A gene signature or gene expression signature is a single or combined group of genes in a cell with a uniquely characteristic pattern of gene expression[1] that occurs as a result of an altered or unaltered biological process or pathogenic medical condition.[2] This is not to be confused with the concept of gene expression profiling. Activating pathways in a regular physiological process or a physiological response to a stimulus results in a cascade of signal transduction and interactions that elicit altered levels of gene expression, which is classified as the gene signature of that physiological process or response.[3] The clinical applications of gene signatures breakdown into prognostic, diagnostic[4][5] and predictive signatures. The phenotypes that may theoretically be defined by a gene expression signature range from those that predict the survival or prognosis of an individual with a disease, those that are used to differentiate between different subtypes of a disease, to those that predict activation of a particular pathway. Ideally, gene signatures can be used to select a group of patients[6] for whom a particular treatment will be effective.[7][8]

Timeline of gene signature detection

In 1995, 2 studies conducted identified unique approaches to analyzing global gene expression of a genome which collectively promoted the value of identifying and analyzing gene signatures for physiological relevance. The first study reports a technique that improves expressed sequence tag (EST) analysis, known as Serial Analysis of Gene Expression (SAGE) that hinged on sequencing and quantifying mRNA samples which acquired levels of gene expression that eventually revealed characteristic gene expression patterns.[9]

The second study identified a technique that is now widely known as the microarray which quantifies complementary DNA (cDNA) hybridization on a glass slide to analyze the expression of many genes in parallel.[10] These studies drew greater attention to the wealth of information that analysis of gene signatures bear that may or may not be physiologically relevant.

Pressing forward, the latter technique has revolutionized research in genetics and DNA chip technology[11] as it is a widely adopted technique to profile gene expression signatures such that these physiological responses can be cataloged[12] in repositories such as NCBI Gene Expression Omnibus. This catalogue of prognostic, diagnostic and predictive gene expression signatures allow for predictions of onset of pathogenic diseases in patients,[13] tumour and cancer classification,[14] and enhanced therapeutic strategies that predict the optimal target candidates subjects and genes.[15]

Today, microarrays and other quantitative methods such as RNA-seq that encompass gene expression profiling, are moving towards promotion of re-analysis and integration of the large, publicly available database of gene expression signatures and profiles to uncover the full threshold of information these expression signatures hold.[16]

Types of gene signatures

Prognostic gene signature

Prognostic refers to predicting the likely outcome or course of a disease. Classifying a biological phenotype or medical condition based on a specific gene signature or multiple gene signatures, can serve as a prognostic biomarker for the associated phenotype or condition. This concept termed prognostic gene signature, serves to offer insight into the overall outcome of the condition regardless of therapeutic intervention.[17] Several studies have been conducted with focus on identifying prognostic gene signatures with the hopes of improving the diagnostic methods and therapeutic courses adopted in a clinical settings. It is important to note that prognostic gene signatures are not a target of therapy; they offer additional information to consider when discussing details such as duration or dosage or drug sensitivity etc. in therapeutic intervention. The criteria a gene signature must meet to be deemed a prognostic marker include demonstration of its association with the outcomes of the condition, reproducibility and validation of its association in an independent group of patients and lastly, the prognostic value must demonstrate independence from other standard factors in a multivariate analysis.[3] The applications of these prognostic signatures include prognostic assays for breast cancer,[18][19] hepatocellular carcinoma,[20] leukaemia[21] and are continually being developed for other types of cancers and disorders as well.

Diagnostic gene signatures

A diagnostic gene signature serves as a biomarker that distinguishes phenotypically similar medical conditions that have a threshold of severity consisting of mild, moderate or severe phenotypes.[5] Establishing verified methods of diagnosing clinically indolent and significant cases allows practitioners to provide more accurate care and therapeutic options that range from no therapy, preventative care to symptomatic relief. These diagnostic signatures also allow for a more accurate representation of test samples used in research.[6] Similar to the procedure of validation of prognostic gene signature, a criterion exists for classifying a gene signature as a biomarker for a disorder or diseases outlined by Chau et al.[22][23]

Predictive gene signatures

A predictive gene signature is similar to a predictive biomarker, where it predicts the effect of treatment in patients or study participants that exhibit a particular disease phenotype. A predictive gene signature unlike a prognostic gene signature can be a target for therapy.[17] The information predictive signatures provide are more rigorous than that of prognostic signatures as they are based on treatment groups with therapeutic intervention on the likely benefit from treatment, completely independent of prognosis.[24] Predictive gene signatures addresses the paramount need for ways to personalize and tailor therapeutic intervention in diseases. These signatures have implications in facilitating personalized medicine through identification of more novel therapeutic targets and identifying the most qualified subjects for optimal benefit of specific treatments.[3][25][26]

See also

References

  1. ↑ Itadani H, Mizuarai S, Kotani H (Aug 2008). "Can systems biology understand pathway activation? Gene expression signatures as surrogate markers for understanding the complexity of pathway activation". Curr Genomics. 9 (5): 349–60. doi:10.2174/138920208785133235. PMC 2694555. PMID 19517027.
  2. ↑ Liu J, Campen A, Huang S, Peng SB, Ye X, Palakal M, Dunker AK, Xia Y, Li S (Sep 2008). "Identification of a gene signature in cell cycle pathway for breast cancer prognosis using gene expression profiling data". BMC Med. Genom. 1: 39. doi:10.1186/1755-8794-1-39. PMC 2551605. PMID 18786252.
  3. 1 2 3 Chibon F (May 2013). "Cancer gene expression signatures - the rise and fall?". European Journal of Cancer. 49 (8): 2000–9. doi:10.1016/j.ejca.2013.02.021. PMID 23498875.
  4. ↑ Warner DF (March 2016). "Defining a diagnostic gene signature for tuberculosis". The Lancet. Respiratory Medicine. 4 (3): 170–1. doi:10.1016/s2213-2600(16)00063-1. PMID 26907219.
  5. 1 2 Nguyen HG, Welty CJ, Cooperberg MR (January 2015). "Diagnostic associations of gene expression signatures in prostate cancer tissue" (PDF). Current Opinion in Urology. 25 (1): 65–70. doi:10.1097/mou.0000000000000131. PMID 25405934. S2CID 29746661.
  6. 1 2 Wouters BJ, Löwenberg B, Erpelinck-Verschueren CA, van Putten WL, Valk PJ, Delwel R (Mar 2009). "Double CEBPA mutations, but not single CEBPA mutations, define a subgroup of acute myeloid leukemia with a distinctive gene expression profile that is uniquely associated with a favorable outcome". Blood. 113 (13): 3088–91. doi:10.1182/blood-2008-09-179895. PMC 2662648. PMID 19171880.
  7. ↑ Hassane DC, Guzman ML, Corbett C, Li X, Abboud R, Young F, Liesveld JL, Carroll M, Jordan CT (Jun 2008). "Discovery of agents that eradicate leukemia stem cells using an in silico screen of public gene expression data". Blood. 111 (12): 5654–62. doi:10.1182/blood-2007-11-126003. PMC 2424160. PMID 18305216.
  8. ↑ Corsello SM, Roti G, Ross KN, Chow KT, Galinsky I, DeAngelo DJ, Stone RM, Kung AL, Golub TR, Stegmaier K (Jun 2009). "Identification of AML1-ETO modulators by chemical genomics". Blood. 113 (24): 6193–205. doi:10.1182/blood-2008-07-166090. PMC 2699238. PMID 19377049.
  9. ↑ Velculescu VE, Zhang L, Vogelstein B, Kinzler KW (October 1995). "Serial analysis of gene expression". Science. 270 (5235): 484–7. doi:10.1126/science.270.5235.484. PMID 7570003. S2CID 16281846.
  10. ↑ Schena M, Shalon D, Davis RW, Brown PO (October 1995). "Quantitative monitoring of gene expression patterns with a complementary DNA microarray". Science. 270 (5235): 467–70. doi:10.1126/science.270.5235.467. PMID 7569999. S2CID 6720459.
  11. ↑ Kurian KM, Watson CJ, Wyllie AH (February 1999). "DNA chip technology". The Journal of Pathology. 187 (3): 267–71. doi:10.1002/(SICI)1096-9896(199902)187:3<267::AID-PATH275>3.0.CO;2-#. PMID 10398077. S2CID 196540833.
  12. ↑ Lamb J, Crawford ED, Peck D, Modell JW, Blat IC, Wrobel MJ, Lerner J, Brunet JP, Subramanian A, Ross KN, Reich M, Hieronymus H, Wei G, Armstrong SA, Haggarty SJ, Clemons PA, Wei R, Carr SA, Lander ES, Golub TR (September 2006). "The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease". Science. 313 (5795): 1929–35. doi:10.1126/science.1132939. PMID 17008526. S2CID 8728079.
  13. ↑ Russo, Antonio; Iacobelli, Stefano; Iovanna, Juan (2012). Russo, Antonio; Iacobelli, Stefano; Iovanna, Juan (eds.). Diagnostic, Prognostic and Therapeutic Value of Gene Signatures | SpringerLink. doi:10.1007/978-1-61779-358-5. hdl:10447/110836. ISBN 978-1-61779-357-8.
  14. ↑ Sørlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS, Thorsen T, Quist H, Matese JC, Brown PO, Botstein D, Lønning PE, Børresen-Dale AL (September 2001). "Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications". Proceedings of the National Academy of Sciences of the United States of America. 98 (19): 10869–74. doi:10.1073/pnas.191367098. PMC 58566. PMID 11553815.
  15. ↑ Scherf U, Ross DT, Waltham M, Smith LH, Lee JK, Tanabe L, Kohn KW, Reinhold WC, Myers TG, Andrews DT, Scudiero DA, Eisen MB, Sausville EA, Pommier Y, Botstein D, Brown PO, Weinstein JN (March 2000). "A gene expression database for the molecular pharmacology of cancer". Nature Genetics. 24 (3): 236–44. doi:10.1038/73439. PMID 10700175. S2CID 1494000.
  16. ↑ Wang Z, Monteiro CD, Jagodnik KM, Fernandez NF, Gundersen GW, Rouillard AD, et al. (September 2016). "Extraction and analysis of signatures from the Gene Expression Omnibus by the crowd". Nature Communications. 7: 12846. doi:10.1038/ncomms12846. PMC 5052684. PMID 27667448.
  17. 1 2 Oldenhuis CN, Oosting SF, Gietema JA, de Vries EG (May 2008). "Prognostic versus predictive value of biomarkers in oncology". European Journal of Cancer. 44 (7): 946–53. doi:10.1016/j.ejca.2008.03.006. PMID 18396036.
  18. ↑ Nielsen T, Wallden B, Schaper C, Ferree S, Liu S, Gao D, Barry G, Dowidar N, Maysuria M, Storhoff J (March 2014). "Analytical validation of the PAM50-based Prosigna Breast Cancer Prognostic Gene Signature Assay and nCounter Analysis System using formalin-fixed paraffin-embedded breast tumor specimens". BMC Cancer. 14: 177. doi:10.1186/1471-2407-14-177. PMC 4008304. PMID 24625003.
  19. ↑ Liu R, Wang X, Chen GY, Dalerba P, Gurney A, Hoey T, Sherlock G, Lewicki J, Shedden K, Clarke MF (January 2007). "The prognostic role of a gene signature from tumorigenic breast-cancer cells". The New England Journal of Medicine. 356 (3): 217–26. doi:10.1056/nejmoa063994. PMID 17229949.
  20. ↑ Hoshida Y, Villanueva A, Sangiovanni A, Sole M, Hur C, Andersson KL, Chung RT, Gould J, Kojima K, Gupta S, Taylor B, Crenshaw A, Gabriel S, Minguez B, Iavarone M, Friedman SL, Colombo M, Llovet JM, Golub TR (May 2013). "Prognostic gene expression signature for patients with hepatitis C-related early-stage cirrhosis". Gastroenterology. 144 (5): 1024–30. doi:10.1053/j.gastro.2013.01.021. PMC 3633736. PMID 23333348.
  21. ↑ Verhaak RG, Goudswaard CS, van Putten W, Bijl MA, Sanders MA, Hugens W, Uitterlinden AG, Erpelinck CA, Delwel R, Löwenberg B, Valk PJ (December 2005). "Mutations in nucleophosmin (NPM1) in acute myeloid leukemia (AML): association with other gene abnormalities and previously established gene expression signatures and their favorable prognostic significance". Blood. 106 (12): 3747–54. doi:10.1182/blood-2005-05-2168. PMID 16109776.
  22. ↑ Chau CH, Rixe O, McLeod H, Figg WD (October 2008). "Validation of analytic methods for biomarkers used in drug development". Clinical Cancer Research. 14 (19): 5967–76. doi:10.1158/1078-0432.ccr-07-4535. PMC 2744124. PMID 18829475.
  23. ↑ Pepe MS, Feng Z, Janes H, Bossuyt PM, Potter JD (October 2008). "Pivotal evaluation of the accuracy of a biomarker used for classification or prediction: standards for study design". Journal of the National Cancer Institute. 100 (20): 1432–8. doi:10.1093/jnci/djn326. PMC 2567415. PMID 18840817.
  24. ↑ Baker SG, Kramer BS (August 2015). "Evaluating surrogate endpoints, prognostic markers, and predictive markers: Some simple themes". Clinical Trials. 12 (4): 299–308. doi:10.1177/1740774514557725. PMC 4451440. PMID 25385934.
  25. ↑ Grob JJ, Mortier L, D'Hondt L, Grange F, Baurain JF, Dréno B, Lebbe C, Robert C, Dompmartin A, Neyns B, Gillet M, Louahed J, Jarnjak S, Lehmann FF (2017-11-01). "Safety and immunogenicity of MAGE-A3 cancer immunotherapeutic with dacarbazine in patients with MAGE-A3-positive metastatic cutaneous melanoma: an open phase I/II study with a first assessment of a predictive gene signature". ESMO Open. 2 (5): e000203. doi:10.1136/esmoopen-2017-000203. PMC 5687540. PMID 29177094.
  26. ↑ Tavassoly, Iman; Hu, Yuan; Zhao, Shan; Mariottini, Chiara; Boran, Aislyn; Chen, Yibang; Li, Lisa; Tolentino, Rosa E.; Jayaraman, Gomathi; Goldfarb, Joseph; Gallo, James (2019). "Genomic signatures defining responsiveness to allopurinol and combination therapy for lung cancer identified by systems therapeutics analyses". Molecular Oncology. 13 (8): 1725–1743. doi:10.1002/1878-0261.12521. ISSN 1878-0261. PMC 6670022. PMID 31116490.
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