Proteomic Analysis of Patient Plasma Identifies Parathyroid Hormone Related Protein (PTHrP12-48) as a Potential Biomarker of Breast Cancer Bone Metastasis.
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AbstractBackground: Bone metastasis is a devastating and often incurable phase of breast cancer progression that significantly compromises patient morbidity and mortality. Despite the well-characterized issues associated with tumor progression, there is currently no reliable method to detect or predict which patients have or are at increased risk for developing bone metastasis. In this study a validated plasma-based proteomic profile for the diagnosis of breast cancer bone metastasis was developed and a highly discriminatory protein component of the profile identified as a novel fragment of parathyroid hormone related protein (PTHrP).Materials and Methods: Plasma samples were collected from a total of 110 breast cancer patients. The training set consisted of 38 breast cancer patients with clinical evidence of bone metastasis and 38 with no evidence of a bone metastasis from time of diagnosis to clinical outcome. The independent validation cohort consisted of 34 breast cancer patients with an unknown bone metastasis classification. The training set was analyzed using surface enhanced laser desorption time-of-flight mass spectrometry (SELDI-TOF MS) and 13 discriminatory protein peaks that contributed to a homogeneous partitioning of the training set (n = 76) in multiple statistical, bioinformatics, and machine learning modeling scenarios were identified and used to construct a RandomForest classifier for the detection of breast cancer bone metastasis (sensitivity: 100%, specificity: 100%).Results: The diagnostic profile identified was then independently confirmed in a blinded fashion using the validation cohort (sensitivity: 97%; specificity: 82%). Importantly, the most discriminatory protein peak (m/z 4260.92 Da) in the plasma of bone metastasis patients was subsequently identified using specific immunodepletion, tryptic peptide mapping and peptide sequencing as a unique proteolytic PTHrP fragment, PTHrP(12-48). Ongoing studies are determining the biogenesis and biological activity of this unique PTHrP peptide. Discussion: Our discovery of PTHrP(12-48) as a novel plasma biomarker of breast cancer bone metastasis validates our plasma proteomic approach and provides the first direct evidence for the existence of a circulating PTHrP biomarker in breast cancer patient plasma that is associated with bone metastasis.Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-16-01.
