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:

Comprehensive characterization of HNPCC-related colorectal cancers reveals striking molecular features in families with no germline mismatch repair gene mutations

Oncogene volume 24, pages 1542–1551 (2005)Cite this article

Abstract

A considerable fraction of families with HNPCC shows no germline mismatch repair (MMR) gene mutations. We previously detected ‘hidden’ MMR gene defects in 42% of such families, leaving the remaining 58% ‘truly’ mutation negative. Here, we characterized 50 colorectal carcinomas and five adenomas arising in HNPCC families; 24 truly MMR gene mutation negative and 31 MMR gene mutation positive. Among 31 tumors from MMR gene mutation positive families, 25 (81%) had active Wnt signaling as indicated by aberrant β-catenin localization with or without CTNNB1 mutations, compared to only 7/18 tumors from MMR gene mutation negative families (39%; P=0.005). CGH studies revealed stable profiles in 9/16 (56%) of MMR gene mutation negative tumors, which was significantly associated with membranous β-catenin (P=0.005). Tumors with membranous β-catenin from the MMR gene mutation negative group also showed low frequency of TP53 mutations compared to those with nuclear β-catenin. Thus, a majority of the MMR gene mutation negative cases exhibited a novel molecular pattern characterized by the paucity of changes in common pathways to colorectal carcinogenesis. This feature distinguishes the MMR gene mutation negative families from both HNPCC families linked to MMR defects and sporadic cases, suggesting the involvement of novel predisposition genes and pathways in such families.

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

Similar content being viewed by others

References

  • Abdel-Rahman WM, Katsura K, Rens W, Gorman PA, Sheer D, Bicknell D, Bodmer WF, Arends MJ, Wyllie AH and Edwards PAW . (2001). Proc. Natl. Acad. Sci. USA, 98, 2538–2543.

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

  • Chan TL, Curtis LC, Leung SY, Farrington SM, Ho JWC, Chan ASY, Lam PWY, Tse CW, Dunlop MG, Wyllie AH and Yuen ST . (2001). Oncogene, 20, 4871–4876.

  • Costa A, Marasca R, Valentinis B, Savarino M, Faranda A, Silvestrini R and Torelli G . (1995). J. Pathol., 176, 45–53.

  • Curtis LJ, Georgiades IB, White S, Bird CC, Harrison DJ and Wyllie AH . (2000). J. Pathol., 192, 440–445.

  • da Costa LT, He TC, Yu J, Sparks AB, Morin PJ, Polyak K, Laken S, Vogelstein B and Kinzler KW . (1999). Oncogene, 18, 5010–5014.

  • Deng GR, Bell I, Crawley S, Gum J, Terdiman JP, Allen BA, Truta B, Sleisenger MH and Kim YS . (2004). Clin. Cancer Res., 10, 191–195.

  • El-Rifai W, Larramendy ML, Bjorkqvist AM, Hemmer S and Knuutila S . (1997). Lab. Invest., 77, 699–700.

  • Fujiwara T, Stolker JM, Watanabe T, Rashid A, Longo P, Eshleman JR, Booker S, Lynch HT, Jass JR, Green JS, Kim H, Jen J, Vogelstein B and Hamilton SR . (1998). Am. J. Pathol., 153, 1063–1078.

  • Hao XP, Frayling IM, Willcocks TC, Han W, Tomlinson IPM, Pignatelli MN, Pretlow TP and Talbot IC . (2002). Virchows Arch., 440, 362–366.

  • Hinoi T, Loda M and Fearon ER . (2003). J. Biol. Chem., 278, 44608–44616.

  • Hinoi T, Tani M, Lucas PC, Caca K, Dunn RL, Macri E, Loda M, Appelman HD, Cho KR and Fearon ER . (2001). Am. J. Pathol., 159, 2239–2248.

  • Holmberg M, Kristo P, Chadwick RB, Mecklin J-P, Järvinen H, de la Chapelle A, Nyström-Lahti M and Peltomäki P . (1998). Hum. Mutat., 11, 482.

  • Huang J, Papadopoulos N, McKinley AJ, Farrington SM, Curtis LJ, Wyllie AH, Zheng S, Willson JKV, Markowitz SD, Morin P, Kinzler KW, Vogelstein B and Dunlop MG . (1996). Proc. Natl. Acad. Sci. USA, 93, 9049–9054.

  • Huang JQ, Kuismanen SA, Liu T, Chadwick RB, Johnson CK, Stevens MW, Richards SK, Meek JE, Gao X, Wright FA, Mecklin JP, Järvinen HJ, Gronberg H, Bisgaard ML, Lindblom A and Peltomäki P . (2001). Cancer Res., 61, 1619–1623.

  • Ilyas M, Tomlinson IPM, Rowan A, Pignatelli M and Bodmer WF . (1997). Proc. Natl. Acad. Sci. USA, 94, 10330–10334.

  • Iwamoto M, Ahnen DJ, Franklin WA and Maltzman TH . (2000). Carcinogenesis, 21, 1935–1940.

  • Kariola R, Abdel-Rahman WM, Ollikainen M, Butzow R, Peltomäki P and Nyström M . (2005). Fam. Cancer (in press).

  • Kim HG, Jen J, Vogelstein B and Hamilton SR . (1994). Am. J. Pathol., 145, 148–156.

  • Kitaeva MN, Grogan L, Williams JP, Dimond E, Nakahara K, Hausner P, DeNobile JW, Soballe PW and Kirsh IR . (1997). Cancer Res., 57, 4478–4481.

  • Konishi M, Kikuchiyanoshita R, Tanaka K, Muraoka M, Onda A, Okumura Y, Kishi N, Iwama T, Mori T, Koike M, Ushio K, Chiba M, Nomizu S, Konishi F, Utsunomiya J and Miyaki M . (1996). Gastroenterology, 111, 307–317.

  • Kuismanen SA, Moisio AL, Schweizer P, Truninger K, Salovaara R, Arola J, Butzow R, Jiricny J, Nyström-Lahti M and Peltomäki P . (2002). Am. J. Pathol., 160, 1953–1958.

  • Kumar R, Angelini S and Hemminki K . (2003). Oncogene, 22, 9217–9224.

  • Lengauer C, Kinzler KW and Vogelstein B . (1997). Nature, 386, 623–627.

  • Leslie A, Pratt NR, Gillespie K, Sales M, Kernohan NM, Smith G, Wolf CR, Carey FA and Steele RJC . (2003). Cancer Res., 63, 4656–4661.

  • Liu T, Yan H, Kuismanen S, Percesepe A, Bisgaard ML, Pedroni M, Benatti P, Kinzler KW, Vogelstein B, de Leon MP, Peltomäki P and Lindblom A . (2001). Cancer Res., 61, 7798–7802.

  • Lovig T, Meling GI, Diep CB, Thorstensen L, Andersen SN, Lothe RA and Rognum TO . (2002). Scand J. Gastroenterol., 37, 1184–1193.

  • Mirabelli-Primdahl L, Gryfe R, Kim H, Millar A, Luceri C, Dale D, Holowaty E, Bapat B, Gallinger S and Redston M . (1999). Cancer Res., 59, 3346–3351.

  • Miyaki M, Iijima T, Kimura J, Yasuno M, Mori T, Hayashi Y, Koike M, Shitara N, Iwama T and Kuroki T . (1999). Cancer Res., 59, 4506–4509.

  • Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B and Kinzler KW . (1997). Science, 275, 1787–1790.

  • Muleris M, Dutrillaux AM, Olschwang S, Salmon RJ and Dutrillaux B . (1995). Genes Chromosomes Cancer, 14, 223–226.

  • Nyström-Lahti M, Kristo P, Nicolaides NC, Chang SY, Aaltonen LA, Moisio AL, Järvinen HJ, Mecklin JP, Kinzler KW, Vogelstein B, de la Chapelle A and Peltomäki P . (1995). Nat. Med., 1, 1203–1206.

  • Nyström-Lahti M, Wu Y, Moisio AL, Hofstra RMW, Osinga J, Mecklin JP, Järvinen HJ, Leisti J, Buys C, de la Chapelle A and Peltomäki P . (1996). Hum. Mol. Genet., 5, 763–769.

  • Oliveira C, Pinto M, Duval A, Brennetot C, Domingo E, Espin E, Armengol M, Yamamoto H, Hamelin R, Seruca R and Schwartz S . (2003). Oncogene, 22, 9192–9196.

  • Peltomäki P . (2003). J. Clin. Oncol., 21, 1174–1179.

  • Qualtrough D, Hinoi T, Fearon E and Paraskeva C . (2002). Gut, 51, 184–190.

  • Renkonen E, Zhang YG, Lohi H, Salovaara R, Abdel-Rahman WM, Nilbert M, Aittomaki K, Järvinen HJ, Mecklin JP, Lindblom A and Peltomäki P . (2003). J. Clin. Oncol., 21, 3629–3637.

  • Rodriguez-Bigas MA, Boland CR, Hamilton SR, Henson DE, Jass JR, Khan PM, Lynch H, Perucho M, Smyrk T, Sobin L and Srivastava S . (1997). J. Natl. Cancer Inst., 89, 1758–1762.

  • Rowan AJ, Lamlum H, Ilyas M, Wheeler J, Straub J, Papadopoulou A, Bicknell D, Bodmer WF and Tomlinson IPM . (2000). Proc. Natl. Acad. Sci. USA, 97, 3352–3357.

  • Salahshor S, Kressner U, Pahlman L, Glimelius B, Lindmark G and Lindblom A . (1999). Genes Chromosomes Cancer, 26, 247–252.

  • Schlegel J, Stumm G, Scherthan H, Bocker T, Zirngibl H, Ruschoff J and Hofstadter F . (1995). Cancer Res., 55, 6002–6005.

  • Schweizer P, Moisio AL, Kuismanen SA, Truninger K, Vierumaki R, Salovaara R, Arola J, Butzow R, Jiricny J, Peltomäki P and Nyström-Lahti M . (2001). Cancer Res., 61, 2813–2815.

  • Sparks AB, Morin PJ, Vogelstein B and Kinzler KW . (1998). Cancer Res., 58, 1130–1134.

  • Vasen HF, Watson P, Mecklin J-P and Lynch HT . (1999). Gastroenterology, 116, 1453–1456.

  • Vasen HFA, Mecklin J-P, Khan PM and Lynch HT . (1991). Dis. Colon Rectum, 34, 424–425.

  • Vogelstein B, Lane D and Levine AJ . (2000). Nature, 408, 307–310.

  • Wicking C, Simms LA, Evans T, Walsh M, Chawengsaksophak K, Beck F, Chenevix-Trench G, Young J, Jass J, Leggett B and Wainwright B . (1998). Oncogene, 17, 657–659.

  • Wijnen J, Khan PM, Vasen H, vander Klift H, Mulder A, van Leeuwen Cornelisse I, Bakker B, Losekoot M, Moller P and Fodde R . (1997). Am. J. Hum. Genet., 61, 329–335.

  • Yagi OK, Akiyama Y and Yuasa Y . (1999). Br. J. Cancer, 79, 440–444.

Download references

Acknowledgements

We thank Saila Saarinen for expert technical assistance and Katja Kuosa for help with sample collection. This work was supported by the Academy of Finland, the Sigrid Juselius Foundation, the Finnish Cancer Foundation, the Finnish Cultural Foundation, the Paulo Foundation and the Helsinki University Central Hospital.

Author information

Authors and Affiliations

  1. Department of Medical Genetics, University of Helsinki, Helsinki, Finland

    Wael M Abdel-Rahman, Miina Ollikainen, Sakari Knuutila & Päivi Peltomäki

  2. Department of Pathology, Faculty of Medicine, Zagazig University, Egypt

    Wael M Abdel-Rahman

  3. Department of Biological and Environmental Sciences, Genetics, University of Helsinki, Helsinki, Finland

    Reetta Kariola & Minna Nyström-Lahti

  4. Department of Clinical Genetics and the Second Department of Surgery, Helsinki University Hospital, Helsinki, Finland

    Heikki J Järvinen

  5. Department of Surgery, Jyväskylä Central Hospital, Jyväskylä, Finland

    Jukka-Pekka Mecklin

  6. Department of Pathology, Laboratory of Cytomolecular Genetics, Haartman Institute and HUSLAB, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

    Sakari Knuutila

Authors
  1. Wael M Abdel-Rahman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Miina Ollikainen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Reetta Kariola
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Heikki J Järvinen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jukka-Pekka Mecklin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Minna Nyström-Lahti
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sakari Knuutila
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Päivi Peltomäki
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wael M Abdel-Rahman.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Abdel-Rahman, W., Ollikainen, M., Kariola, R. et al. Comprehensive characterization of HNPCC-related colorectal cancers reveals striking molecular features in families with no germline mismatch repair gene mutations. Oncogene 24, 1542–1551 (2005). https://doi.org/10.1038/sj.onc.1208387

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1208387

Keywords

This article is cited by

Search

Advanced search

Quick links