Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, The Netherlands.
BMC Cancer. 2011 Aug 26;11:381. doi: 10.1186/1471-2407-11-381.
Serum protein profiles have been investigated frequently to discover early biomarkers for breast cancer. So far, these studies used biological samples collected at or after diagnosis. This may limit these studies' value in the search for cancer biomarkers because of the often advanced tumor stage, and consequently risk of reverse causality. We present for the first time pre-diagnostic serum protein profiles in relation to breast cancer, using the Prospect-EPIC (European Prospective Investigation into Cancer and nutrition) cohort.
In a nested case-control design we compared 68 women diagnosed with breast cancer within three years after enrollment, with 68 matched controls for differences in serum protein profiles. All samples were analyzed with SELDI-TOF MS (surface enhanced laser desorption/ionization time-of-flight mass spectrometry). In a subset of 20 case-control pairs, the serum proteome was identified and relatively quantified using isobaric Tags for Relative and Absolute Quantification (iTRAQ) and online two-dimensional nano-liquid chromatography coupled with tandem MS (2D-nanoLC-MS/MS).
Two SELDI-TOF MS peaks with m/z 3323 and 8939, which probably represent doubly charged apolipoprotein C-I and C3a des-arginine anaphylatoxin (C3adesArg), were higher in pre-diagnostic breast cancer serum (p = 0.02 and p = 0.06, respectively). With 2D-nanoLC-MS/MS, afamin, apolipoprotein E and isoform 1 of inter-alpha trypsin inhibitor heavy chain H4 (ITIH4) were found to be higher in pre-diagnostic breast cancer (p < 0.05), while alpha-2-macroglobulin and ceruloplasmin were lower (p < 0.05). C3a(desArg) and ITIH4 have previously been related to the presence of symptomatic and/or mammographically detectable breast cancer.
We show that serum protein profiles are already altered up to three years before breast cancer detection.
为了发现乳腺癌的早期生物标志物，人们经常研究血清蛋白谱。到目前为止，这些研究使用的是在诊断时或诊断后采集的生物样本。由于肿瘤分期往往较晚，存在反向因果关系的风险，因此这些研究在寻找癌症生物标志物方面的价值可能会受到限制。我们首次使用欧洲癌症与营养前瞻性调查（EPIC）队列研究了与乳腺癌相关的诊断前血清蛋白谱。
在巢式病例对照设计中，我们比较了 68 名在入组后三年内被诊断患有乳腺癌的女性与 68 名匹配的对照者的血清蛋白谱差异。所有样本均采用表面增强激光解吸电离飞行时间质谱（SELDI-TOF MS）进行分析。在 20 对病例对照者的亚组中，使用相对和绝对定量同位素标记（iTRAQ）和在线二维纳流液相色谱-串联质谱（2D-nanoLC-MS/MS）对血清蛋白质组进行了鉴定和相对定量。
两个 m/z 为 3323 和 8939 的 SELDI-TOF MS 峰，可能分别代表载脂蛋白 C-I 双电荷和 C3a 去精氨酸过敏毒素（C3adesArg），在乳腺癌的诊断前血清中较高（p = 0.02 和 p = 0.06）。通过 2D-nanoLC-MS/MS，发现 afamin、载脂蛋白 E 和 α1-胰蛋白酶抑制剂重链 H4 的同工型 1（ITIH4）在乳腺癌的诊断前较高（p < 0.05），而 α-2-巨球蛋白和铜蓝蛋白较低（p < 0.05）。C3a（desArg）和 ITIH4 以前与有症状和/或乳房 X 线照相术可检测到的乳腺癌有关。
我们表明，在乳腺癌检测前长达三年，血清蛋白谱就已经发生改变。
