significantly shorter than that of tumor stroma cells and adjacent normal epithelial cells. It is closely related to the size, clinical stage, and pathological grade of tumors. Tumors have large size, higher clinical stage, and pathological grade tend to have shorter telomeres. Both telomere length and telomere attrition are potential bio-markers for breast cancer prognosis.
引文
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