Abstract
Flat colorectal tumors, characterized by high-grade dysplasia from early small flat mucosal lesions, exhibit a relatively aggressive clinical behavior and are known for their infrequent K-ras mutations. In this study, we investigated the methylation status of the RASSF1A promoter in association with 3p LOH and K-ras mutations in 48 flat colorectal tumors (39 early carcinomas and nine intramucosal high-grade dysplasias). RASSF1A hypermethylation was detected in 39 of 48 (81.3%) tumors and RASSF1A methylation was also detected in 19 of 39 (49%) normal colonic mucosal tissues. 3p21.3 LOH was detected in 20 of 42 (47.6%) cases, but RASSF1 methylation was detected in cases with LOH (14 cases) and retention of 3p21.3 (20 cases). K-ras mutations were detected in seven of 48 (14.6%) tumors and the concordant occurrence of K-ras mutation and RASSF1A methylation was detected in three of 48 cases (6.3%). Overall, there was a statistically significant mutually exclusive relationship between K-ras mutations and RASSF1A methylation. In conclusion, promoter hypermethylation of RASSF1A is a frequent event and may start early in the background normal mucosa in this tumor type. An alternative cascade of abnormalities in RAS transduction pathways may be responsible for the flat morphology and aggressive nature of flat colorectal neoplasms.
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Abbreviations
- RASSF1A :
-
Ras association domain family 1 gene A
- LOH:
-
loss of heterozygosity
- MSP:
-
methylation-specific PCR
- SSCP:
-
single-strand conformation polymorphism
References
Agathanggelou A, Honorio S, Macartney DP, Martinez A, Dallol A, Rader J, Fullwood P, Chauhan A, Walker R, Shaw JA, Hosoe S, Lerman MI, Minna JD, Maher ER and Latif F . (2001). Oncogene, 20, 1509–1518.
Burbee DG, Forgacs E, Zochbauer-Muller S, Shivakumar L, Fong K, Gao B, Randle D, Kondo M, Virmani A, Bader S, Sekido Y, Latif F, Milchgrub S, Toyooka S, Gazdar AF, Lerman MI, Zabarovsky E, White M and Minna JD . (2001). J. Natl. Cancer Inst., 93, 691–699.
Byun DS, Lee MG, Chae KS, Ryu BG and Chi SG . (2001). Cancer Res., 61, 7034–7038.
Celeste A, Difilippantonio S, Difilippantonio MJ, Fernandez-Capetillo O, Pilch DR, Sedelnikova OA, Eckhaus M, Ried T, Bonner WM and Nussenzweig A . (2003). Cell, 114, 371–383.
Chiang JM, Chou YH and Chou TB . (1998). Cancer Res., 58, 3289–3293.
Dammann R, Li C, Yoon JH, Chin PL, Bates S and Pfeifer GP . (2000). Nat. Genet., 25, 315–319.
Dammann R, Schagdarsurengin U, Liu L, Otto N, Gimm O, Dralle H, Boehm BO, Pfeifer GP and Hoang-Vu C . (2003a). Oncogene, 22, 3806–3812.
Dammann R, Schagdarsurengin U, Strunnikova M, Rastetter M, Seidel C, Liu L, Tommasi S and Pfeifer GP . (2003b). Histol. Histopathol., 18, 665–677.
Dammann R, Takahashi T and Pfeifer GP . (2001). Oncogene, 20, 3563–3567.
Fenoglio CM and Lane N . (1974). Cancer, 34 (Suppl), 819–823.
Fujii H, Ajioka Y, Kazami S, Takagaki T, Gong Zhu X, Hirose S, Watanabe H and Shirai T . (2002). J. Pathol., 197, 298–306.
Fujimori T, Satonaka K, Yamamura-Idei Y, Nagasako K and Maeda S . (1994). Int. J. Cancer, 57, 51–55.
Herman JG, Graff JR, Myohanen S, Nelkin BD and Baylin SB . (1996). Proc. Natl. Acad. Sci. USA, 93, 9821–9826.
Issa JP, Ahuja N, Toyota M, Bronner MP and Brentnall TA . (2001). Cancer Res., 61, 3573–3577.
Khokhlatchev A, Rabizadeh S, Xavier R, Nedwidek M, Chen T, Zhang XF, Seed B and Avruch J . (2002). Curr. Biol., 12, 253–265.
Kuroki T, Trapasso F, Yendamuri S, Matsuyama A, Alder H, Mori M and Croce CM . (2003). Cancer Res., 63, 3724–3728.
Lehmann U, Langer F, Feist H, Glockner S, Hasemeier B and Kreipe H . (2002). Am. J. Pathol., 160, 605–612.
Lerman MI and Minna JD . (2000). Cancer Res., 60, 6116–6133.
Liu L, Yoon JH, Dammann R and Pfeifer GP . (2002). Oncogene, 21, 6835–6840.
Lo KW, Kwong J, Hui AB, Chan SY, To KF, Chan AS, Chow LS, Teo PM, Johnson PJ and Huang DP . (2001). Cancer Res., 61, 3877–3881.
Lusher ME, Lindsey JC, Latif F, Pearson AD, Ellison DW and Clifford SC . (2002). Cancer Res., 62, 5906–5911.
Maruyama R, Toyooka S, Toyooka KO, Harada K, Virmani AK, Zochbauer-Muller S, Farinas AJ, Vakar-Lopez F, Minna JD, Sagalowsky A, Czerniak B and Gazdar AF . (2001). Cancer Res., 61, 8659–8663.
Minamoto T, Sawaguchi K, Mai M, Yamashita N, Sugimura T and Esumi H . (1994). Cancer Res., 54, 2841–2844.
Morrissey C, Martinez A, Zatyka M, Agathanggelou A, Honorio S, Astuti D, Morgan NV, Moch H, Richards FM, Kishida T, Yao M, Schraml P, Latif F and Maher ER . (2001). Cancer Res., 61, 7277–7281.
Morson B . (1974). Proc. R. Soc. Med., 67, 451–457.
Mueller JD, Haegle N, Keller G, Mueller E, Saretzky G, Bethke B, Stolte M and Hofler H . (1998). Am. J. Pathol., 153, 1977–1984.
Olschwang S, Slezak P, Roze M, Jaramillo E, Nakano H, Koizumi K, Rubio CA, Laurent-Puig P and Thomas G . (1998). Int. J. Cancer, 77, 366–369.
Pfeifer GP, Yoon JH, Liu L, Tommasi S, Wilczynski SP and Dammann R . (2002). Biol. Chem., 383, 907–914.
Rubio CA and Rodensjo M . (1996). Dis. Colon Rectum, 39, 143–147.
Schagdarsurengin U, Gimm O, Hoang-Vu C, Dralle H, Pfeifer GP and Dammann R . (2002). Cancer Res., 62, 3698–3701.
Schagdarsurengin U, Wilkens L, Steinemann D, Flemming P, Kreipe HH, Pfeifer GP, Schlegelberger B and Dammann R . (2003). Oncogene, 22, 1866–1871.
Serrano M . (1997). Exp. Cell Res., 237, 7–13.
Shimoda T, Ikegami M, Fujisaki J, Matsui T, Aizawa S and Ishikawa E . (1989). Cancer, 64, 1138–1146.
Shivakumar L, Minna J, Sakamaki T, Pestell R and White MA . (2002). Mol. Cell. Biol., 22, 4309–4318.
Sparks AB, Morin PJ, Vogelstein B and Kinzler KW . (1998). Cancer Res., 58, 1130–1134.
Spugnardi M, Tommasi S, Dammann R, Pfeifer GP and Hoon DS . (2003). Cancer Res., 63, 1639–1643.
Tada S, Yao T, Iida M, Koga H, Hizawa K and Fujishima M . (1994). Cancer, 74, 2430–2435.
van Engeland M, Roemen GM, Brink M, Pachen MM, Weijenberg MP, de Bruine AP, Arends JW, van den Brandt PA, de Goeij AF and Herman JG . (2002). Oncogene, 21, 3792–3795.
Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, Nakamura Y, White R, Smits AM and Bos JL . (1988). N. Engl. J. Med., 319, 525–532.
Vos MD, Ellis CA, Bell A, Birrer MJ and Clark GJ . (2000). J. Biol. Chem., 275, 35669–35672.
Wagner KJ, Cooper WN, Grundy RG, Caldwell G, Jones C, Wadey RB, Morton D, Schofield PN, Reik W, Latif F and Maher ER . (2002). Oncogene, 21, 7277–7282.
Yashiro M, Carethers JM, Laghi L, Saito K, Slezak P, Jaramillo E, Rubio C, Koizumi K, Hirakawa K and Boland CR . (2001). Cancer Res., 61, 2676–2683.
Yoon JH, Dammann R and Pfeifer GP . (2001). Int. J. Cancer, 94, 212–217.
Yukawa M, Fujimori T, Maeda S, Tabuchi M and Nagasako K . (1994). Gut, 35, 1258–1261.
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Sakamoto, N., Terai, T., Ajioka, Y. et al. Frequent hypermethylation of RASSF1A in early flat-type colorectal tumors. Oncogene 23, 8900–8907 (2004). https://doi.org/10.1038/sj.onc.1207993
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DOI: https://doi.org/10.1038/sj.onc.1207993
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