Abstract
Background and aim
Colorectal cancer (CRC) is one of the most rapidly increasing cancers in Korea, but no comprehensive analysis has been performed to speculate the genetic basis of CRC development. We investigated the presence of adenomatous polyposis coli gene (APC), Kirsten-ras (K-ras), p53, microsatellite instability (MSI), and melanoma antigen gene (MAGE) alterations in CRC and correlated the results obtained with clinical data.
Materials and methods
We collected 78 cancer tissues from CRC patients. Genetic analyses were performed on APC, K-ras, p53, and MSI (BAT 25 and BAT 26), and in addition, MAGE expression was tested by reverse transcription polymerase chain reaction. Correlations between genetic markers and clinical factors were analyzed after reviewing medical records.
Result
The positive rates for alterations of APC, K-ras, p53, MSI, and MAGE in 78 tissue samples were 33.3, 29.5, 34.6, 9.0, and 68.4%, respectively. Mutations were frequently detected in codons 1291 and 1450 of APC, in codon 12 of K-ras and in codons 248, 282, and 176 of p53. APC mutations were frequently noted in early-stage cancer, whereas MSI was observed in right-sided and multiple cancers. No associations were found between the presence of alterations in APC, K-ras, p53, MSI, and MAGE.
Interpretation
In Koreans, positive rates of alterations in APC and p53 were slightly lower than those of APC and p53 in Caucasians, and the genetic alterations including MAGE expression are involved in 92.1% of CRCs. The lack of multiple mutations and of a relation between mutation rates and clinical stage suggest that genetic alterations might have independent influences on CRC development in Koreans.
Similar content being viewed by others
References
Goh KL, Quek KF, Yeo GTS, Hilmi IN, Lee CK, Hasnida N, Aznan M, Kwan KL, Ong KT (2005) Colorectal cancer in Asians: a demographic and anatomic survey in Malaysian patients undergoing colonoscopy. Aliment Pharmacol Ther 22:859–864
Kim DH, Ahn YO (2004) Molecular epidemiology of colon cancer. Cancer Res Treat 36:93–99
Kim JP, Park IS, Ahn YO, Shin MH, Ahn DH, Kang TW, Ko UR, Ku PS, Kim KY, Kim KH, Kim NK, Kim DJ, Kim DH, Kim BS, Kim SH, Park CT, Min JS, Park TK, Woo BH, Yoo H, Lee SW, Lee SJ, Cho KS, Joo HZ, Ham EK (1995) 1991 Cancer incidence in Seoul, Korea: results of the implementation study of the Seoul cancer registry. J Korean Med Sci 10:74–84
Kim DH, Shin MH, Ahn YO (2000) Incidence pattern of colorectal cancer in Korea by subsite origin. J Korean Med Sci 15:675–681
Suh CI, Suh KA, Park SH, Chang HJ, Ko JW, Ahn DH (2000) Annual report of the central cancer registry in Korea—1998. J Korean Cancer Assoc 32:827–834
Shin HR, Jung KW, Won YJ, Park JG (2004) 2002 Annual report of the Korea central cancer registry: based on registered data from 139 hospitals. Cancer Res Treat 36:93–99
Vogelstein B, Kinzler KW (2002) The genetic basis human cancer. In: Kinzler KW, Vogelstin B (eds) Colorectal cancers. McGraw-Hill, New York, pp 587–593
Smith G, Carey FA, Beattie J, Wilkie MJ, Lightfoot TJ, Coxhead J, Garner RC, Steele RJ, Wolf CR (2002) Mutations in APC, Kirsten-ras, and p53-alternative genetic pathways to colorectal cancer. PNAS 99:9433–9438
Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, Nakamura Y, White R, Smits AM, Bos JL (1988) Genetic alterations during colorectal-tumor development. N Engl J Med 319:525–532
Jeong SY, Shin KH, Shin JH, Ku JL, Shin YK, Park SY, Kim WH, Park JG (2003) Microsatellite instability and mutations in DNA mismatch repair genes in sporadic colorectal cancers. Dis Colon Rectum 46:1069–1077
Bruggen P, Traversari C, Chomez P, Lurquin C, Plaen E, Eynde B, Knuth A, Boon T (1991) A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science 13:1643–1647
Plaen E, Arden K, Traversari C, Gaforio JJ, Szikora JP, Smet C, Brasseur F, Bruggen P, Lethe B, Lurquin C, Brasseur R, Chomez P, Backer O, Cavenee W, Boon T (1994) Structure, chromosomal localization, and expression of 12 genes of the MAGE family. Immunogenetics 40:360–369
Park MS, Park JW, Jeon CH, Lee KD, Chang HK (2002) Expression of melanoma antigen-encoding genes (MAGE) by common primers for MAGE-A1 to A6 in colorectal carcinomas among Koreans. J Korean Med Sci 17:497–501
Kim KH, Choi JS, Kim IJ, Ku JL, Park JG (2006) Promoter hypomethylation and reactivation of MAGE-A1 and MAGE-A3 genes in colorectal cancer cell lines and cancer tissues. World J Gastroenterol 21:5651–5657
Fearnhead NS, Wilding JL, Bodmer WF (2002) Genetics of colorectal cancer: hereditary aspects and overview of colorectal tumorigenesis. Br Med Bull 64:27–43
Giehl K (2005) Oncogenic Ras in tumour progression and metastasis. Biol Chem 386:193–205
Vogelstein B, Kinzler KW (1992) p53 function and dysfunction. Cell 70:523–526
Park JW, Kwon TK, Kim IH, Sohn SS, Kim YS, Kim CI, Bae OS, Lee KS, Lee KD, Lee CS, Chang HK, Choe BK, Ahn YS, Jeon CH (2002) A new strategy for the diagnosis of MAGE-expressing cancers. J Immunol Methods 266:79–86
Dietmaier W, Hofstadter F (2001) Detection of microsatellite instability by real time PCR and hybridization probe melting point analysis. Lab Invest 81:1453–1456
Won YJ, Park KJ, Kwon HJ, Lee JH, Kim JH, Kim YJ, Chun SH, Han HJ, Park JG (1999) Germline mutations of the APC gene in Korean familial adenomatous polyposis patients. J Hum Genet 44:103–108
Hutter P, Rey-Berthod C, Chappuis PO (2001) Molecular and clinical characteristics in 32 families affected with familial adenomatous polyposis. Human Mutat 18:550
Gavert N, Yaron Y, Maiman T, Bercovich D, Rozen P, Shomrat R, Legum C Orr-Urtreger A (2002) Molecular analysis of the APC gene in 71 Israeli families: 17 novel mutations. Human Mutat 19:664
Luijt RB, Khan PM, Vasen HFA, Tops CMJ, Leeuwen-Cornelisse ISJ, Wijnen JT, Klift HM, Plug RJ, Griffioen G, Fodde G (1997) Molecular analysis of the APC gene in 105 Dutch kindreds with familial adenomatous polyposis: 67 germline mutations identified by DGGE, PTT, and southern Analysis. Human Mutat 9:7–16
Calistri D, Rengucci C, Seymour I, Lattuneddu A, Polifemo A, Monti F, Saragoni L, Amadori D (2005) Mutation analysis of p53, K-ras, and BRAF genes in colorectal cancer progression. J Cell Physiol 204:484–488
Oh HE, Cho SJ, Won NH, Lee D, Kim I, Yeom BW (2001) K-ras gene mutations and expression of K-ras, p16, cyclin D1 and p53 in synchronous lesions of the colon adenoma carcinoma sequences. Korean J Pathol 35:291–298
Oliver M, Eeles R, Hollstein M, Khan MA, Harris CC, Hainaut P (2002) The IARC TP53 database: new online mutation analysis and recommendations to users. Human Mutat 19:607–614
Hong SI, Hong WS, Jang JJ, Lee DS, Cho NS, Jung ME, Kim HB, Ha GW, Park IC, Cho DS (1994) Alterations of p53 gene in primary gastric cancer tissues. Anticancer Res 14:1251–1255
Alves PM, Levy N, Bouzourene H, Viatte S, Bricard G, Ayyoub M, Vuilleumier H, Givel JC, Halkic N, Speiser DE, Romero P, Levy F (2007) Molecular and immunological evaluation of the expression of cancer/testis gene products in human colorectal cancer. Cancer Immunol Immunother 56:839–847
Koketsu S, Watanabe T, Kazama S, Ishihara S, Komuro Y, Nagawa H (2004) What types of colorectal cancer overexpress the MAGE protein? Hepatogastroenterology 51:1648–1652
Fodde R (2002) The APC gene in colorectal cancer. Eur J Cancer 38:867–871
Muta H, Noguchi M, Perucho M, Ushio K, Sugihara K, Ochiai A, Nawata J, Hirohashi S (1996) Clinical implications of microsatellite instability in colorectal cancers. Cancer 77:265–270
Ruschoff J, Bocker T, Schlegel J, Stumm G, Hofstaedter F (1995) Microsatellite instability: new aspects in the carcinogenesis of colorectal carcinoma. Virchows Arch 426:215–222
Cravo ML, Fidalgo PO, Lage PA, Albuquerque CM, Chaves PP, Claro I, Gomes T, Gaspar C, Soares JO, Nobre-Leitao C (1999) Validation and simplification of Bethesda guidelines for identifying apparently sporadic forms of colorectal carcinoma with microsatellite instability. Cancer 85:779–785
Acknowledgments
This work was equally supported by two research funds. (The Korean Institute of Industrial Technology Evaluation and Planning through the Biomolecular Engineering Center at Kyungpook National University and grant no. RTI04-03-01 from the Regional Technology Innovation Program of the Ministry of Commerce, Industry and Energy).
Author information
Authors and Affiliations
Corresponding author
Additional information
Dual first authorship: Chang-Ho Jeon and Han-IL Lee.
Rights and permissions
About this article
Cite this article
Jeon, CH., Lee, HI., Shin, IH. et al. Genetic alterations of APC, K-ras, p53, MSI, and MAGE in Korean colorectal cancer patients. Int J Colorectal Dis 23, 29–35 (2008). https://doi.org/10.1007/s00384-007-0373-0
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00384-007-0373-0