Loss of imprinting in normal tissue of colorectal cancer patients with microsatellite instability


Loss of imprinting (LOI) is an epigenetic alteration of some cancers involving loss of parental origin-specific expression of imprinted genes. We observed LOI of the insulin-like growth factor-II gene in twelve of twenty-seven informative colorectal cancer patients (44%), as well as in the matched normal colonic mucosa of the patients with LOI in their cancers, and in peripheral blood samples of four patients. Ten of eleven cancers (91%) with microsatellite instability showed LOI, compared with only two of sixteen tumors (12%) without microsatellite instability ( P < 0.001). Control patients without cancer showed LOI in colonic mucosa of only two of sixteen cases (12%, P < 0.001) and two of fifteen blood samples (13%, P < 0.001). These data suggest that LOI in tumor and normal tissue identifies most colorectal cancer patients with microsatellite instability in their tumors, and that LOI may identify an important subset of the population with cancer or at risk of developing cancer.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Strategy for quantitative analysis of IGF2 imprinting in colon cancer.
Figure 2: Genomic imprinting in colorectal cancer, matched normal mucosa, and mucosa of control patients.
Figure 3: Link between LOI in colorectal cancer, LOI in matched normal mucosa, and microsatellite instability in cancer.
Figure 4: Analysis of promoter-specific imprinting in colon cancer patients.
Figure 5: Loss of imprinting in blood, colonic mucosa, and tumor of colon cancer patients.


  1. 1

    Ford, D., Easton, D.F. & Peto, J. Estimates of the gene frequency of BRCA1 and its contribution to breast and ovarian cancer incidence. Am. J. Hum. Genet. 57, 1457–1462 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2

    Newman, B. et al. Frequency of breast cancer attributable to BRCA1 in a population-based series of American women. JAMA 279, 915– 921 (1998).

    CAS  Article  Google Scholar 

  3. 3

    Deng, G., Lu, Y., Zlotnikov, G., Thor, A.D. & Smith, H.S. Loss of heterozygosity in normal tissue adjacent to breast carcinomas. Science 274, 2057– 2059 (1996).

    CAS  Article  Google Scholar 

  4. 4

    Bisgaard, M.L., Fenger, K., Bulow, S., Niebuhr, E. & Mohr, J. Familial adenomatous polyposis (FAP): frequency, penetrance, and mutation rate. Hum. Mutat. 3, 121– 125 (1994).

    CAS  Article  Google Scholar 

  5. 5

    Aaltonen, L.A. et al. Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the disease. N. Engl. J. Med. 338, 1481–1487 ( 1998).

    CAS  Article  Google Scholar 

  6. 6

    Liu, B. et al. Mismatch repair gene defects in sporadic colorectal cancers with microsatellite instability. Nat. Genet. 9, 48–55 (1995).

    CAS  Article  Google Scholar 

  7. 7

    Chetty, R., Naidoo, R. & Schneider, J. Allelic imbalance and microsatellite instability of the dcc gene in colorectal cancer in patients under the age of 35 using fluorescent DNA technology. Mol. Pathol. 51, 35– 38 (1998).

    CAS  Article  Google Scholar 

  8. 8

    Thibodeau, S.N. et al. Microsatellite instability in colorectal cancer - different mutator phenotypes and the principal involvement of HMLH1. Cancer Res. 58, 1713–1718 ( 1998).

    CAS  PubMed  Google Scholar 

  9. 9

    Kim, H. et al. Expression of HMSH2 and HMLH1 in colorectal carcinomas with microsatellite instability. Pathol. Res. Pract. 194, 3– 9 (1998).

    CAS  Article  Google Scholar 

  10. 10

    Kim, H., Jen, J., Vogelstein, B. & Hamilton, S.R. Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences. Am. J. Pathol. 145, 148–156 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Brassett, C. et al. Microsatellite instability in early onset and familial colorectal cancer. J. Med. Genet. 33, 981– 985 (1996).

    CAS  Article  Google Scholar 

  12. 12

    Bubb, V.J. et al. Microsatellite instability and the role of hMSH2 in sporadic colorectal cancer. Oncogene 12, 2641– 2649 (1996).

    CAS  PubMed  Google Scholar 

  13. 13

    Lukish, J.R. et al. Prognostic significance of DNA replication errors in young patients with colorectal cancer. Ann. Surg. 227, 51–56 (1998).

    CAS  Article  Google Scholar 

  14. 14

    Senba, S. et al. Clinicopathologic and genetic features of nonfamilial colorectal carcinomas with DNA replication errors. Cancer 82, 279–285 (1998).

    CAS  Article  Google Scholar 

  15. 15

    Lynch, H.T. & Smyrk, T.C. Identifying hereditary nonpolyposis colorectal cancer. N. Engl. J. Med. 338, 1537–1538 (1998).

    CAS  Article  Google Scholar 

  16. 16

    Feinberg, A.P. in The Genetic Basis of Human Cancer (eds. Vogelstein, B. & Kinzler, K.W.) 95 (McGraw-Hill, New York,1998).

    Google Scholar 

  17. 17

    Rainier, S. et al. Relaxation of imprinted genes in human cancer. Nature 362, 747–749 ( 1993).

    CAS  Article  Google Scholar 

  18. 18

    Ogawa, O. et al. Relaxation of insulin-like growth factor II gene imprinting implicated in Wilms' tumour. Nature 362, 749–751 (1993).

    CAS  Article  Google Scholar 

  19. 19

    Weksberg, R., Shen, D.R., Fei, Y.L., Song, Q.L. & Squire, J. Disruption of insulin-like growth factor 2 imprinting in Beckwith-Weidemann syndrome. Nature Genet. 5, 143–150 (1993).

    CAS  Article  Google Scholar 

  20. 20

    Feinberg, A.P., Kalikin, L.M. & Johnson, L.A., Thompson, J.S. Loss of imprinting in human cancer. Cold Spring Harb. Symp. 59, 357–364 (1994).

    CAS  Article  Google Scholar 

  21. 21

    Suzuki, H., Veda, R., Takahashi, T. & Takahashi, T. Altered imprinting in lung cancer. Nature Genet. 6, 332– 333 (1994).

    CAS  Article  Google Scholar 

  22. 22

    Randhawa, G.S. et al. Loss of imprinting in disease progression in chronic myelogenous leukemia. Blood 91, 3144– 3147 (1998).

    CAS  PubMed  Google Scholar 

  23. 23

    Boland, C.R. et al. National Cancer Institute workshop on microsatellite instability for cancer detection and familial predisposition: Development of international criteria for the determination of microsatellite instability in colorectal cancer (submitted).

  24. 24

    Vu, T.H. & Hoffman, A.R. Promoter-specific imprinting of the human insulin-like growth factor-II gene. Nature 371, 714–717 (1994).

    CAS  Article  Google Scholar 

  25. 25

    He, L. et al. Hypervariable allelic expression patterns of the imprinted IGF2 gene in tumor cells. Oncogene 16, 113– 119 (1998).

    CAS  Article  Google Scholar 

  26. 26

    Issa, J.P., Vertino, P.M., Boehm, C.D., Newsham, I.F. & Baylin, S.B. Switch from monoallelic to biallelic human IGF2 promoter methylation during aging and carcinogenesis. Proc. Natl. Acad. Sci. USA 93: 11757– 11762 (1996).

    CAS  Article  Google Scholar 

  27. 27

    Kitsbert, D. et al. Allele-specific replication timing of imprinted gene regions. Nature 364, 459–463 (1993).

    Article  Google Scholar 

  28. 28

    LaSalle, J.M. & Lalande, M. Homologous association of oppositely imprinted chromosomal domains. Science 272, 725–728 (1996).

    CAS  Article  Google Scholar 

  29. 29

    Aparicio, O.M., Billington, B.L. & Gottschling, D.E. Modifiers of position effect are shared between telomeric and silent mating-type loci in S. cerevisiae. Cell 66, 1279–1287 (1991).

    CAS  Article  Google Scholar 

  30. 30

    Strahl-Bolsinger, S., Hecht, A., Luo, K. & Grunstein, M. SIR2 and SIR4 interactions differ in core and extended telomeric heterochromatin in yeast. Genes Dev. 11, 83–93 (1997).

    CAS  Article  Google Scholar 

  31. 31

    Buck, S.W. & Shore, D. Action of a RAP1 carboxy-terminal silencing domain reveals an underlying competition between HMR and telomeres in yeast. Genes Dev. 9, 370– 384 (1995).

    CAS  Article  Google Scholar 

  32. 32

    Brachmann, C.B. et al. The SIR2 gene family, conserved from bacteria to humans, functions in silencing, cell cycle progression, and chromosome stability. Genes Dev. 9, 2888–2902 (1995).

    CAS  Article  Google Scholar 

  33. 33

    Feinberg, A. & Vogelstein, B. Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature 301, 89–92 ( 1983).

    CAS  Article  Google Scholar 

  34. 34

    Steenman, M. et al. Loss of imprinting of IGF2 in linked to reduced expression and abnormal methylation of H19 in Wilms' tumour. Nature Genet. 7:433–439, 1994.

    CAS  Article  Google Scholar 

  35. 35

    Herman, J.G. et al. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc. Natl. Acad. Sci. USA 95, 6870–6875 (1998).

    CAS  Article  Google Scholar 

  36. 36

    Suzuki, K. et al. Microsatellite instability in female non-small-cell lung cancer patients with familial clustering of malignancy. Br. J. Cancer 77, 1003–1008 ( 1998).

    CAS  Article  Google Scholar 

  37. 37

    Sekine, I. et al. Microsatellite instability in lung cancer patients 40 years of age or younger. Jpn. J. Cancer Res. 88, 559–563 (1997).

    CAS  Article  Google Scholar 

  38. 38

    Ottini, L. et al. Microsatellite instability in gastric cancer is associated with tumor location and family history in a high-risk population from Tuscany. Cancer Res. 57, 4523–4529 (1997).

    CAS  PubMed  Google Scholar 

  39. 39

    Shinmura, K. et al. Stage-dependent evaluation of microsatellite instability in gastric carcinoma with familial clustering. Cancer Epidemiol. Biomarkers 6, 693–697 ( 1997).

    CAS  Google Scholar 

  40. 40

    Vogelsang, H.E. et al. Microsatellite instability and positive family anamnesis in patients with stomach carcinoma. Langenbecks Arch. Chir. Suppl. 114, 113–116 ( 1997).

    Google Scholar 

  41. 41

    Ohlsson, R. et al. IGF2 is parentally imprinted during human embryogenesis and in the Beckwith-Wiedemann syndrome. Nature Genet. 4 , 94–97 (1993).

    CAS  Article  Google Scholar 

  42. 42

    Dietmaier, W. et al. Diagnostic microsatellite instability: definition and correlation with mismatch repair protein expression. Cancer Res. 57, 4749–4756 (1997).

    CAS  PubMed  Google Scholar 

Download references


We thank J. Barletta, R. Robinson and K. Romans for technical assistance; P. Kwiterovich for blood samples; M. Lee, J. Nathans, T. Kelly, C. Dang, and B. Chernow for discussions; and P. Rusche for manuscript preparation. This work was supported by NIH grants CA65145 (A.P.F) and CA62924 (S.R.H.).

Author information



Corresponding author

Correspondence to Andrew P. Feinberg.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Cui, H., Horon, I., Ohlsson, R. et al. Loss of imprinting in normal tissue of colorectal cancer patients with microsatellite instability. Nat Med 4, 1276–1280 (1998). https://doi.org/10.1038/3260

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing