Skip to main content
SpringerLink
Log in

Association of familial colorectal cancer with variants in the E-cadherin (CDH1) and cyclin D1 (CCND1) genes

  • Original Article
  • Published:
International Journal of Colorectal Disease Aims and scope Submit manuscript

Abstract

Introduction

About 20% of colorectal cancer (CRC) patients show some kind of familiarity, which might be caused by yet unknown combinations of low penetrance susceptibility genes. We aimed to identify genetic factors for familial CRC (fCRC) in a unique study design that includes phenotypic extremes as represented by fCRC cases and ‘hyper-normal’ controls without CRC history and no adenomatous polyps on colonoscopy.

Materials and methods

Candidate gene variants were determined by allele-specific amplification (SLC10A2 c.169C>T and c.171G>T) and restriction fragment length polymorphism assays (CCND1 c.870A>G; CDH1 –160C>A; TP53 R72P; VDR T2M). In total, 98 patients with fCRC, 96 patients with sporadic CRC, and 220 hyper-normal controls were included.

Results

The minor allele of the CDH1 –160C>A polymorphism occurred significantly more often in controls compared to fCRC cases (OR = 0.664; p = 0.042). Homozygosity of the minor allele was significantly associated with affiliation to the control group (OR = 0.577; p = 0.029), indicating that both heterozygous and homozygous carriers of the common allele are at-risk for CRC. With respect to the CCND1 c.870A>G mutation, comparison of fCRC and sporadic CRC cases showed that A/A homozygosity was more common than G/G homozygosity among fCRC patients compared to controls (OR = 2.119; p = 0.045). However, no differences in allele or genotype frequencies were detected between sporadic CRC cases and controls, and no associations were observed for SLC10A2, TP53, and VDR polymorphisms.

Conclusions

We report a potential association of variants in the CCND1 and CDH1 genes with fCRC using a unique study design with phenotypic extremes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Boyle P, Langman JS (2000) ABC of colorectal cancer: epidemiology. BMJ 321:805–808

    Article  PubMed  CAS  Google Scholar 

  2. Butterworth AS, Higgins JP, Pharoah P (2006) Relative and absolute risk of colorectal cancer for individuals with a family history: a meta-analysis. Eur J Cancer 42:216–227

    Article  PubMed  Google Scholar 

  3. Houlston RS, Tomlinson IP (2001) Polymorphisms and colorectal tumor risk. Gastroenterology 21:282–301

    Article  Google Scholar 

  4. Morabia A, Cayanis E, Costanza MC, Ross BM, Flaherty MS, Alvin GB, Das K, Gilliam TC (2003) Association of extreme blood lipid profile phenotypic variation with 11 reverse cholesterol transport genes and 10 non-genetic cardiovascular disease risk factors. Hum Mol Genet 12:2733–2743

    Article  PubMed  CAS  Google Scholar 

  5. Porter TR, Richards FM, Houlston RS, Evans DG, Jankowski JA, Macdonald F, Norbury G, Payne SJ, Fisher SA, Tomlinson I, Maher ER (2002) Contribution of cyclin D1 (CCND1) and E-cadherin (CDH1) polymorphisms to familial and sporadic colorectal cancer. Oncogene 21:1928–1933

    Article  PubMed  CAS  Google Scholar 

  6. Richards FM, McKee SA, Rajpar MH, Cole TR, Evans DG, Jankowski JA, McKeown C, Sanders DS, Maher ER (1999) Germline E-cadherin gene (CDH1) mutations predispose to familial gastric cancer and colorectal cancer. Hum Mol Genet 8:607–610

    Article  PubMed  CAS  Google Scholar 

  7. Gemignani F, Moreno V, Landi S, Moullan N, Chabrier A, Gutierrez-Enriquez S, Hall J, Guino E, Peinado MA, Capella G, Canzian F (2004) A TP53 polymorphism is associated with increased risk of colorectal cancer and with reduced levels of TP53 mRNA. Oncogene 23:1954–1956

    Article  PubMed  CAS  Google Scholar 

  8. Slattery ML, Neuhausen SL, Hoffman M, Caan B, Curtin K, Ma KN, Samowitz W (2004) Dietary calcium, vitamin D, VDR genotypes and colorectal cancer. Int J Cancer 111:750–756

    Article  PubMed  CAS  Google Scholar 

  9. Ingles SA, Wang J, Coetzee GA, Lee ER, Frankl HD, Haile RW (2001) Vitamin D receptor polymorphisms and risk of colorectal adenomas (United States). Cancer Causes Control 12:607–614

    Article  PubMed  CAS  Google Scholar 

  10. Wang W, Xue S, Ingles SA, Chen Q, Diep AT, Frankl HD, Stolz A, Haile RW (2001) An association between genetic polymorphisms in the ileal sodium-dependent bile acid transporter gene and the risk of colorectal adenomas. Cancer Epidemiol Biomark Prev 10:931–936

    CAS  Google Scholar 

  11. Lamberti C, Di Blasi K, Archut D, Fimmers R, Mathiak M, Bollmann M, Vogel J, Kindermann D, Mezger J, Schmidt-Wolf IG, Sauerbruch T (2005) Population-based registration of unselected colorectal cancer patients: five-year survival in the region of Bonn/Rhine–Sieg, Germany. Z Gastroenterol 43:149–154

    Article  PubMed  CAS  Google Scholar 

  12. Bouwhuis CB, Moll HA (2003) Determination of ethnicity in children in The Netherlands: two methods compared. Eur J Epidemiol 18:385–388

    Article  PubMed  Google Scholar 

  13. Biondi G, Raspe P, Mascie-Taylor CG (2000) Genetic structure through surnames in Campobasso Province, Italy. J Biosoc Sci 32:459–465

    Article  PubMed  CAS  Google Scholar 

  14. Perez-Stable EJ, Hiatt RA, Sabogal F, Otero-Sabogal R (1995) Use of Spanish surnames to identify Latinos: comparison to self-identification. J Natl Cancer Inst Monographs 18:11–15

    PubMed  Google Scholar 

  15. Engel C, Forberg J, Holinski-Feder E, Pagenstecher C, Plaschke J, Kloor M, Poremba C, Pox CP, Ruschoff J, Keller G, Dietmaier W, Rummele P, Friedrichs N, Mangold E, Buettner R, Schackert HK, Kienle P, Stemmler S, Moeslein G, Loeffler M (2006) Novel strategy for optimal sequential application of clinical criteria, immunohistochemistry and microsatellite analysis in the diagnosis of hereditary nonpolyposis colorectal cancer. Int J Cancer 118:115–122

    Article  PubMed  CAS  Google Scholar 

  16. Boardman LA, Schmidt S, Lindor NM, Burgart LJ, Cunningham JM, Price-Troska T, Snow K, Ahlquist DA, Thibodeau SN (2001) A search for germline APC mutations in early onset colorectal cancer or familial colorectal cancer with normal DNA mismatch repair. Genes Chromosomes Cancer 30:181–186

    Article  PubMed  CAS  Google Scholar 

  17. Lothe RA, Hektoen M, Johnsen H, Meling GI, Andersen TI, Rognum TO, Lindblom A, Borresen-Dale AL (1998) The APC gene I1307K variant is rare in Norwegian patients with familial and sporadic colorectal or breast cancer. Cancer Res 58:2923–2924

    PubMed  CAS  Google Scholar 

  18. Rovella V, Carrara S, Crucitti SC, Coco C, Magistrelli P, Lucci-Cordisco E, Anti M, Neri G, Genuardi M (2001) Familial microsatellite-stable non-polyposis colorectal cancer: incidence and characteristics in a clinic-based population. Ann Oncol 12:813–818

    Article  PubMed  CAS  Google Scholar 

  19. Verma L, Porter TR, Richards FM, Rajpar MH, Evans DG, Macdonald F, Maher ER (2001) Germline mutation analysis of the transforming growth factor beta receptor type II (TGFBR2) and E-cadherin (CDH1) genes in early onset and familial colorectal cancer. J Med Genet 38:e7

    Article  PubMed  CAS  Google Scholar 

  20. Plaschke J, Kruger S, Dietmaier W, Gebert J, Sutter C, Mangold E, Pagenstecher C, Holinski-Feder E, Schulmann K, Moeslein G, Ruschoff J, Engel C, Evans G, Schackert HK (2004) Eight novel MSH6 germline mutations in patients with familial and nonfamilial colorectal cancer selected by loss of protein expression in tumor tissue. Human Mutat 23:285

    Article  Google Scholar 

  21. Salahshor S, Hou H, Diep CB, Loukola A, Zhang H, Liu T, Chen J, Iselius L, Rubio C, Lothe RA, Aaltonen L, Sun XF, Lindmark G, Lindblom A (2001) A germline E-cadherin mutation in a family with gastric and colon cancer. Int J Mol Med 8:439–443

    PubMed  CAS  Google Scholar 

  22. Huber A, Bentz EK, Schneeberger C, Huber JC, Hefler L, Tempfer C (2005) Ten polymorphisms of estrogen-metabolizing genes and a family history of colon cancer—an association study of multiple gene-gene interactions. J Soc Gynecol Investig 12:e51–e54

    Article  PubMed  Google Scholar 

  23. Le Marchand L, Kolonel LN, Henderson BE, Wilkens LR (2005) Association of an exon 1 polymorphism in the IGFBP3 gene with circulating IGFBP-3 levels and colorectal cancer risk: the multiethnic cohort study. Cancer Epidemiol Biomark Prev 14:1319–1321

    Article  Google Scholar 

  24. Bala S, Peltomaki P (2001) Cyclin D1 as a genetic modifier in hereditary nonpolyposis colorectal cancer. Cancer Res 61:6042–6045

    PubMed  CAS  Google Scholar 

  25. Le Marchand L, Seifried A, Lum-Jones A, Donlon T, Wilkens LR (2003) Association of the cyclin D1 A870G polymorphism with advanced colorectal cancer. JAMA 290:2843–2848

    Article  PubMed  Google Scholar 

  26. Lewis RC, Bostick RM, Xie D, Deng Z, Wargovich MJ, Fina MF, Roufail WM, Geisinger KR (2003) Polymorphism of the cyclin D1 gene, CCND1, and risk for incident sporadic colorectal adenomas. Cancer Res 63:8549–8553

    PubMed  CAS  Google Scholar 

  27. Schernhammer ES, Tranah GJ, Giovannucci E, Chan AT, Ma J, Colditz GA, Hunter DJ, Willett WC, Fuchs CS (2006) Cyclin D1 A870G polymorphism and the risk of colorectal cancer and adenoma. Br J Cancer 94:928–934

    Article  PubMed  CAS  Google Scholar 

  28. Wang L, Habuchi T, Mitsumori K, Li Z, Kamoto T, Kinoshita H, Tsuchiya N, Sato K, Ohyama C, Nakamura A, Ogawa O, Kato T (2003) Increased risk of prostate cancer associated with AA genotype of cyclin D1 gene A870G polymorphism. Int J Cancer 103:116–120

    Article  PubMed  CAS  Google Scholar 

  29. Catarino RJ, Breda E, Coelho V, Pinto D, Sousa H, Lopes C, Medeiros R (2006) Association of the A870G cyclin D1 gene polymorphism with genetic susceptibility to nasopharyngeal carcinoma. Head Neck 28:603–608

    Article  PubMed  Google Scholar 

  30. Huang D, Chen C, Sun W, Strom CM, Bender RA (2004) High-throughput gene sequencing assay development for hereditary nonpolyposis colon cancer. Clin Colorectal Cancer 4:275–279

    Article  PubMed  CAS  Google Scholar 

  31. Jiang J, Wang J, Suzuki S, Gajalakshmi V, Kuriki K, Zhao Y, Nakamura S, Akasaka S, Ishikawa H, Tokudome S (2006) Elevated risk of colorectal cancer associated with the AA genotype of the cyclin D1 A870G polymorphism in an Indian population. J Cancer Res Clin Oncol 132:193–199

    Article  PubMed  CAS  Google Scholar 

  32. Kong S, Amos CI, Luthra R, Lynch PM, Levin B, Frazier ML (2000) Effects of cyclin D1 polymorphism on age of onset of hereditary nonpolyposis colorectal cancer. Cancer Res 60:249–252

    PubMed  CAS  Google Scholar 

  33. Efstathiou JA, Liu D, Wheeler JM, Kim HC, Beck NE, Ilyas M, Karayiannakis AJ, Mortensen NJ, Kmiot W, Playford RJ, Pignatelli M, Bodmer WF (1999) Mutated epithelial cadherin is associated with increased tumorigenicity and loss of adhesion and of responsiveness to the motogenic trefoil factor 2 in colon carcinoma cells. Proc Natl Acad Sci U S A 96:2316–2321

    Article  PubMed  CAS  Google Scholar 

  34. Kim HC, Wheeler JM, Kim JC, Ilyas M, Beck NE, Kim BS, Park KC, Bodmer WF (2000) The E-cadherin gene (CDH1) variants T340A and L599V in gastric and colorectal cancer patients in Korea. Gut 47:262–267

    Article  PubMed  CAS  Google Scholar 

  35. Pharoah PD, Guilford P, Caldas C (2001) Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric cancer families. Gastroenterology 121:1348–1353

    Article  PubMed  CAS  Google Scholar 

  36. Lei H, Sjoberg-Margolin S, Salahshor S, Werelius B, Jandakova E, Hemminki K, Lindblom A, Vorechovsky I (2002) CDH1 mutations are present in both ductal and lobular breast cancer, but promoter allelic variants show no detectable breast cancer risk. Int J Cancer 98:199–204

    Article  PubMed  CAS  Google Scholar 

  37. Jonsson BA, Bergh A, Stattin P, Emmanuelsson M, Gronberg H (2002) Germline mutations in E-cadherin do not explain association of hereditary prostate cancer, gastric cancer and breast cancer. Int J Cancer 98:838–843

    Article  PubMed  CAS  Google Scholar 

  38. Wu MS, Huang SP, Chang YT, Lin MT, Shun CT, Chang MC, Wang HP, Chen CJ, Lin JT (2002) Association of the –160 C–> a promoter polymorphism of E-cadherin gene with gastric carcinoma risk. Cancer 94:1443–1448

    Article  PubMed  CAS  Google Scholar 

  39. Li LC, Chui RM, Sasaki M, Nakajima K, Perinchery G, Au HC, Nojima D, Carroll P, Dahiya R (2000) A single nucleotide polymorphism in the E-cadherin gene promoter alters transcriptional activities. Cancer Res 60:873–876

    PubMed  CAS  Google Scholar 

  40. Kuraoka K, Oue N, Yokozaki H, Kitadai Y, Ito R, Nakayama H, Yasui W (2003) Correlation of a single nucleotide polymorphism in the E-cadherin gene promoter with tumorigenesis and progression of gastric carcinoma in Japan. Int J Oncol 23:421–427

    PubMed  CAS  Google Scholar 

  41. Guillem JG, Rapaport BS, Kirchhoff T, Kolachana P, Nafa K, Glogowski E, Finch R, Huang H, Foulkes WD, Markowitz A, Ellis NA, Offit K (2003) A636P is associated with early-onset colon cancer in Ashkenazi Jews. J Am Coll Surg 196:222–225

    Article  PubMed  Google Scholar 

  42. Sotamaa K, Liyanarachchi S, Mecklin JP, Jarvinen H, Aaltonen LA, Peltomaki P, de la Chapelle A (2005) p53 codon 72 and MDM2 SNP309 polymorphisms and age of colorectal cancer onset in Lynch syndrome. Clin Cancer Res 11:6840–6844

    Article  PubMed  CAS  Google Scholar 

  43. Gong YL, Xie DW, Deng ZL, Bostick RM, Miao XJ, Zhang JH, Gong ZH (2005) Vitamin D receptor gene Tru9I polymorphism and risk for incidental sporadic colorectal adenomas. World J Gastroenterol 11:4794–4799

    PubMed  CAS  Google Scholar 

  44. Kim HS, Newcomb PA, Ulrich CM, Keener CL, Bigler J, Farin FM, Bostick RM, Potter JD (2001) Vitamin D receptor polymorphism and the risk of colorectal adenomas: evidence of interaction with dietary vitamin D and calcium. Cancer Epidemiol Biomark Prev 10:869–874

    CAS  Google Scholar 

  45. Peters U, McGlynn KA, Chatterjee N, Gunter E, Garcia-Closas M, Rothman N, Sinha R (2001) Vitamin D, calcium, and vitamin D receptor polymorphism in colorectal adenomas. Cancer Epidemiol Biomark Prev 10:1267–1274

    CAS  Google Scholar 

  46. Wactawski-Wende J, Kotchen JM, Anderson GL, Assaf AR, Brunner RL, O’Sullivan MJ, Margolis KL, Ockene JK, Phillips L, Pottern L, Prentice RL, Robbins J, Rohan TE, Sarto GE, Sharma S, Stefanick ML, Van Horn L, Wallace RB, Whitlock E, Bassford T, Beresford SA, Black HR, Bonds DE, Brzyski RG, Caan B, Chlebowski RT, Cochrane B, Garland C, Gass M, Hays J, Heiss G, Hendrix SL, Howard BV, Hsia J, Hubbell FA, Jackson RD, Johnson KC, Judd H, Kooperberg CL, Kuller LH, LaCroix AZ, Lane DS, Langer RD, Lasser NL, Lewis CE, Limacher MC, Manson JE (2006) Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med 354:684–696

    Article  PubMed  CAS  Google Scholar 

  47. Bayerdorffer E, Mannes GA, Ochsenkuhn T, Dirschedl P, Wiebecke B, Paumgartner G (1995) Unconjugated secondary bile acids in the serum of patients with colorectal adenomas. Gut 36:268–273

    Article  PubMed  CAS  Google Scholar 

  48. Bayerdorffer E, Mannes GA, Richter WO, Ochsenkuhn T, Wiebecke B, Kopcke W, Paumgartner G (1993) Increased serum deoxycholic acid levels in men with colorectal adenomas. Gastroenterology 104:145–151

    PubMed  CAS  Google Scholar 

  49. De Kok TM, van Faassen A, Glinghammar B, Pachen DM, Eng M, Rafter JJ, Baeten CG, Engels LG, Kleinjans JC (1999) Bile acid concentrations, cytotoxicity, and pH of fecal water from patients with colorectal adenomas. Dig Dis Sci 44:2218–2225

    Article  PubMed  Google Scholar 

  50. Gelb AM, McSherry CK, Sadowsky JR, Mosbach EH (1982) Tissue bile acids in patients with colon cancer and colonic polyps. Am J Gastroenterol 77:314–317

    PubMed  CAS  Google Scholar 

  51. Moorehead RJ, Campbell GR, Donaldson JD, McKelvey ST (1987) Relationship between duodenal bile acids and colorectal neoplasia. Gut 28:1454–1459

    Article  PubMed  CAS  Google Scholar 

  52. Ochsenkuhn T, Bayerdorffer E, Meining A, Schinkel M, Thiede C, Nussler V, Sackmann M, Hatz R, Neubauer A, Paumgartner G (1999) Colonic mucosal proliferation is related to serum deoxycholic acid levels. Cancer 85:1664–1669

    Article  PubMed  CAS  Google Scholar 

  53. Owen RW (1997) Faecal steroids and colorectal carcinogenesis. Scand J Gastroenterol Suppl 222:76–82

    PubMed  CAS  Google Scholar 

  54. Owen RW, Day DW, Thompson MH (1992) Faecal steroids and colorectal cancer: steroid profiles in subjects with adenomatous polyps of the large bowel. Eur J Cancer Prev 1:105–112

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Internal Medicine I, University Hospital Bonn, University of Bonn, Sigmund-Freud-Str. 25, 53105, Bonn, Germany

    Frank Grünhage, Matthias Jungck, Christoph Lamberti, Christine Berg, Ursula Becker, Tilman Sauerbruch & Frank Lammert

  2. Outpatient Clinics for Gastroenterology and Hepatology, Bonn, Germany

    Hildegard Schulte-Witte & Dominik Plassmann

  3. Institute of Human Genetics, University Hospital Bonn, University of Bonn, Bonn, Germany

    Nils Rahner & Stefan Aretz

  4. Institute for Pathology, University Hospital Bonn, University of Bonn, Bonn, Germany

    Nicolaus Friedrichs & Reinhard Buettner

Authors
  1. Frank Grünhage
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Matthias Jungck
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christoph Lamberti
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christine Berg
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ursula Becker
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hildegard Schulte-Witte
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dominik Plassmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Nils Rahner
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Stefan Aretz
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Nicolaus Friedrichs
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Reinhard Buettner
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Tilman Sauerbruch
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Frank Lammert
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Frank Grünhage.

Additional information

Frank Grünhage and Matthias Jungck contributed equally.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Grünhage, F., Jungck, M., Lamberti, C. et al. Association of familial colorectal cancer with variants in the E-cadherin (CDH1) and cyclin D1 (CCND1) genes. Int J Colorectal Dis 23, 147–154 (2008). https://doi.org/10.1007/s00384-007-0388-6

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00384-007-0388-6

Keywords

Search

Navigation