MAGEA4 explained

Melanoma-associated antigen 4 is a protein that in humans is encoded by the MAGEA4 gene.^{[1] [2]}

This gene is a member of the MAGEA gene family. The members of this family encode proteins with 50 to 80% sequence identity to each other. The promoters and first exons of the MAGEA genes show considerable variability, suggesting that the existence of this gene family enables the same function to be expressed under different transcriptional controls.

Clinical importance

The MAGEA genes are clustered at chromosomal location Xq28. They have been implicated in some hereditary disorders, such as dyskeratosis congenita. At least four variants encoding the same protein have been found for this gene.

In salivary gland carcinomas, MAGE4 expression correlates to lower-grade histology, lower likelihood of metastases and more favourable survival.^[3]

While MAGEA4 is expressed by many tumours,^[4] it is almost universally expressed by synovial sarcomas.^[5] A targeted treatment to use genetically modified autologous T cells is undergoing clinical trials.^[6]

Further reading

• Brasseur F, Rimoldi D, Liénard D, Lethé B, Carrel S, Arienti F, Suter L, Vanwijck R, Bourlond A, Humblet Y . 6 . Expression of MAGE genes in primary and metastatic cutaneous melanoma . International Journal of Cancer . 63 . 3 . 375–80 . November 1995 . 7591235 . 10.1002/ijc.2910630313 . 38676798 .
• Imai Y, Shichijo S, Yamada A, Katayama T, Yano H, Itoh K . Sequence analysis of the MAGE gene family encoding human tumor-rejection antigens . Gene . 160 . 2 . 287–90 . July 1995 . 7642112 . 10.1016/0378-1119(94)00680-Q .
• De Plaen E, Arden K, Traversari C, Gaforio JJ, Szikora JP, De Smet C, Brasseur F, van der Bruggen P, Lethé B, Lurquin C . 6 . Structure, chromosomal localization, and expression of 12 genes of the MAGE family . Immunogenetics . 40 . 5 . 360–9 . 1994 . 7927540 . 10.1007/BF01246677 . 11331427 .
• Ding M, Beck RJ, Keller CJ, Fenton RG . Cloning and analysis of MAGE-1-related genes . Biochemical and Biophysical Research Communications . 202 . 1 . 549–55 . July 1994 . 8037761 . 10.1006/bbrc.1994.1963 .
• De Plaen E, Naerhuyzen B, De Smet C, Szikora JP, Boon T . Alternative promoters of gene MAGE4a . Genomics . 40 . 2 . 305–13 . March 1997 . 9119398 . 10.1006/geno.1996.4566 .
• Hillig RC, Coulie PG, Stroobant V, Saenger W, Ziegler A, Hülsmeyer M . High-resolution structure of HLA-A*0201 in complex with a tumour-specific antigenic peptide encoded by the MAGE-A4 gene . Journal of Molecular Biology . 310 . 5 . 1167–76 . July 2001 . 11502003 . 10.1006/jmbi.2001.4816 .
• Yutani S, Tanaka M, Mutsumoto H, Imai N, Sata M, Shichijo S, Harada M, Itoh K . 6 . Elevation of serum MAGE-4 protein levels and prediction of hepatocellular carcinogenesis in patients with liver cirrhosis . Japanese Journal of Cancer Research . 93 . 4 . 453–8 . April 2002 . 11985796 . 5927013 . 10.1111/j.1349-7006.2002.tb01277.x .
• Kocher T, Zheng M, Bolli M, Simon R, Forster T, Schultz-Thater E, Remmel E, Noppen C, Schmid U, Ackermann D, Mihatsch MJ, Gasser T, Heberer M, Sauter G, Spagnoli GC . 6 . Prognostic relevance of MAGE-A4 tumor antigen expression in transitional cell carcinoma of the urinary bladder: a tissue microarray study . International Journal of Cancer . 100 . 6 . 702–5 . August 2002 . 12209610 . 10.1002/ijc.10540 . 31224612 .
• Resnick MB, Sabo E, Kondratev S, Kerner H, Spagnoli GC, Yakirevich E . Cancer-testis antigen expression in uterine malignancies with an emphasis on carcinosarcomas and papillary serous carcinomas . International Journal of Cancer . 101 . 2 . 190–5 . September 2002 . 12209997 . 10.1002/ijc.10585 . free .
• Nagao T, Higashitsuji H, Nonoguchi K, Sakurai T, Dawson S, Mayer RJ, Itoh K, Fujita J . 6 . MAGE-A4 interacts with the liver oncoprotein gankyrin and suppresses its tumorigenic activity . The Journal of Biological Chemistry . 278 . 12 . 10668–74 . March 2003 . 12525503 . 10.1074/jbc.M206104200 . free . 2433/148472 . free .
• Sarcevic B, Spagnoli GC, Terracciano L, Schultz-Thater E, Heberer M, Gamulin M, Krajina Z, Oresic T, Separovic R, Juretic A . 6 . Expression of cancer/testis tumor associated antigens in cervical squamous cell carcinoma . Oncology . 64 . 4 . 443–9 . 2003 . 12759544 . 10.1159/000070305 . 578770 .
• Sakurai T, Itoh K, Higashitsuji H, Nagao T, Nonoguchi K, Chiba T, Fujita J . A cleaved form of MAGE-A4 binds to Miz-1 and induces apoptosis in human cells . The Journal of Biological Chemistry . 279 . 15 . 15505–14 . April 2004 . 14739298 . 10.1074/jbc.M310437200 . free . 2433/147540 . free .
• Miyahara Y, Naota H, Wang L, Hiasa A, Goto M, Watanabe M, Kitano S, Okumura S, Takemitsu T, Yuta A, Majima Y, Lemonnier FA, Boon T, Shiku H . 6 . Determination of cellularly processed HLA-A2402-restricted novel CTL epitopes derived from two cancer germ line genes, MAGE-A4 and SAGE . Clinical Cancer Research . 11 . 15 . 5581–9 . August 2005 . 16061876 . 10.1158/1078-0432.CCR-04-2585 . 2102185 .
• Hudolin T, Juretic A, Spagnoli GC, Pasini J, Bandic D, Heberer M, Kosicek M, Cacic M . 6 . Immunohistochemical expression of tumor antigens MAGE-A1, MAGE-A3/4, and NY-ESO-1 in cancerous and benign prostatic tissue . The Prostate . 66 . 1 . 13–8 . January 2006 . 16114059 . 10.1002/pros.20312 . 24732367 .
• Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M . 6 . Towards a proteome-scale map of the human protein-protein interaction network . Nature . 437 . 7062 . 1173–8 . October 2005 . 16189514 . 10.1038/nature04209 . 2005Natur.437.1173R . 4427026 .
• Yoshida N, Abe H, Ohkuri T, Wakita D, Sato M, Noguchi D, Miyamoto M, Morikawa T, Kondo S, Ikeda H, Nishimura T . 6 . Expression of the MAGE-A4 and NY-ESO-1 cancer-testis antigens and T cell infiltration in non-small cell lung carcinoma and their prognostic significance . International Journal of Oncology . 28 . 5 . 1089–98 . May 2006 . 16596224 . 10.3892/ijo.28.5.1089 . free .
• Peikert T, Specks U, Farver C, Erzurum SC, Comhair SA . Melanoma antigen A4 is expressed in non-small cell lung cancers and promotes apoptosis . Cancer Research . 66 . 9 . 4693–700 . May 2006 . 16651421 . 10.1158/0008-5472.CAN-05-3327 . free .

Notes and References

1. Rogner UC, Wilke K, Steck E, Korn B, Poustka A . The melanoma antigen gene (MAGE) family is clustered in the chromosomal band Xq28 . Genomics . 29 . 3 . 725–31 . October 1995 . 8575766 . 10.1006/geno.1995.9945 .
2. Web site: Entrez Gene: MAGEA4 melanoma antigen family A, 4.
3. Vital D, Ikenberg K, Moch H, Roessle M, Huber GF . The expression of the cancer testis antigen MAGE A4: A favorable prognostic biomarker in salivary gland carcinomas related to low tumor grading . Laryngoscope Investigative Otolaryngology . 3 . 3 . 182–190 . June 2018 . 30062133 . 6057220 . 10.1002/lio2.160 .
4. Yakirevich E, Sabo E, Lavie O, Mazareb S, Spagnoli GC, Resnick MB . Expression of the MAGE-A4 and NY-ESO-1 cancer-testis antigens in serous ovarian neoplasms . Clinical Cancer Research . 9 . 17 . 6453–60 . December 2003 . 14695148 .
5. Web site: Specific Peptide-Enhanced Affinity Receptor MAGE-A4 T Cells for Synovial Sarcoma. 2021-07-02. www.healio.com.
6. Hong DS, Butler MO, Johnson M, Olszanski AJ, Norry E, Van Winkle E, Chagin KD, Amado RG . 6 . October 2018 . Initial safety assessment of MAGE-A4 SPEAR T-cells . Annals of Oncology. en. 29. viii412. 10.1093/annonc/mdy288.029. free.