Skip to main content

Advertisement

SpringerLink
Log in

Genome-wide linkage analysis and tumoral characterization reveal heterogeneity in familial colorectal cancer type X

  • Original Article—Alimentary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Background

Familial colorectal cancer type X (FCCTX) fulfils clinical criteria defining Lynch syndrome (LS), but is not related to germline mutations in DNA mismatch-repair genes. Its aetiology remains unexplained and there is little evidence of involvement of the common colorectal carcinogenetic pathways. We aimed to identify susceptibility loci and gain insights into carcinogenic pathways involved FCCTX tumour development.

Methods

We performed a linkage analysis in 22 FCCTX families. We also constructed a tissue microarray in order to define an immunohistochemical (IHC) profile for FCCTX tumours (N = 27) by comparing them to three other types of colorectal tumors: LS (N = 18), stable early-onset (N = 31) and other sporadic disease (N = 80). Additionally, we screened for BRAF/KRAS mutations and determined CpG island methylator phenotype (CIMP) status for all FCCTX tumours.

Results

We found suggestive evidence of linkage at four chromosomal regions; 2p24.3, 4q13.1, 4q31.21 and 12q21.2–q21.31. We screened genes in 12q21 and ruled out the implication of RASSF9 and NTS, good candidates due to their potential involvement in carcinogenesis and colorectal epithelium development. Based on IHC profiles FCCTX tumours did not form a single, exclusive cluster. They were clearly different from LS, but very similar to stable early onset tumours. The CIMP and chromosomal instability pathways were implicated in one-third and one-quarter of FCCTX cases, respectively. The remaining cases did not have alterations in any known carcinogenic pathways.

Conclusions

Our results highlight the heterogeneity of FCCTX tumours and call into question the utility of using only clinical criteria to identify FCCTX cases.

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
Fig. 2

Similar content being viewed by others

References

  1. Lindor NM, Rabe K, Petersen GM, et al. Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X. JAMA. 2005;293:1979–85.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Jover R, Castells A. Molecular information defines a new entity of hereditary colorectal cancer. Gastroenterology. 2008;134:888–9 (Discussion 9–90).

    Article  PubMed  Google Scholar 

  3. Valle L, Perea J, Carbonell P, et al. Clinicopathologic and pedigree differences in Amsterdam I-positive hereditary nonpolyposis colorectal cancer families according to tumor microsatellite instability status. J Clin Oncol. 2007;25:781–6.

    Article  CAS  PubMed  Google Scholar 

  4. Llor X, Pons E, Xicola RM, et al. Differential features of colorectal cancers fulfilling Amsterdam criteria without involvement of the mutator pathway. Clin Cancer Res. 2005;11:7304–10.

    Article  CAS  PubMed  Google Scholar 

  5. Wiesner GL, Daley D, Lewis S, et al. A subset of familial colorectal neoplasia kindreds linked to chromosome 9q22.2–31.2. Proc Natl Acad Sci USA. 2003;100:12961–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Djureinovic T, Skoglund J, Vandrovcova J, et al. A genome wide linkage analysis in Swedish families with hereditary non-familial adenomatous polyposis/non-hereditary non-polyposis colorectal cancer. Gut. 2006;55:362–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Kemp Z, Carvajal-Carmona L, Spain S, et al. Evidence for a colorectal cancer susceptibility locus on chromosome 3q21–q24 from a high-density SNP genome-wide linkage scan. Hum Mol Genet. 2006;15:2903–10.

    Article  CAS  PubMed  Google Scholar 

  8. Skoglund J, Djureinovic T, Zhou XL, et al. Linkage analysis in a large Swedish family supports the presence of a susceptibility locus for adenoma and colorectal cancer on chromosome 9q22.32–31.1. J Med Genet. 2006;43:e7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Papaemmanuil E, Carvajal-Carmona L, Sellick GS, et al. Deciphering the genetics of hereditary non-syndromic colorectal cancer. Eur J Hum Genet. 2008;16:1477–86.

    Article  CAS  PubMed  Google Scholar 

  10. Picelli S, Vandrovcova J, Jones S, et al. Genome-wide linkage scan for colorectal cancer susceptibility genes supports linkage to chromosome 3q. BMC Cancer. 2008;8:87.

    Article  PubMed Central  PubMed  Google Scholar 

  11. Cicek MS, Cunningham JM, Fridley BL, et al. Colorectal cancer linkage on chromosomes 4q21, 8q13, 12q24, and 15q22. PLoS One. 2012;7:e38175.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Neklason DW, Kerber RA, Nilson DB, et al. Common familial colorectal cancer linked to chromosome 7q31: a genome-wide analysis. Cancer Res. 2008;68:8993–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Middeldorp A, Jagmohan-Changur SC, van der Klift HM, et al. Comprehensive genetic analysis of seven large families with mismatch repair proficient colorectal cancer. Genes Chromosom Cancer. 2010;49:539–48.

    CAS  PubMed  Google Scholar 

  14. Abdel-Rahman WM, 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. 2005;24:1542–51.

    Article  CAS  PubMed  Google Scholar 

  15. Goel A, Xicola RM, Nguyen TP, et al. Aberrant DNA methylation in hereditary nonpolyposis colorectal cancer without mismatch repair deficiency. Gastroenterology. 2010;138:1854–62.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Goel A, Nagasaka T, Arnold CN, et al. The CpG island methylator phenotype and chromosomal instability are inversely correlated in sporadic colorectal cancer. Gastroenterology. 2007;132:127–38.

    Article  CAS  PubMed  Google Scholar 

  17. Nagasaka T, Koi M, Kloor M, et al. Mutations in both KRAS and BRAF may contribute to the methylator phenotype in colon cancer. Gastroenterology. 2008;134:1950–60 60 e1.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Toyota M, Ahuja N, Ohe-Toyota M, et al. CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci USA. 1999;96:8681–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Joensuu EI, Abdel-Rahman WM, Ollikainen M, et al. Epigenetic signatures of familial cancer are characteristic of tumor type and family category. Cancer Res. 2008;68:4597–605.

    Article  CAS  PubMed  Google Scholar 

  20. Oliphant A, Barker DL, Stuelpnagel JR, et al. BeadArray technology: enabling an accurate, cost-effective approach to high-throughput genotyping. Biotechniques. 2002;32:56–8 (pp 60–1).

    Google Scholar 

  21. Shen R, Fan JB, Campbell D, et al. High-throughput SNP genotyping on universal bead arrays. Mutat Res. 2005;573:70–82.

    Article  CAS  PubMed  Google Scholar 

  22. Maoret JJ, Anini Y, Rouyer-Fessard C, et al. Neurotensin and a non-peptide neurotensin receptor antagonist control human colon cancer cell growth in cell culture and in cells xenografted into nude mice. Int J Cancer. 1999;80:448–54.

    Article  CAS  PubMed  Google Scholar 

  23. Sherwood V, Recino A, Jeffries A, et al. The N-terminal RASSF family: a new group of Ras-association-domain-containing proteins, with emerging links to cancer formation. Biochem J. 2009;425:303–11.

    Article  PubMed  Google Scholar 

  24. Richter AM, Pfeifer GP, Dammann RH. The RASSF proteins in cancer; from epigenetic silencing to functional characterization. Biochim Biophys Acta. 2009;1796:114–28.

    CAS  PubMed  Google Scholar 

  25. Evers BM, Zhou Z, Celano P, et al. The neurotensin gene is a downstream target for Ras activation. J Clin Investig. 1995;95:2822–30.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Ogino S, Cantor M, Kawasaki T, et al. CpG island methylator phenotype (CIMP) of colorectal cancer is best characterised by quantitative DNA methylation analysis and prospective cohort studies. Gut. 2006;55:1000–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Weisenberger DJ, Siegmund KD, Campan M, et al. CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet. 2006;38:787–93.

    Article  CAS  PubMed  Google Scholar 

  28. Nygren AO, Ameziane N, Duarte HM, et al. Methylation-specific MLPA (MS-MLPA): simultaneous detection of CpG methylation and copy number changes of up to 40 sequences. Nucleic Acids Res. 2005;33:e128.

    Article  PubMed Central  PubMed  Google Scholar 

  29. Gray-McGuire C, Guda K, Adrianto I, et al. Confirmation of linkage to and localization of familial colon cancer risk haplotype on chromosome 9q22. Cancer Res. 2010;70:5409–18.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Chen L, Johnson RC, Milgram SL. P-CIP1, a novel protein that interacts with the cytosolic domain of peptidylglycine alpha-amidating monooxygenase, is associated with endosomes. J Biol Chem. 1998;273:33524–32.

    Article  CAS  PubMed  Google Scholar 

  31. Lichtenstein P, Holm NV, Verkasalo PK, et al. Environmental and heritable factors in the causation of cancer––analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med. 2000;343:78–85.

    Article  CAS  PubMed  Google Scholar 

  32. Rustgi AK. The genetics of hereditary colon cancer. Genes Dev. 2007;21:2525–38.

    Article  CAS  PubMed  Google Scholar 

  33. Daley D, Lewis S, Platzer P, et al. Identification of susceptibility genes for cancer in a genome-wide scan: results from the colon neoplasia sibling study. Am J Hum Genet. 2008;82:723–36.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. el-Deiry WS, Tokino T, Velculescu VE, et al. WAF1, a potential mediator of p53 tumor suppression. Cell. 1993;75:817–25.

    Article  CAS  PubMed  Google Scholar 

  35. Sanchez-de-Abajo A, de la Hoya M, van Puijenbroek M, et al. Molecular analysis of colorectal cancer tumors from patients with mismatch repair proficient hereditary nonpolyposis colorectal cancer suggests novel carcinogenic pathways. Clin Cancer Res. 2007;13:5729–35.

    Article  CAS  PubMed  Google Scholar 

  36. Jass JR. Serrated adenoma of the colorectum and the DNA-methylator phenotype. Nat Clin Pract Oncol. 2005;2:398–405.

    Article  CAS  PubMed  Google Scholar 

  37. Snover DC. Update on the serrated pathway to colorectal carcinoma. Hum Pathol. 2011;42:1–10.

    Article  PubMed  Google Scholar 

  38. Nagasaka T, Sasamoto H, Notohara K, et al. Colorectal cancer with mutation in BRAF, KRAS, and wild-type with respect to both oncogenes showing different patterns of DNA methylation. J Clin Oncol. 2004;22:4584–94.

    Article  CAS  PubMed  Google Scholar 

  39. Fearon ER. Molecular genetics of colorectal cancer. Annu Rev Pathol. 2011;6:479–507.

    Article  CAS  PubMed  Google Scholar 

  40. Kawasaki T, Nosho K, Ohnishi M, et al. Correlation of beta-catenin localization with cyclooxygenase-2 expression and CpG island methylator phenotype (CIMP) in colorectal cancer. Neoplasia. 2007;9:569–77.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Ogino S, Stampfer M. Lifestyle factors and microsatellite instability in colorectal cancer: the evolving field of molecular pathological epidemiology. J Natl Cancer Inst. 2010;102:365–7.

    Article  PubMed Central  PubMed  Google Scholar 

  42. Toyota M, Ohe-Toyota M, Ahuja N, et al. Distinct genetic profiles in colorectal tumors with or without the CpG island methylator phenotype. Proc Natl Acad Sci USA. 2000;97:710–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Samowitz WS, Holden JA, Curtin K, et al. Inverse relationship between microsatellite instability and K-ras and p53 gene alterations in colon cancer. Am J Pathol. 2001;158:1517–24.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Goldstein NS. Serrated pathway and APC (conventional)-type colorectal polyps: molecular-morphologic correlations, genetic pathways, and implications for classification. Am J Clin Pathol. 2006;125:146–53.

    Article  CAS  PubMed  Google Scholar 

  45. Pino MS, Chung DC. The chromosomal instability pathway in colon cancer. Gastroenterology. 2010;138:2059–72.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Francisco I, Albuquerque C, Lage P, et al. Familial colorectal cancer type X syndrome: two distinct molecular entities? Fam Cancer. 2011;10:623–31.

    Article  PubMed  Google Scholar 

  47. Casimiro MC, Crosariol M, Loro E, et al. ChIP sequencing of cyclin D1 reveals a transcriptional role in chromosomal instability in mice. J Clin Invest. 2012;122(3):833–43.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Therkildsen C, Jonsson G, Dominguez-Valentin M, et al. Gain of chromosomal region 20q and loss of 18 discriminates between Lynch syndrome and familial colorectal cancer. Eur J Cancer. 2013;49(6):1226–35.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was funded by the Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (FIS-PI07/1081 and FIS-PI10/00554). We thank the Spanish National Tumor Bank Network for providing us with the paraffin-embedded tissue, and Maika González Neira and Roger Milne for their contributions.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Familial Cancer Clinical Unit, Spanish National Cancer Research Center (CNIO), Madrid, Spain

    E. Sánchez-Tomé, B. Rivera, F. Mercadillo & M. Urioste

  2. Surgery Department, Hospital Universitario 12 de Octubre, Madrid, Spain

    J. Perea

  3. Spanish National Genotyping Center, CNIO, Madrid, Spain

    G. Pita & A. Gonzalez-Neira

  4. Laboratory of Molecular Biology, Hematology Division, Hospital Universitario 12 de Octubre, Madrid, Spain

    D. Rueda & A. Canal

  5. Human Genetics Group, CNIO, Madrid, Spain

    J. Benitez

  6. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain

    J. Benitez & M. Urioste

Authors
  1. E. Sánchez-Tomé
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. B. Rivera
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J. Perea
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G. Pita
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D. Rueda
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. F. Mercadillo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A. Canal
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A. Gonzalez-Neira
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. J. Benitez
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. M. Urioste
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E. Sánchez-Tomé.

Additional information

Article note

E. Sanchez-Tome and B. Rivera have contributed equally.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 1459 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sánchez-Tomé, E., Rivera, B., Perea, J. et al. Genome-wide linkage analysis and tumoral characterization reveal heterogeneity in familial colorectal cancer type X. J Gastroenterol 50, 657–666 (2015). https://doi.org/10.1007/s00535-014-1009-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-014-1009-0

Keywords

Search

Navigation