Perspective:  A Program to Improve Protein Biomarker Discovery for Cancer

Aebersold, Ruedi; Anderson, Leigh; Caprioli, Richard M.; Druker, Brian J.; Hartwell, Lee; Smith, Richard

doi:10.1021/pr050027n

Cited by 145 publications

(123 citation statements)

References 23 publications

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“…Biomarkers have attracted significant attention for disease diagnosis, prognosis, and therapeutic response monitoring in recent years (1). The development of clinical biomarkers involves discovery, verification, and validation.…”

mentioning

confidence: 99%

Use of an Immunoaffinity-Mass Spectrometry-based Approach for the Quantification of Protein Biomarkers from Serum Samples of Lung Cancer Patients

Nicol¹,

Han²,

Kim³

et al. 2008

Molecular & Cellular Proteomics

106

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It is a challenging task to verify and quantify potential biomarkers expressed at elevated levels in sera from cancer patients. An immunoaffinity-mass spectrometrybased approach has been developed using antibodies to enrich proteins of interest from sera followed by mass spectrometry-based quantification. Antibodies specific to the protein of interest were immobilized to hydrazide resin via the carbohydrate moiety on the Fc region of the antibody. Captured proteins were eluted, reduced, alkylated, and digested with trypsin. Peptides were analyzed by LC coupled with multiple reaction monitoring approach, and quantification was achieved by the addition of stable isotope-labeled (heavy) standard peptides. Using this methodology, we were able to achieve a linear response from 15 to 250 ng/ml for carcinoembryonic antigen (CEA), a known tumor biomarker. Moreover we observed elevated levels of CEA in sera samples from lung cancer patients that to our knowledge is the first time that circulating CEA has been detected by mass spectrometry-based analysis. This approach was further applied to potential protein biomarkers discovered from tumor cell lines and tumor tissues. A linear response was obtained from a multiplex spiking experiment in normal human sera for secretory leukocyte peptidase inhibitor (4 -500 ng/ml), tissue factor pathway inhibitor (TFPI) (42-1000 ng/ml), tissue factor pathway inhibitor 2 (TFPI2) (2-250 ng/ml), and metalloproteinase inhibitor 1 (TIMP1) (430 -1000 ng/ml). A replicate experiment for a single concentration value yielded a relative coefficient of variation better than 11% for TFPI, secretory leukocyte peptidase inhibitor, and TFPI2. The expression level of the proteins in lung cancer patient sera was assayed by an immunoaffinitymultiple reaction monitoring method, and the results were comparable with those obtained from ELISA. This immunoaffinity-mass spectrometry-based quantification approach thus provides a specific and accurate assay for verifying the expression of potential biomarkers in patient serum samples especially for those proteins Biomarkers have attracted significant attention for disease diagnosis, prognosis, and therapeutic response monitoring in recent years (1). The development of clinical biomarkers involves discovery, verification, and validation. Progress in genomics and proteomics has led to a large number of potential biomarkers (2-4). However, the promise of these discoveries requires proper verification and validation in the disease of interest (5). The ELISA has been the established platform for quantification of proteins in sera. However, for many of these newly identified potential biomarkers there are no ELISA kits available, and development of an ELISA kit is time-consuming (6), making it impractical to examine large panels of biomarkers. Although ELISA remains the "gold standard" for clinical applications, mass spectrometry-based quantification analysis has been shown as a possible intermediate technology in the validation process to prioritize candidates for ELIS...

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mentioning

confidence: 99%

Use of an Immunoaffinity-Mass Spectrometry-based Approach for the Quantification of Protein Biomarkers from Serum Samples of Lung Cancer Patients

Nicol¹,

Han²,

Kim³

et al. 2008

Molecular & Cellular Proteomics

106

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“…Alternative splicing of mRNA combined with numerous unique posttranslational protein modifications can give rise to multiple protein species (38). Hence, compared to the genome, the proteome can provide a more dynamic and accurate reflection of both the intrinsic genetic programme of the cell and the impact of its immediate environment (39).…”

Section: A Biomarkers In Breast Cancermentioning

confidence: 99%

Serial Changes in Expression of Proteins in Response to Neoadjuvant Chemotherapy in Breast Cancer

Chan¹,

Lee²

2013

Oncogene and Cancer - From Bench to Clinic

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“…Constantly perfusing and percolating the human body, the blood compartment endows a protein-rich information archive [27]. Besides the expected circulatory proteins, this archive also contains specific tumour-secreted proteins, normal tissue-and plasma-proteins digested by tumour-secreted proteases, and proteins produced by local and distant responses to the tumour [11,28,29]. Moreover, whole blood is an easy to sample, readily accessible matrix that allows repeated collection, thereby augmenting the clinical relevance of candidate blood-borne biomarkers [28,30].…”

Section: Protein Profiling Of Serum and Plasmamentioning

confidence: 99%

“…Due to alternative splicing of both mRNA and proteins, combined with more than 100 unique post-translational modifications, one gene can give rise to multiple protein species [10]. Hence, compared to the genome, the proteome can provide a more dynamic and accurate reflection of both the intrinsic genetic programme of the cell and the impact of its immediate environment [11]. Since proteome analysis can provide the link between gene sequence and cellular physiology [12], proteomics is expected to complement gene analyses for evaluating disease development, prognosis, and response to treatment [13].…”

Section: Introductionmentioning

confidence: 99%

Clinical proteomics in breast cancer: a review

Gast

Schellens

Beijnen

2008

Breast Cancer Res Treat

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Breast cancer imposes a significant healthcare burden on women worldwide. Early detection is of paramount importance in reducing mortality, yet the diagnosis of breast cancer is hampered by the lack of an adequate detection method. In addition, better breast cancer prognostication may improve selection of patients eligible for adjuvant therapy. Hence, new markers for early diagnosis, accurate prognosis and prediction of response to treatment are warranted to improve breast cancer care. Since proteomics can bridge the gap between the genetic alterations underlying cancer and cellular physiology, much is expected from proteome analyses for the detection of better protein biomarkers. Recent technical advances in mass spectrometry, such as matrix-assisted laser desorption/ ionisation time-of-flight mass spectrometry (MALDI-TOF MS) and its variant surface-enhanced laser desorption/ ionisation (SELDI-) TOF MS, have enabled highthroughput proteome analysis. In the current review, we give a comprehensive overview of the results of expression proteomics (i.e. protein profiling) research performed in breast cancer using these two platforms. Many protein peaks have been reported to bear significant diagnostic, prognostic or predictive value, however, only few candidate markers have been structurally identified yet. In addition, although of pivotal importance in preventing overfitting of data and systematic bias by pre-analytical parameters, validation of biomarker candidates by other, quantitative, methods and/or in new populations is very limited. Moreover, none of the identified candidate biomarkers has been investigated for their utility as breast cancer markers in large, prospective, clinical settings. As such, the candidate biomarkers discussed in this overview have not been validated sufficiently to be used for clinical patient care. Nonetheless, regarding the promising results up to now, MALDI-and SELDI-TOF MS protein profiling studies could eventually fulfil the great promise that protein biomarkers have for improving cancer patient outcome, provided that these studies are performed with adequate statistical power and analytical rigour.

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Perspective: A Program to Improve Protein Biomarker Discovery for Cancer

Cited by 145 publications

References 23 publications

Use of an Immunoaffinity-Mass Spectrometry-based Approach for the Quantification of Protein Biomarkers from Serum Samples of Lung Cancer Patients

Use of an Immunoaffinity-Mass Spectrometry-based Approach for the Quantification of Protein Biomarkers from Serum Samples of Lung Cancer Patients

Serial Changes in Expression of Proteins in Response to Neoadjuvant Chemotherapy in Breast Cancer

Clinical proteomics in breast cancer: a review

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