Prohibitin 3'-UTR 基因多态性与粤东乳腺癌发病风险的研究

目的： 探讨Prohibitin (PHB) 3'-非翻译区 (untranslated region,UTR)基因多态性与粤东汉族女性乳腺癌易感性的关系。方法：采用病例-对照研究,收集231例乳腺癌患者和169例健康对照,提取血液基因组DNA,利用高分辨率熔解曲线 (high resolution melting,HRM)法对PHB基因单核苷酸多态性位点rs1049620、rs9893420、rs4987083进行基因分型,并对检测结果进行非条件Logistic回归分析和χ2检验。结果：PHB基因rs9893420和rs4987083位点在病例组和对照组人群均表现为单一基因型,rs1049620三种基因型G/G、A/G、A/A在病例组和对照组间分布差异均无统计学意义(P>0.05),在不同组织病理学分型和不同激素受体表达病例中分布差异亦无统计学意义(P>0.05)。结论：未发现PHB基因3'-UTR SNP与粤东汉族女性乳腺癌易感性存在关联。     

CRY1基因单核苷酸多态性与乳腺癌风险的关联研究

背景与目的:隐花色素-1(cryptochrome-1,CRY1)基因属于生物钟基因家族,它最早在植物体内发现,是生物钟基因负反馈环的主要部分.近年来生物钟基因多态性与乳腺癌易感性的关系引起国内外研究者的广泛关注,本研究探讨生物钟基因CRY1的单核苷酸多态性与乳腺癌易感性的关系.方法:采用TaqMan 单核苷酸多态性分型技术检测1 523例中国汉族女性乳腺癌患者和1 599名正常女性对照者CRY1基因rs1056560位点的基因型,采用SPSS 16.0软件进行数据处理.结果:CRY1基因rs1056560位点三种基因型(TT/GT/GG)在乳腺癌患者和对照间的分布差异具有显著性(x2=6.394,P=0.041),与TT基因型相比,GT基因型可以显著降低乳腺癌的发病风险(OR=0.743,95%CI:0.580～0.951),携带至少一个G等位基因(GT/GG)的个体乳腺癌风险降低23.2%(OR=0.768,95%CI:0.606～0.971).分层分析后发现,rs1056560 T＞G保护作用在绝经后妇女、初潮≥13岁、初孕≥25岁、无肿瘤家族史者、无乳腺良性病史及流产0～1次妇女中尤为显著.结论:CRY1基因rs1056560 T＞G单核苷酸多态性与中国人群乳腺癌的发病风险相关,这一结论有待于不同种族人群的关联研究以及功能学研究的进一步证实.     

与乳腺癌发病风险相关的基因多态性研究进展

据统计,全球每年约有120万～140万妇女患乳腺癌,约有50万患者死于该病.近年来,我国妇女乳腺癌的发病率呈逐年上升趋势,且年轻化趋势越来越明显,已经严重威胁妇女的身心健康.     

PTEN基因单核苷酸多态性与乳腺癌的关系

目的:研究PTEN基因-9C/G单核苷酸多态性与中国汉族女性人群乳腺癌之间的相关性。方法:采用基于人群的病例-对照研究,以聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法进行基因分型,检测210例中国汉族女性乳腺癌患者和210例健康女性的PTEN基因-9C/G多态性。结果:PTEN基因-9C/G位点(rs11202592)多态性基因型分布频率在两组间比较无显著性差异(P=0.862)。PTEN基因-9C/G单核甘酸多态性不同基因型间在ER、Her-2表达上无显著性差异(P>0.05)。结论:PTEN基因-9C/G位点多态性与中国汉族女性乳腺癌易感性无明显关联,ER、HER-2表达同此位点多态性也无明显关联。     

FGFR2基因多态性与乳腺癌的相关性研究

目的:探讨成纤维细胞生长因子受体2基因(FGFR2)第二内含子单核苷酸多态性在女性群体中的频率分布及其与女性乳腺癌易感性之间的相关性.方法:运用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法结合琼脂糖凝胶电泳技术,对106例女性乳腺癌患者(乳腺癌组)和116例正常女性(对照组)对照进行检测,分析两组贵州地区人群FGFR2基因第二内含子的两个单核苷酸多态性位点rs2420946和rs2981579的基因及基因型的分布情况.结果:乳腺癌组FGFR2基因单核苷酸多态性位点rs2420946的基因型(AA,AG.CG)频率分别为15.09%、48.11%、36.79%,对照组为18.10%、43.97%、37.93%;乳腺癌组与对照组A等位基因频率分别为39.15%和40.09%,G等位基因频率分别为60.85%和59.91%;两组人群分别进行比较,基因型及等位基因频率分布的差异均无统计学意义(P>0.05);FGFR2基因rs2981579的基因型(CC,CT,TT)频率在乳腺癌组分别为30.19%、45.28%、24.53%,对照组为27.59%、48.28%、24.14%;乳腺癌组与对照组c等位基因频率分别为52.83%和51.72%,T等位基因频率分别为47.17%和48.28%;两组人群分别进行比较,基因型频率与等位基因频率分布的差异均无统计学意义(P>0.05).结论:FGFR2基因第二内含子的两个单核苷酸多态性位点rs2420946及rs2981579在乳腺癌及对照人群中基因型频率与等位基因频率分布差异均无统计学意义,提示两个位点的多态性与乳腺癌无明显相关性.     

缺氧诱导因子2α基因多态性与乳腺癌相关性

摘 要：［目的］探讨缺氧诱导因子2α（HIF-2α）基因多态性与乳腺癌的关系。［方法］ 研究入组2019年1月至 2022年1月间在青海省肿瘤医院乳腺科就诊的258例乳腺癌患者和270名健康女性（对照组）,研究对象检测4个HIF-2α单核苷酸多态性（rs12619696、rs13419896、rs2881504和rs4953354）,分析HIF-2α多态 性与乳腺癌易感性之间的关联。使用Kaplan-Meier分析分析来自癌症基因组图谱（TCGA）数据库的1 376个乳腺癌样本的总体生存率。［结果］ 免疫组织化学染色显示,乳腺肿瘤组织标本中的HIF-2α表达高于癌旁组织标本（P<0.05）。TCGA数据集分析显示,HIF-2α高表达乳腺癌患者的总体生存率较低表达显著性降低（P<0.05）。具有CT基因型的HIF-2α rs13419896者患乳腺癌可能性是TT纯合子的2.20倍（AOR=2.20, 95%CI：1.70~2.85,P<0.05）。具有HIF-2α rs4953354多态性的C等位基因的女性比具有T等位基因的女性更容易患乳腺癌（AOR=1.29,95%CI：1.06~1.57,P<0.05）。在rs13419896 HIF-2α基因型中,具有CT基因型的患者较具有TT基因型者增加患Ⅲ~Ⅳ期疾病（OR=1.72,95%CI：1.11~2.67）。［结论］ HIF-2α基因变异与乳腺癌易感性及其在携带HIF-2α rs13419896多态性女性的乳腺癌进展之间存在关联性。     

DNA修复基因XRCC1基因多态性与乳腺癌临床病理参数的相关性

目的 :研究XRCC1基因Arg194Trp和Arg399Gln多态性与中国女性乳腺癌临床病理参数的关系,探讨其在乳腺癌预后中的潜在意义。 方法 :采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法,对250例原发性乳腺癌患者进行XRCC1基因Arg194Trp、Arg399Gln多态性分析,用Pearsonχ²检验分析基因型与临床病理特征的关系。 结果 :XRCC1基因Arg194Trp和Arg399Gln多态性与乳腺癌患者的月经状态、肿瘤大小、腋窝淋巴结转移、TNM分期、雌激素受体均无显著相关性(P>0.05)。但该多态位点与乳腺癌患者的孕激素受体(PR)状态和C-erbB2蛋白表达显著相关。携带194纯合突变型的患者PR阴性率(81.0%)显著高于携带194野生型和杂合型患者(55.4%),(P=0.034);携带399纯合突变型的患者C-erbB2蛋白表达阳性率(61.1%)显著高于携带399野生型和杂合型的患者(29.3%),(P=0.006)。 结论 :PR阴性和(或)C-erbB2高表达的乳腺癌患者常提示预后不良。XRCC1基因多态性与PR阴性或C-erbB2高表达显著相关,提示携带XRCC1纯合突变(194或399)乳腺癌患者可能预后不良。     

MDM2 启动子区309 位点基因多态性与乳腺癌风险的关系*

目的:采用病例- 对照研究检测MDM2 启动子区309 位点T>G 单核苷酸多态（SNP 309）在中国女性人群中的频率分布,分析其与中国女性乳腺癌发病风险的关系。方法:提取病例组698 例原发性乳腺癌患者及对照组525 例健康人的外周血单核细胞DNA,采用聚合酶链反应- 限制性片段长度多态性（PCR-RFLP ）分析法,检测MDM2 启动子区309 位点基因多态性,确定此位点三种基因型,即T/T、T/G、G/G 基因型。统计分析病例组和对照组人群MDM2 SNP 309 各基因型频率分布,及各基因型与乳腺癌发病风险的相关性。结果:在研究的病例组与对照组整体人群中,经年龄、月经状态、家族史及生育史等因素校正后,与MDM2 SNP 309 T/T基因型比较,T/G 型及G/G 型与乳腺癌的发病风险无显著相关性（T/G,adjusted OR= 1.2,95%CI:0.8～1.6,P=0.30;G/G,adjusted OR= 1.0,95%CI:0.7～1.5,P=0.88）。 进一步分层分析后显示:在绝经后人群中,与T/T基因型比较,T/G 基因型及G/G 基因型显著增加乳腺癌的发病风险（T/G,adjusted OR= 1.8,95%CI:1.2～3.0,P=0.011;G/G,adjusted OR= 1.9,95%CI:1.2～3.3,P=0.014）。 提示绝经后人群携带T/G 型、G/G 型者比携带T/T基因型者患乳腺癌的风险分别升高约1.8、1.9 倍。在绝经前人群中,各基因型与乳腺癌的发病风险无显著相关性（P>0.05）。 结论:MDM2 启动子309 位点突变型G 等位基因携带者显著增加绝经后女性乳腺癌的发病风险。      

XRCC3基因多态性与西北地区妇女乳腺癌的关联性研究

目的：通过对中国西北地区妇女乳腺癌与健康人群XRCC3基因多态性位点的研究,找出基因多态性与乳腺癌发病的相关性。方法：采集西北地区的517例乳腺癌患者和1 008例健康人群外周血,提取DNA后采用高通量芯片检测方法,测定XRCC3基因rs861534、rs861537、rs3212092和rs861530共4个多态性位点的基因分型。结果：Logistic回归分析发现XRCC3 rs861534位点的AG/AA基因型,病例组与对照组比较差异有统计学意义（P < 0.01,OR=0.36;P=0.013,OR=0.08）,同时,GG+AG基因型与对照组比较差异有统计学意义（P < 0.01）,XRCC3 rs861530位点的Logistic回归分析显示AG+AA基因型与对照组比较差异有统计学意义（P=0.044）。相关临床病理学指标分析显示rs861537位点的GG/AG基因型在ER⁺与ER^-患者中的分布差异有统计学意义（P=0.048,OR=1.50）。rs3212092位点的CC+CT基因型在Her-2^-与Her-2⁺患者中的分布差异具有统计学意义（P=0.027,OR=2.06）。结论：在中国西北地区妇女人群中XRCC3基因rs861534和rs861530两个位点的多态性与乳腺癌的发病有相关性。在XRCC3 rs861537位点,GG/AG基因型ER⁺携带者可能具有较高的乳腺癌内分泌治疗风险;在rs3212092位点,携带CT和TT基因型的Her-2⁺表达患者具有明显的乳腺癌转移复发风险。     

CLOCK基因单核苷酸多态性与乳腺癌易感性的病例对照研究

目的：探讨生物钟CLOCK基因的单核苷酸多态性与乳腺癌易感性的关系。方法：采用应用聚合酶链式反应-限制性片断长度多态性（PCR-RFLP）技术检测1 499例中国汉族女性乳腺癌患者和1 592例正常女性对照者CLOCK基因rs3805151位点的基因型,采用SPSS 16.0软件进行数据处理。结果：CLOCK基因CC型、CT型和TT型在病例组和对照组间的分布差异有统计学意义（χ2=9.712,P=0.008）,与CC型相比,杂合型CT可以显著增加乳腺癌的发病风险 （OR=1.41,95% CI：1.07～1.87）,携带T等位基因（CT/TT）的个体乳腺癌风险增加35%（OR=1.35,95% CI：1.04～1.76）。分层分析显示,携带T等位基因绝经后、无肿瘤家族史者、无乳腺良性病史的个体患乳腺癌风险增加。结论：CLOCK基因rs3805151 C>T可增加乳腺癌发病风险,这一结论有待于进一步通过不同种族人群的关联研究以及功能学研究的证实。     

AR基因外显子1的CAG重复多态性与乳腺癌发生的关系

目的探讨AR(雄激素受体)基因外显子1的CAG重复多态性与乳腺癌发生的关系。方法研究对象为50例乳腺癌患者和50例健康者,从外周血淋巴细胞中提取基因组DNA,对AR基因外显子1的编码序列进行PCR扩增,扩增产物进行DNA序列测定,计算CAG重复频率。Wilcoxon rank test比较病例组和对照组的[CAG]n分布,采用多因素log回归分析[CAG]n对乳腺癌发病风险的影响。结果病例组[CAG]n为15～26,对照组为16～26;两组重复频率分布有差异(P=0.015),[CAG]n≥24时乳腺癌发病风险为[CAG]n≤20的5.6倍(P=0.04,OR=5.6)。结论 AR基因外显子1的CAG重复频率对乳腺癌风险发病有影响,长[CAG]n可增大乳腺癌发病风险。     

Association between Epstein-Barr Virus Gene Polymorphism and Breast Cancer Risk among Egyptian Females

Background: Epstein-Barr virus (EBV) has been implicated in the development of breast cancer (BC) since 1995. It is classified into A/B genotypes, C/D subtypes, and F/f variants according to variations in its genome. Aim: To determine the distribution difference of EBV types between BC patients and healthy controls in Egypt and to detect the association between different EBV types and BC characteristics. Methods: Three hundred and sixty-two participants (142 BC patients and 220 controls) were enrolled in this study. All participants were screened for EBV infection by determination of viral-capsid-IgG antibodies in their sera. EBNA-1 gene was detected by PCR in tumor biopsies of seropositive patients and in peripheral blood mononuclear cells of controls. A/B genotyping of EBV was performed by nested-PCR targeting the EBNA-2 gene. C/D subtypes and F/f variants were identified by Restriction fragment length polymorphism at BamHI-I W1/I1 and BamHI-F regions of EBV genome, respectively. Results: Among 362 participants, 300(82.9%) were EBV-seropositive, including 120/142(84.5%) of the BC patients and 180/220(81.8 %) of the controls. EBNA-1 gene was positive in 54(45%) of seropositive BC patients and in 38(21.1%) of seropositive controls. There was a significant association of EBNA-1 gene with breast cancer (OR=3.05, 95%CI=1.84-5.07). Moreover, EBNA-1 gene positivity was significantly associated with the more aggressive tumors. Genotype-A and prototype-F were predominant among patients (90.4%, 100%, respectively) as well as among controls (91.7%, 100%, respectively) with no statistical significant association with BC risk.  However, subtype-D was significantly more frequent in patients (95.6%) than in controls (64.7%) and was significantly associated with a higher BC risk as compared to subtype-C (OR=11.7, 95%CI=2.4-57.08). Subtype-D was significantly associated with higher grades tumors (100% among grade III),  with progesteron receptor-negative tumors and with HER2-positive tumors (100% for each). The combined genotypes that significantly associated with BC risk were ADF (OR=4.9) and BDF (OR=5.5). Conclusions: Subtype-D of EBV could be the only EBV type implicated in BC development among Egyptian females and associated more with poor prognosis.     

Lack of Association of the Cyclooxygenase-2 Gene 8473T>C Polymorphism with Breast Cancer Risk: a Meta-analysis

Background: Associations between the 8473T>C polymorphism (rs5275) in the cyclooxygenase-2 (COX-2)gene and breast cancer (BC) risk are still inconclusive and ambiguous. The aim of this meta-analysis was tocomprehensively estimate the genetic risk of 8473T>C polymorphism in the COX-2 gene for BC. Materials andMethods: We searched PubMed, Web of Science, Medline, Chinese biomedical (CBM), Weipu, China nationalknowledge infrastructure (CNKI), and Wanfang databases, covering all publications (last search was updated onAug 17, 2014). Statistical analyses were performed using Revman 5.3 and STATA 10.0 software. Results: A totalof 6,720 cases and 9,794 controls in 12 studies were included in this study. The results indicated no significantassociations between the 8473T>C polymorphism of the COX-2 gene and BC risk for the CC+TC vs TT model(pooled odds ratio (OR)=0.97, 95% confidence interval (CI)=0.90-1.03, and p=0.29). On subgroup analysis, wealso found that subdivision on ethnicity among Caucasians, Asians and others also revealed no relationshipwith BC susceptibility. With the study design (CC+TC vs TT), no significant associations were found in eitherpopulation-based case-control studies (PCC), or hospital-based case-control studies (HCC). Conclusions: Thispresent meta-analysis suggests that the 8473T>C polymorphism in the COX-2 gene is not a conspicuous lowpenetrantrisk factor for developing BC.     

Association of a VDR Gene Polymorphism with Risk of Colorectal Cancer in Kashmir

Roles of the vitamin D receptor in etiology of cancers, including colorectal cancer, have been repeatedlystressed in different parts of the world. A case control study aimed to evaluate the relationship between thetwo was therefore initiated in Kashmir, known both for its increasing incidence of gastrointestinal cancers anddeficiency of micro-nutrients especially vitamin D. The study included a total of 617 subjects (312 colorectalcancer cases and 305 controls), with sampling carried out over a period of 5 years. DNA samples from the bloodof the subjects were analyzed for start codon Fok I VDR polymorphism. We obtained a 1.3 fold increased riskamong individuals homozygous for f variants as compared to subjects homozygous for F allele (odds ratioOR 1.3, 95%CI, 0.861-1.65). Our study also showed statistically significant results when dwelling and tumorlocation characteristics were stratified with Fok I polymorphism, all of which suggests a possible role of Fok Ipolymorphism in the etiology of CRC in Kashmir     

MnSOD Gene Polymorphism Association with Steroid-Dependent Cancer

Oxidative stress enhances carcinogenesis due to DNA damage. Manganese superoxide dismutase (MnSOD) Val16Ala polymorphism has been recently associated with breast and prostate cancer. The role of oxidative stress in male breast cancer is poorly investigated due to the low prevalence of this neoplasia. We studied the relationship between prostate cancer (PC), male (MBC) and female breast cancer (FBC) and this polymorphism in a case–control study. Human genetic polymorphism Val16Ala of MnSOD was obtained from blood and paraffin-embedded tumor samples. The polymorphism was determined in 11 cases of MBC, 51 cases of PC, 89 cases of FBC and 372 age-adjusted healthy controls by polymerase chain reaction–restriction fragment length polymorphism techniques using restriction enzyme Hae III. Chi-square or Fisher test were used to compare the MnSOD frequency distribution. The observed genotypic frequencies of all samples were AA = 9.6% (n = 50), VV = 25.4% (n = 133) and AV = 64% (n = 340), all at Hardy–Weinberg equilibrium. Breast and prostate cancer risk was elevated in male and female patients with the Ala/Ala genotype compared to controls (p = 0.006, odds ratio = 2.5, 95% confidence interval 1.393–4.541). Even though the frequency of the Ala allele was low (9.6%) in the studied population, these data support the hypothesis that MnSOD and oxidative stress play a significant role in breast cancer risk both in males and females and also brings new information on the role of this polymorphism in prostate cancer. This is the first study which provides some evidence that genetic polymorphism in the MnSOD gene may be associated with an increased risk of male breast cancer. Studies with a larger sample size are needed to confirm the findings.     

No Association of the rs17822931 Polymorphism in ABCC11 with Breast Cancer Risk in Koreans

ABCC11 is reported to be associated with breast cancer. However, whether ABCC11 polymorphisms relate to breast cancer risk remains unclear. This study aimed to evaluate any association of a single nucleotide polymorphism (SNP), rs17822931, in ABCC11 with breast cancer in Koreans. Genomic DNA samples of 170 women with breast cancer and 100 controls were assessed for SNP rs17822931 of ABCC11 by single-strand conformation polymorphism (SSCP) and DNA sequencing. A 27-bp deletion (27) of ABCC11 was analyzed by PCR amplification. The genotype of SNP rs17822931 was confirmed to be AA in all samples from breast cancer patients and 27 was found in none of the samples. Our finding indicated that the SNP rs17822931 in ABCC11 is not associated with breast cancer. However, this study does provide information on fundamental genetic aspects of ABCC11 with regard to breast cancer risk in Koreans.     

GPX1的198位点多态性与肺癌和乳腺癌易感性的关系

[目的]探索和研究谷胱甘肽过氧化酶(GPX1)的198号位点的多态性与肺癌和乳腺癌易感性之间的关系。[方法]收集2007年12月31日前有关GPX1基因198位点多态性与肺癌和乳腺癌易感性关系的病例对照文献,进行Meta分析。[结果]通过文献检索和筛选,共得到10篇文献。在Meta分析中肺癌和乳腺癌的合并OR值(杂合型加上突变纯合型对比于野生纯合型)分别为1.35和1.06,95%可信区间分别为(0.92～1.17)和(0.91～2.01)。[结论]GPX1198位点多态性和乳腺癌易感性无关;但是GPX1198位点多态性和肺癌易感性有关,Lue198基因型携带者比其他人多35%的肺癌发生概率。     

雌激素受体基因多态性、膳食大豆摄入与乳腺癌患病风险的关系

目的:评价雌激素受体α(estrogen receptorα,ERα)基因XbaⅠ酶切片段多态性(XbaⅠ多态性)、膳食大豆摄入与乳腺癌患病风险的关系。方法:采用病例对照研究设计,序贯收集病例对照各291例。采用问卷调查收集乳腺癌常见危险因素信息;采用频次调查及单次摄入量调查,收集膳食大豆类食物摄入情况,并转换为大豆异黄酮日摄入量。采用限制性片段长度多态性技术,检测XbaⅠ(rs9340799)A→G(x→X)基因突变。采用多因素Logistic回归分析XbaⅠ多态性、膳食大豆摄入的主效应和交互效应,并计算相乘交互系数。采用delta原理计算相加交互系数及其可信区间。结果:在总人群及绝经前后亚组中,携带X突变等位基因与乳腺癌患病风险无关(Xx vs.xx:OR=0.61~0.82;XX vs.xx:OR=0.60~3.62;Xx+XX vs.xx:OR=0.61~0.92,95%CI均包括1)。膳食大豆高摄入对乳腺癌具有保护作用(总人群:OR=0.64,95%CI:0.42~0.97;绝经后:OR=0.40,95%CI:0.19~0.81)。总人群中,携带X等位基因且膳食大豆高摄入进一步降低乳腺癌风险(OR=0.47,95%CI:0.25~0.89)。两者相乘交互系数IOR=1.15,95%CI:0.49~2.76;相加交互系数RERI=0.19,95%CI:-0.35~0.73;API=0.41,95%CI:-0.75~1.57;S=0.73,95%CI:0.34~1.59。结论:膳食大豆摄入可能会降低乳腺癌风险,但ERα基因XbaⅠ酶切片段多态性位点X等位基因与膳食大豆高摄入之间是否存在交互作用尚需进一步探讨。     

No Association of the 5'Promoter Region Polymorphism of CYP17 with Breast Cancer Risk in Japan

To examine the association between breast cancer risk and a T-to-C substitution polymorphism at the 5'promoter region of CYP17, a case-control study was conducted at Aichi Cancer Center Hospital in Japan. Subjects were 144 histologically confirmed breast cancer patients diagnosed in the past 4 years and 166 hospital controls without cancer. Allele frequency among controls was 44.9% (95% confidence interval; 39.5–50.2) for C allele. Odds ratio (OR) of the polymorphism relative to TT-genotype was 0.97 (0.58-1.64) for TC-genotype and 0.81 (0.39–1.68) for CC-genotype. Subgroup analyses revealed that the OR was not statistically significant for the subgroups stratified by interval after diagnosis, age at menarche, age at first birth, menopausal status, body mass index, and mother/sisters' history of breast cancer. Consistent with previous studies conducted in other countries, the 5'promoter region polymorphism of CYP17 affected breast cancer risk of Japanese women to a limited extent. Although this is not a large-scale case-control study with population controls, these findings provide enough information to discourage further studies on the association between this polymorphism and breast cancer risk in Japan at large, and suggest that this polymorphism is useless for breast cancer risk estimation.