title: Large-scale delineation of secreted protein biomarkers overexpressed in cancer tissue and serum.
abstract: Genetic alterations in tumor cells often lead to the emergence of growth-stimulatory autocrine and paracrine signals, involving overexpression of secreted peptide growth factors, cytokines, and hormones. Increased levels of these soluble proteins may be exploited for cancer diagnosis and management or as points of therapeutic intervention. Here, we combined the use of controlled vocabulary terms and sequence-based algorithms to predict genes encoding secreted proteins from among approximately 12,500 sequences represented on oligonucleotide microarrays. Expression of these genes was queried in 150 carcinomas from 10 anatomic sites of origin and compared with 46 normal tissues derived from the corresponding sites of tumor origin and other body tissues and organs. Of 74 different genes identified as overexpressed in cancer tissues, several encode proteins with demonstrated clinical diagnostic application, such as alpha-fetoprotein in liver carcinoma, and kallikreins 6 and 10 in ovarian cancer, or therapeutic utility, such as gastrin-releasing peptide/bombesin in lung carcinomas. We show that several of the other candidate genes encode proteins with high levels of tumor-associated expression by immunohistochemistry on tissue microarrays and further demonstrate significantly elevated levels of another novel candidate protein, macrophage inhibitory cytokine 1, a distant member of the transforming growth factor-beta superfamily, in the serum of patients with metastatic prostate, breast, and colorectal carcinomas. Our results suggest that the combination of annotation/protein sequence analysis, transcript profiling, immunohistochemistry, and immunoassay is a powerful approach for delineating candidate biomarkers with potential clinical significance and may be broadly applicable to other human diseases.
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.
authors.forename: John B
authors.initials: JB
authors.lastname: Welsh
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Sapinoso
authors.forename: Suzanne G
authors.initials: SG
authors.lastname: Kern
authors.forename: David A
authors.initials: DA
authors.lastname: Brown
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.forename: Asne R
authors.initials: AR
authors.lastname: Bauskin
authors.forename: Robyn L
authors.initials: RL
authors.lastname: Ward
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Hawkins
authors.forename: David I
authors.initials: DI
authors.lastname: Quinn
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Russell
authors.forename: Robert L
authors.initials: RL
authors.lastname: Sutherland
authors.forename: Samuel N
authors.initials: SN
authors.lastname: Breit
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Moskaluk
authors.forename: Henry F
authors.initials: HF
authors.lastname: Frierson
authors.forename: Garret M
authors.initials: GM
authors.lastname: Hampton
mesh_terms: D014408:Biomarkers, Tumor / Q000097:blood* / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000097:blood / Q000235:genetics; D030541:Databases, Genetic; D005260:Female; D020869:Gene Expression Profiling; D055436:Growth Differentiation Factor 15; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis / Q000235:genetics; D009363:Neoplasm Proteins / Q000097:blood* / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000097:blood* / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis
chemical_list: D014408:Biomarkers, Tumor; D016207:Cytokines; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D009363:Neoplasm Proteins