Identification of PTHrP(12-48) as a plasma biomarker associated with breast cancer bone metastasis.
Identification of PTHrP(12-48) as a plasma biomarker associated with breast cancer bone metastasis.
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DOI：
10.1158/1055-9965.epi-12-1318-t
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发表时间：
2013-05
期刊：
影响因子：
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通讯作者：
Suva LJ
中科院分区：
文献类型：
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作者：
Washam CL;Byrum SD;Leitzel K;Ali SM;Tackett AJ;Gaddy D;Sundermann SE;Lipton A;Suva LJ
乳腺癌骨转移（BM）是一种严重影响患者生存的并发症，部分原因是缺乏允许早期和准确诊断的疾病特异性生物标志物。使用质谱蛋白质谱分析，从3个独立的具有和不具有骨转移临床证据的乳腺癌患者队列中筛选血浆样品。结果确定了13种生物标志物，对所有110例患者进行了分类，灵敏度为91%，特异性为93% [受试者工作特征曲线下面积（AUC=1.00）]。最具鉴别力的蛋白质随后被鉴定为甲状旁腺相关蛋白（PTHrP）的独特的12- 48 aa肽片段。BM患者血浆中PTHrP（12-48）与无BM患者相比显著增加（p<0.0001）。使用逻辑回归模型来评估PTHrP（12-48）作为单一生物标志物或与临床标志物I型胶原蛋白的N-端肽（NTx）的测量组合的诊断潜力。PTHrP（12-48）和NTx逻辑回归模型没有显著差异，并且分别以高准确度（AUC=0.85和0.95）对患者组进行分类。有趣的是，与血清NTx组合，PTHrP（12-48）的血浆浓度增加了诊断特异性和准确性（AUC=0.99）。这些数据表明PTHrP（12-48）在乳腺癌患者血浆中循环，并且是乳腺癌BM的新型和预测性生物标志物。重要的是，PTHrP（12-48）与NTx组合的临床测量改善了乳腺癌BM的检测。总之，我们提出了第一个经过验证的用于诊断乳腺癌BM的血浆生物标志物特征，其可以改善高危个体的早期诊断。
Breast cancer bone metastasis (BM) is a complication that significantly compromises patient survival due, in part, to the lack of disease-specific biomarkers that allow early and accurate diagnosis. Using mass spectrometry protein profiling, plasma samples were screened from 3 independent breast cancer patient cohorts with and without clinical evidence of bone metastasis. The results identified 13 biomarkers that classified all 110 patients with a sensitivity of 91% and specificity of 93% [receiver operating characteristics area under the curve (AUC=1.00)]. The most discriminatory protein was subsequently identified as a unique 12-48aa peptide fragment of parathyroid hormone-related protein (PTHrP). PTHrP(12-48) was significantly increased in BM patients plasma compared with patients without BM (p<0.0001). Logistic regression models were used to evaluate the diagnostic potential of PTHrP(12-48) as a single biomarker or in combination with the measurement of the clinical marker N-telopeptide of type I collagen (NTx). The PTHrP(12-48) and NTx logistic regression models were not significantly different and classified the patient groups with high accuracy (AUC=0.85 and 0.95) respectively. Interestingly, in combination with serum NTx, the plasma concentration of PTHrP(12-48) increased diagnostic specificity and accuracy (AUC=0.99). These data demonstrate that PTHrP(12-48) circulates in breast cancer patient plasma and is a novel and predictive biomarker of breast cancer BM. Importantly, the clinical measurement of PTHrP(12-48) in combination with NTx improves the detection of breast cancer BM. In summary, we present the first validated, plasma biomarker signature for diagnosis of breast cancer BM that may improve the early diagnosis of high-risk individuals.