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Abstract
Cancer is a major and increasing public health problem worldwide. Traditionally, the diagnosis and staging of cancer, as well as the evaluation of response to therapy have been primarily based on morphology, with relatively few cancer biomarkers currently in use. Conventional biomarker studies have been focused on single genes or discrete pathways, but this approach has had limited success because of the complex and heterogeneous nature of many cancers. The completion of the human genome project and the development of new technologies have greatly facilitated the identification of biomarkers for assessment of cancer risk, early detection of primary cancers, monitoring cancer treatment, and detection of recurrence. This article reviews the various approaches used for development of such markers and describes markers of potential clinical interest in major types of cancer. Finally, we discuss the reasons why so few cancer biomarkers are currently available for clinical use.
Key words :
- Genetic mutation
- loss of heterozygosity
- DNA methylation
- comparative genomic hybridization array
- DNA microarray
- two-dimensional polyacrylamide gel electrophoresis
- mass spectrometry
- reverse transcriptase-polymerase chain reaction
- methylation-specific polymerase chain reaction
- MethyLight
- enzyme-linked immunosorbent assay
- early detection
- diagnostic marker
- prognostic marker
- microsatellite instability
- genomics
- proteomics
- circulating DNA
- serum protein marker
| Abbreviations | ||
| AFLP-DD | = | amplified fragment-length polymorphism-differential display |
| APC | = | adenomatous polyposis coli |
| ATM | = | ataxia telangiectasia mutated |
| B305D | = | a breast tissue-specific gene |
| B726P | = | an isoform of NY-BR-1, a breast tissue-specific gene |
| BAC | = | bacterial artificial chromosome |
| BAT-26 | = | microsatellite instability marker, a 26-repeat adenine tract located within the fifth intron of the MSH2 gene |
| BCL2 | = | antagonist of cell death |
| BJ-TSA-9 | = | lung cancer-specific gene, family with sequence similarity 83, member A |
| BPH | = | benign prostatic hypertrophy |
| CA125 | = | ovarian carcinoma antigen 125 |
| CA19.9 | = | carcinoma antigen 19.9 |
| CCND2 | = | cyclin D2 |
| CCSP-2 | = | colon cancer-secreted protein-2 |
| CD44 | = | cell adhesion molecule 44 |
| CDH1 | = | epithelial cadherin 1 |
| CDKN2A | = | cyclin-dependent kinase inhibitor 2A |
| CEA | = | carcinoembryonic antigen |
| CGH | = | comparative genomic hybridization |
| CHK2 | = | check point protein kinase 2 |
| cIAP1 | = | apoptosis inhibitor 1 |
| CK19 | = | cytokeratin 19 |
| CK20 | = | cytokeratin 20 |
| Cot-1 DNA | = | DNA with a cot value of 1, consisting largely of highly repetitive sequences |
| CpG | = | cytosine-phosphate-guanine |
| CyPA | = | peptidylprolyl isomerase A |
| 2D-DIGE | = | two-dimensional difference gel electrophoresis |
| 2D-PAGE | = | two-dimensional polyacrylamide gel electrophoresis |
| DAC | = | 5-aza-2′-deoxycytidine |
| DAPK1 | = | death-associated protein kinase 1 |
| DASH | = | dynamic allele-specific hybridization |
| DD3 | = | prostate cancer antigen 3 |
| ddNTP | = | dideoxynucleotide |
| DMH | = | differential methylation hybridization |
| EBV | = | Epstein Barr virus |
| E-cadherin | = | epithelial calcium-dependent adhesion protein |
| EGF | = | epidermal growth factor |
| ELISA | = | enzyme-linked immunosorbent assay |
| EPCA | = | early prostate cancer antigen |
| Ep-CAM | = | epithelial cell-adhesion molecule |
| FAP | = | familial polyposis syndrome |
| FDA | = | US Food and Drug Administration |
| FDP | = | fibrin-fibrinogen degradation product |
| FEN | = | flap endonuclease |
| FHIT | = | fragile histidine triad gene |
| FISH | = | fluorescence in situ hybridization |
| GABAπ | = | γ -aminobutyrate type A receptor π -subunit |
| GDF15 | = | growth differentiation factor 15 |
| GST | = | glutathione-S-transferase |
| GSTP1 | = | glutathione-S-transferase pi |
| H3-K27 | = | histone 3 lysine residue 27 |
| H3-K9 | = | histone-3-lysine residue 9 |
| H4-K20 | = | histone-4-lysine residue 20 |
| HDAC | = | histone deacetylase |
| HE4 | = | WAP domain-containing protein |
| HER2 | = | v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, frequently amplified in breast cancer |
| hK4-15 | = | human kallikrein 4-15 |
| HIN1 | = | HIV-1 induced protein, OTU domain containing 4 protein |
| hMLH1 | = | DNA mismatch repair protein, homolog of E.coli MutL |
| hMSH2 | = | mismatch repair protein, homolog 2 of E.coli MutS |
| HNPCC | = | hereditary non-polyposis colorectal cancer |
| HPV | = | human papillomavirus |
| hTERT (TERT, hTRT) | = | human telomerase reverse transcriptase |
| ICAT | = | isotope-coded affinity tags |
| IHC | = | immunohistochemistry |
| IL-6 | = | interleukin-6 |
| IL-8 | = | interleukin-8 |
| KiSS-1 | = | metastasis-suppressor |
| K-ras | = | human oncogene, Kirsten rat sarcoma 2 viral oncogene homolog |
| Lewis X-antigen | = | N-acetylglucosaminyltransferase V |
| LMW | = | low molecular weight |
| LOH | = | loss of heterozygosity |
| LUNX | = | palate, lung and nasal epithelium carcinoma-associated |
| MALDI-TOF | = | matrix-assisted laser desorption and ionization time-of-flight |
| MBD2 | = | methyl-CpG binding domain protein 2 |
| MCA | = | methylated CpG island amplification |
| MGMT | = | O-6-methylguanine-DNA methyltransferase |
| MIF | = | macrophage migration inhibitory factor |
| MIRA | = | methylated-CpG island recovery assay |
| MMP-1 | = | matrix metallopeptidase 1 |
| MSI | = | microsatellite instability |
| MSP | = | methylation-specific PCR |
| MT1G | = | metallothionein 1G |
| MUC1 | = | mucin 1 |
| MYH | = | homolog of E.coli MutY |
| NAPPA | = | nucleic acid programmable protein arrays |
| NMES1 | = | normal mucosa of esophagus-specific 1 |
| NMP22 | = | nuclear matrix protein 22 |
| NPC | = | nasopharyngeal cancer |
| p16 (CDKN2A) | = | cyclin-dependent kinase inhibitor 2A |
| NSCLC | = | non-small cell lung cancer |
| p21 | = | cyclin-dependent kinase inhibitor 1A |
| p33ING1 | = | growth-inhibitor ING1 |
| p53 | = | tumor-suppressor protein |
| PBMC | = | peripheral blood mononuclear cells |
| PGP9.5 (UCHL1) | = | ubiquitin carboxyl-terminal esterase L1 |
| PIK3CA | = | phosphoinositide-3-kinase, catalytic, alpha polypeptide |
| PIN | = | prostatic intraepithelial neoplasia |
| pRB | = | retinoblastoma 1 |
| PSA | = | prostate-specific antigen |
| PSMA | = | prostate-specific membrane antigen |
| PTEN | = | protein tyrosine phosphatase |
| RARB | = | retinoic acid receptor, beta |
| RASSF1A | = | Ras-associated domain family 1 |
| RRAD | = | Ras-related associated with diabetes |
| RT-PCR | = | reverse transcriptase-polymerase chain reaction |
| SAGE | = | serial analysis of gene expression |
| SBE | = | single-base primer extension |
| SCC | = | squamous cell carcinoma antigen |
| SELDI-TOF | = | surface-enhanced laser desorption and ionization time-of-flight |
| SEREX | = | serologic expression cloning |
| SFRP1 | = | secreted frizzled-related protein 1 |
| SKP2 | = | S-phase kinase-associated protein 2 |
| SNP | = | single nucleotide polymorphism |
| SPARC | = | secreted protein acidic and rich in cysteine, or osteonectin |
| STK11 | = | serine/threonine kinase 11 |
| STR | = | short tandem repeats |
| TFPI2 | = | tissue factor pathway-inhibitor 2 |
| TGF-β | = | transforming growth factor, beta 1 |
| TIMP-1 | = | tissue inhibitor of metalloproteinase 1 |
| TSA | = | trichostatin A |
| TWIST | = | Drosophila twist homolog |
| VEGF | = | vascular endothelial growth factor |
| ZNF217 | = | zinc-finger protein 217 |
| Abbreviations | ||
| AFLP-DD | = | amplified fragment-length polymorphism-differential display |
| APC | = | adenomatous polyposis coli |
| ATM | = | ataxia telangiectasia mutated |
| B305D | = | a breast tissue-specific gene |
| B726P | = | an isoform of NY-BR-1, a breast tissue-specific gene |
| BAC | = | bacterial artificial chromosome |
| BAT-26 | = | microsatellite instability marker, a 26-repeat adenine tract located within the fifth intron of the MSH2 gene |
| BCL2 | = | antagonist of cell death |
| BJ-TSA-9 | = | lung cancer-specific gene, family with sequence similarity 83, member A |
| BPH | = | benign prostatic hypertrophy |
| CA125 | = | ovarian carcinoma antigen 125 |
| CA19.9 | = | carcinoma antigen 19.9 |
| CCND2 | = | cyclin D2 |
| CCSP-2 | = | colon cancer-secreted protein-2 |
| CD44 | = | cell adhesion molecule 44 |
| CDH1 | = | epithelial cadherin 1 |
| CDKN2A | = | cyclin-dependent kinase inhibitor 2A |
| CEA | = | carcinoembryonic antigen |
| CGH | = | comparative genomic hybridization |
| CHK2 | = | check point protein kinase 2 |
| cIAP1 | = | apoptosis inhibitor 1 |
| CK19 | = | cytokeratin 19 |
| CK20 | = | cytokeratin 20 |
| Cot-1 DNA | = | DNA with a cot value of 1, consisting largely of highly repetitive sequences |
| CpG | = | cytosine-phosphate-guanine |
| CyPA | = | peptidylprolyl isomerase A |
| 2D-DIGE | = | two-dimensional difference gel electrophoresis |
| 2D-PAGE | = | two-dimensional polyacrylamide gel electrophoresis |
| DAC | = | 5-aza-2′-deoxycytidine |
| DAPK1 | = | death-associated protein kinase 1 |
| DASH | = | dynamic allele-specific hybridization |
| DD3 | = | prostate cancer antigen 3 |
| ddNTP | = | dideoxynucleotide |
| DMH | = | differential methylation hybridization |
| EBV | = | Epstein Barr virus |
| E-cadherin | = | epithelial calcium-dependent adhesion protein |
| EGF | = | epidermal growth factor |
| ELISA | = | enzyme-linked immunosorbent assay |
| EPCA | = | early prostate cancer antigen |
| Ep-CAM | = | epithelial cell-adhesion molecule |
| FAP | = | familial polyposis syndrome |
| FDA | = | US Food and Drug Administration |
| FDP | = | fibrin-fibrinogen degradation product |
| FEN | = | flap endonuclease |
| FHIT | = | fragile histidine triad gene |
| FISH | = | fluorescence in situ hybridization |
| GABAπ | = | γ -aminobutyrate type A receptor π -subunit |
| GDF15 | = | growth differentiation factor 15 |
| GST | = | glutathione-S-transferase |
| GSTP1 | = | glutathione-S-transferase pi |
| H3-K27 | = | histone 3 lysine residue 27 |
| H3-K9 | = | histone-3-lysine residue 9 |
| H4-K20 | = | histone-4-lysine residue 20 |
| HDAC | = | histone deacetylase |
| HE4 | = | WAP domain-containing protein |
| HER2 | = | v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, frequently amplified in breast cancer |
| hK4-15 | = | human kallikrein 4-15 |
| HIN1 | = | HIV-1 induced protein, OTU domain containing 4 protein |
| hMLH1 | = | DNA mismatch repair protein, homolog of E.coli MutL |
| hMSH2 | = | mismatch repair protein, homolog 2 of E.coli MutS |
| HNPCC | = | hereditary non-polyposis colorectal cancer |
| HPV | = | human papillomavirus |
| hTERT (TERT, hTRT) | = | human telomerase reverse transcriptase |
| ICAT | = | isotope-coded affinity tags |
| IHC | = | immunohistochemistry |
| IL-6 | = | interleukin-6 |
| IL-8 | = | interleukin-8 |
| KiSS-1 | = | metastasis-suppressor |
| K-ras | = | human oncogene, Kirsten rat sarcoma 2 viral oncogene homolog |
| Lewis X-antigen | = | N-acetylglucosaminyltransferase V |
| LMW | = | low molecular weight |
| LOH | = | loss of heterozygosity |
| LUNX | = | palate, lung and nasal epithelium carcinoma-associated |
| MALDI-TOF | = | matrix-assisted laser desorption and ionization time-of-flight |
| MBD2 | = | methyl-CpG binding domain protein 2 |
| MCA | = | methylated CpG island amplification |
| MGMT | = | O-6-methylguanine-DNA methyltransferase |
| MIF | = | macrophage migration inhibitory factor |
| MIRA | = | methylated-CpG island recovery assay |
| MMP-1 | = | matrix metallopeptidase 1 |
| MSI | = | microsatellite instability |
| MSP | = | methylation-specific PCR |
| MT1G | = | metallothionein 1G |
| MUC1 | = | mucin 1 |
| MYH | = | homolog of E.coli MutY |
| NAPPA | = | nucleic acid programmable protein arrays |
| NMES1 | = | normal mucosa of esophagus-specific 1 |
| NMP22 | = | nuclear matrix protein 22 |
| NPC | = | nasopharyngeal cancer |
| p16 (CDKN2A) | = | cyclin-dependent kinase inhibitor 2A |
| NSCLC | = | non-small cell lung cancer |
| p21 | = | cyclin-dependent kinase inhibitor 1A |
| p33ING1 | = | growth-inhibitor ING1 |
| p53 | = | tumor-suppressor protein |
| PBMC | = | peripheral blood mononuclear cells |
| PGP9.5 (UCHL1) | = | ubiquitin carboxyl-terminal esterase L1 |
| PIK3CA | = | phosphoinositide-3-kinase, catalytic, alpha polypeptide |
| PIN | = | prostatic intraepithelial neoplasia |
| pRB | = | retinoblastoma 1 |
| PSA | = | prostate-specific antigen |
| PSMA | = | prostate-specific membrane antigen |
| PTEN | = | protein tyrosine phosphatase |
| RARB | = | retinoic acid receptor, beta |
| RASSF1A | = | Ras-associated domain family 1 |
| RRAD | = | Ras-related associated with diabetes |
| RT-PCR | = | reverse transcriptase-polymerase chain reaction |
| SAGE | = | serial analysis of gene expression |
| SBE | = | single-base primer extension |
| SCC | = | squamous cell carcinoma antigen |
| SELDI-TOF | = | surface-enhanced laser desorption and ionization time-of-flight |
| SEREX | = | serologic expression cloning |
| SFRP1 | = | secreted frizzled-related protein 1 |
| SKP2 | = | S-phase kinase-associated protein 2 |
| SNP | = | single nucleotide polymorphism |
| SPARC | = | secreted protein acidic and rich in cysteine, or osteonectin |
| STK11 | = | serine/threonine kinase 11 |
| STR | = | short tandem repeats |
| TFPI2 | = | tissue factor pathway-inhibitor 2 |
| TGF-β | = | transforming growth factor, beta 1 |
| TIMP-1 | = | tissue inhibitor of metalloproteinase 1 |
| TSA | = | trichostatin A |
| TWIST | = | Drosophila twist homolog |
| VEGF | = | vascular endothelial growth factor |
| ZNF217 | = | zinc-finger protein 217 |
Notes
*Editor's Note: This term denotes an in vitro selection process whereby specific peptides are enriched by binding to a target immobilized on a plate or bead; the process may be repeated over several rounds for optimal enrichment allowing identification of the bound proteins.