Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Allelic imbalance of APAF-1 locus at 12q23 is related to progression of colorectal carcinoma

Oncogene volume 23, pages 8292–8300 (2004)Cite this article

Abstract

APAF-1 gene, located at chromosome locus 12q23, is a key factor in the mitochondrial apoptotic pathway downstream of p53, and is a potential tumor suppressor gene. We hypothesized that APAF-1 gene dysfunction due to allelic imbalance (AI) contributes to the development and progression of colorectal carcinoma (CRC). AI at APAF-1 locus and microsatellite instability (MIN) in CRCs and adenomas were assessed by multiple microsatellite markers. The frequency of AI significantly increased with tumor progression; 0 of 33 (0%) adenomas, 14 of 49 (29%) primary CRCs, and 18 of 34 (53%) liver metastases had AI. A total of 12 metastases were matched with corresponding primary CRCs; in 11 of 12 (92%) pairs, the metastasis had same AI status as the corresponding primary tumor. APAF-1 mRNA transcription level was significantly decreased with AI in liver metastases (P=0.009). Promoter hypermethylation was found in three of 35 (9%) primary CRCs and one of 15 (7%) liver metastases by methylation-specific PCR but was not correlated with AI. MIN was observed in 11 of 49 (23%) primary CRCs and was a favorable prognostic factor. Our results suggest that APAF-1 gene haploinsufficiency caused by AI increases with tumor progression, and relates to hepatic metastasis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  • Aaltonen LA, Peltomaki P, Leach FS, Sistonen P, Pylkkanen L, Mecklin JP, Jarvinen H, Powell SM, Jen J, Hamilton SR, de la Chapelle A and Vogelstein B . (1993). Science, 260, 812–816.

  • Baylin SB, Herman JG, Graff JR, Vertino PM and Issa JP . (1998). Adv. Cancer Res., 72, 141–196.

  • Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, Meltzer SJ, Rodriguez-Bigas MA, Fodde R, Ranzani GN and Srivastava S . (1998). Cancer Res., 58, 5248–5257.

  • Deng G, Chen A, Hong J, Chae HS and Kim YS . (1999). Cancer Res., 59, 2029–2033.

  • Esteller M and Herman JG . (2002). J. Pathol., 196, 1–7.

  • Esteller M, Sparks A, Toyota M, Sanchez-Cespedes M, Capella G, Peinado MA, Gonzalez S, Tarafa G, Sidransky D, Meltzer SJ, Baylin SB and Herman JG . (2000). Cancer Res., 60, 4366–4371.

  • Fortin A, Cregan SP, MacLaurin JG, Kushwaha N, Hickman ES, Thompson CS, Hakim A, Albert PR, Cecconi F, Helin K, Park DS and Slack RS . (2001). J. Cell Biol., 155, 207–216.

  • Fujimoto A, Takeuchi H, Taback B, Hsueh EC, Elashoff D, Morton DL and Hoon DS . (2004). Cancer Res., 64, 2245–2250.

  • Gryfe R, Kim H, Hsieh ET, Aronson MD, Holowaty EJ, Bull SB, Redston M and Gallinger S . (2000). N. Engl. J. Med., 342, 69–77.

  • Hao XP, Frayling IM, Sgouros JG, Du MQ, Willcocks TC, Talbot IC and Tomlinson IP . (2002). Gut, 50, 834–839.

  • Hatta Y, Takeuchi S, Yokota J and Koeffler HP . (1997). Br. J. Cancer, 75, 1256–1262.

  • Hemminki A, Mecklin JP, Jarvinen H, Aaltonen LA and Joensuu H . (2000). Gastroenterology, 119, 921–928.

  • Herman JG . (2002). Gastroenterol. Clin. N. Am., 31, 945–958.

  • Herman JG and Baylin SB . (2003). N. Engl. J. Med., 349, 2042–2054.

  • Herman JG, Umar A, Polyak K, Graff JR, Ahuja N, Issa JP, Markowitz S, Willson JK, Hamilton SR, Kinzler KW, Kane MF, Kolodner RD, Vogelstein B, Kunkel TA and Baylin SB . (1998). Proc. Natl. Acad. Sci. USA, 95, 6870–6875.

  • Hermsen M, Postma C, Baak J, Weiss M, Rapallo A, Sciutto A, Roemen G, Arends JW, Williams R, Giaretti W, De Goeij A and Meijer G . (2002). Gastroenterology, 123, 1109–1119.

  • Hoon DS, Fujimoto A, Shu S and Taback B . (2002). Methods Enzymol., 356, 302–309.

  • Jen J, Kim H, Piantadosi S, Liu ZF, Levitt RC, Sistonen P, Kinzler KW, Vogelstein B and Hamilton SR . (1994). N. Engl. J. Med., 331, 213–221.

  • Jones PA . (1996). Cancer Res., 56, 2463–2467.

  • Jones PA . (1999). Trends Genet., 15, 34–37.

  • Kim H, Jung YK, Kwon YK and Park SH . (1999). Cytogenet. Cell Genet., 87, 252–253.

  • Kimura M, Furukawa T, Abe T, Yatsuoka T, Youssef EM, Yokoyama T, Ouyang H, Ohnishi Y, Sunamura M, Kobari M, Matsuno S and Horii A . (1998). Cancer Res., 58, 2456–2460.

  • Lengauer C, Kinzler KW and Vogelstein B . (1998). Nature, 396, 643–649.

  • Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES and Wang X . (1997). Cell, 91, 479–489.

  • Mihara M, Erster S, Zaika A, Petrenko O, Chittenden T, Pancoska P and Moll UM . (2003). Mol. Cell, 11, 577–590.

  • Moroni MC, Hickman ES, Denchi EL, Caprara G, Colli E, Cecconi F, Muller H and Helin K . (2001). Nat. Cell Biol., 3, 552–558.

  • Murty VV, Renault B, Falk CT, Bosl GJ, Kucherlapati R and Chaganti RS . (1996). Genomics, 35, 562–570.

  • Nakayama T, Taback B, Turner R, Morton DL and Hoon DS . (2001). Am. J. Pathol., 158, 1371–1378.

  • Renbaum P, Abrahamove D, Fainsod A, Wilson GG, Rottem S and Razin A . (1990). Nucleic Acids Res., 18, 1145–1152.

  • Robertson KD and Jones PA . (2000). Carcinogenesis, 21, 461–467.

  • Robles AI, Bemmels NA, Foraker AB and Harris CC . (2001). Cancer Res., 61, 6660–6664.

  • Schneider BG, Rha SY, Chung HC, Bravo JC, Mera R, Torres JC, Plaisance Jr KT, Schlegel R, McBride CM, Reveles XT and Leach RJ . (2003). Mol. Pathol., 56, 141–149.

  • Shinozaki M, Fujimoto A, Morton DL and Hoon DS . (2004). Clin. Cancer Res., 10, 1753–1757.

  • Soengas MS, Capodieci P, Polsky D, Mora J, Esteller M, Opitz-Araya X, McCombie R, Herman JG, Gerald WL, Lazebnik YA, Cordon-Cardo C and Lowe SW . (2001). Nature, 409, 207–211.

  • Spugnardi M, Tommasi S, Dammann R, Pfeifer GP and Hoon DS . (2003). Cancer Res., 63, 1639–1643.

  • Takeuchi H, Morton DL, Kuo C, Turner RR, Elashoff D, Elashoff R, Taback B, Fujimoto A and Hoon DS . (2004). J. Clin. Oncol., 22, 2671–2680.

  • Thibodeau SN, Bren G and Schaid D . (1993). Science, 260, 816–819.

  • 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.

  • Watanabe T, Wu TT, Catalano PJ, Ueki T, Satriano R, Haller DG, Benson III AB and Hamilton SR . (2001). N. Engl. J. Med., 344, 1196–1206.

  • Xiong Z, Wu AH, Bender CM, Tsao JL, Blake C, Shibata D, Jones PA, Yu MC, Ross RK and Laird PW . (2001). Cancer Epidemiol. Biomarkers Prev., 10, 799–803.

  • Yatsuoka T, Sunamura M, Furukawa T, Fukushige S, Yokoyama T, Inoue H, Shibuya K, Takeda K, Matsuno S and Horii A . (2000). Am. J. Gastroenterol., 95, 2080–2085.

Download references

Acknowledgements

This study was supported in part by funding from the Rod Fasone Memorial Cancer Fund (Indianapolis, IN), PO CA 29605 from the National Cancer Institute, NIH, and the Roy E Coates Foundation Laboratory.

Author information

Authors and Affiliations

  1. Department of Molecular Oncology, John Wayne Cancer Institute, Saint Johns Health Science Center, Santa Monica, 90404, CA, USA

    Naoyuki Umetani, Akihide Fujimoto, Hiroya Takeuchi, Masaru Shinozaki & Dave S B Hoon

  2. Division of Gastrointestinal Oncology, John Wayne Cancer Institute, Saint Johns Health Science Center, Santa Monica, 90404, CA, USA

    Anton J Bilchik

Authors
  1. Naoyuki Umetani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Akihide Fujimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hiroya Takeuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Masaru Shinozaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anton J Bilchik
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dave S B Hoon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dave S B Hoon.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Umetani, N., Fujimoto, A., Takeuchi, H. et al. Allelic imbalance of APAF-1 locus at 12q23 is related to progression of colorectal carcinoma. Oncogene 23, 8292–8300 (2004). https://doi.org/10.1038/sj.onc.1208022

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1208022

Keywords

This article is cited by

Search

Advanced search

Quick links