Genomic imprinting of insulin-like growth factor 2 (IGF2) has been shown to play an important role in the development of Wilms’ tumor and adult cancers including lung and esophageal cancer. Although IGF2 has been reported to be overexpressed in colorectal cancer, the status of this gene has not been fully elucidated. To clarify genomic imprinting of IGF2 in colorectal cancer, we examined loss of imprinting (LOI) and loss of heterozygosity (LOH) in surgically resected tissues by utilizing Apa1 polymorphism. Of 46 patients with colorectal cancer, 2 exhibited (2/15, 13%) LOH among 15 patients who were heterozygous for IGF2 DNA in nontumorous tissues. Four (4/12, 33%) patients showed LOI of IGF2 gene among informative patients. In these patients, the reverse transcription polymerase chain reaction and immunohistochemistry revealed that IGF2 mRNA is overexpressed in tumorous tissues, compared to nontumorous tissues. Of 15 patients in whom IGF2 was immunohistochemically more highly expressed in tumorous than in normal tissues, there were 2 with LOH and 4 with LOI. The results of the present study suggest that LOI of IGF2 plays an important role in the carcinogenesis of colorectal cancer.

Keywords:
Insulin-like growth factor 2, Colorectal cancer, Genomic imprinting, Loss of imprinting
1.
Kinzler KW, Vogelstein B: Lessons from hereditary colorectal cancer. Cell 1996;87:159–170.
2.
Houslston RS, Collins A, Slack J, Morton NE: Dominant genes for colorectal cancer are not rare. Ann Hum Genet 1992;56:99–103.
3.
Zapf J, Schmid C, Froesch ER: Biological and immunological properties of insulin-like growth factor I and II. Clin Endocrinol Metab 1984;13:3–30.
4.
Reeve AE, Eccles MR, Wilkins RJ, Bell GI, Millow LJ: Expression of insulin-like growth factor II transcripts in Wilms’ tumour. Nature 1985;317:258–260.
5.
Morison IM, Becroft DM, Taniguchi T, Woods CG, Reeve AE: Somatic overgrowth associated with overexpression of insulin-like growth factor II. Nat Med 1996;2:311–316.
6.
Hoppener JW, Mosselman S, Roholl PJ, Lambrechts C, Slebos RJC, de Pagter-Holhuizen P, Lips CJM, Jansz HS, Sussenbach JS: Expression of insulin-like growth factor I and II genes in human smooth muscle tumour. EMBO J 1988;7:1379–1385.
7.
Norstedt GA, Levinovitz A, Moller C, Eriksson LC, Andersson G: Expression of insulin-like growth factor I (IGF-I) and IGF-II mRNA during hepatic development, proliferation and carcinogenesis in the rat. Carcinogenesis 1988;9:209–213.
8.
Tricoli JV, Rall LB, Karakousis CP, Herrera L, Petrelli NJ, Bell GI, Shows TB: Enhanced levels of insulin-like growth factor messenger RNA in human colon carcinomas and liposarcomas. Cancer Res 1986;46:6169–6180.
9.
Lambert S, Vivario J, Boniver J, Gol-Winkler R: Abnormal expression and structural modification of the insulin-like growth factor-II gene in human colorectal tumors. Int J Cancer 1990;46:405–410.
10.
Kawamoto K, Onodera H, Kondo S, Kann S, Ikeuchi D, Maetani S, Imamura M: Expression of insulin-like growth factor-2 can predict the prognosis of human colorectal cancer patients: Correlation with tumor progression, proliferative activity and survival. Oncology 1998;55:242–248.
11.
Solter D: Differential imprinting and expression of maternal and paternal genomes. Annu Rev Genet 1988;22:127–146.
12.
Sapienza C: Genome imprinting and carcinogenesis. Biochim Biophys Acta 1991;1072:51–61.
13.
Ohlsson R, Nystrom A, Pfeifer-Ohlsson S, Tohonen V, Hedborg F, Schofield P, Flam F, Ekstrom TJ: IGF-2 is parentally imprinted during human embryogenesis and in the Beckwith-Wiedemann syndrome. Nat Genet 1993;4:94–97.
14.
Glannoukakis N, Deal C, Paquette J, Goodyer CG, Polychronakos C: Paternal genomic imprinting of the human IGF2 gene. Nat Genet 1993;4:48–101.
15.
Rainer S, Johnson LA, Dobry CJ, Ping AJ, Grundy PE, Feinberg AP: Relaxation of imprinted genes in human cancer. Nature 1993;362:747–749.
16.
Mori M, Inoue H, Shiraishi T, Mimori K, Shibata K, Nakashima H, Mafune K, Tanaka Y, Ueno H, Barnard GF, Sugimachi K, Akiyoshi T: Relaxation of insulin-like growth factor 2 gene imprinting in esophageal cancer. Int J Cancer 1996;68:441–446.
17.
Kondo M, Suzuki H, Ueda R, Osada H, Takagi K, Takahashi T, Takahashi T: Frequent loss of imprinting of the H19 gene is associated with its overexpression in human lung cancers. Oncogene 1995;10:1193–1198.
18.
Yun K, Fukumoto M, Jinno Y: Monoallelic expression of the insulin-like growth factor-2 in ovarian cancer. Am J Pathol 1996;148:1081–1087.
19.
Uyeno S, Aoki Y, Nata M, Sagisaka K, Kayama T, Yoshimoto T, Ono T: IGF2 but not H19 shows loss of imprinting in human glioma. Cancer Res 1996;56:5356–5359.
20.
Japanese Society for Cancer of the Colon and Rectum: General Rules for Clinical and Pathological Studies on Cancer of the Colon, Rectum, and Anus. Tokyo, Kinbara, 1994, pp 33–35.
21.
Gabriel WB, Dukes C, Bussey HJR: Lymphatic spread in a cancer of the rectum. Br J Surg 1936;23:395–413.
22.
Henry I, Botalti-Pelile C, Chehensse V, Beidjord C, Schwartz C, Utermann G, Junien C: Uniparental disomy in a genetic cancer-predisposing syndrome. Nature 1991;351:665–667.
23.
Schroeder WT, Chao LY, Dao DD, Strong LC, Pathak S, Riccardi V, Lewis WH, Saunders GF: Nonrandom loss of maternal chromosome 11 alleles in Wilms’ tumors. Am J Hum Genet 1987;40:413–420.
24.
Scrable H, Cavenee W, Ghavimi F, Lovell M, Morgan K, Sapienza C: A model for embryonal rhabdomyosarcoma tumorigenesis that involves genome imprinting. Proc Natl Acad Sci USA 1989;86:7480–7484.
25.
Pal N, Wadey RB, Buckle B, Yeomans E, Pritchard J, Cowell JK: Preferential loss of maternal alleles in sporadic Wilms’ tumour. Oncogene 1990;5:1665–1668.
26.
El-Atiq F, Garrouste F, Remacle-Bonnet M, Sastre B, Pommier G: Alterations in serum levels of insulin-like growth factor and insulin-like growth factor-binding protein in patients with colorectal cancer. Int J Cancer 1994;57:491–497.
27.
Lahm H, Amstad P, Wyniger J, Yilmaz A, Fischer JR, Schreyer M, Givel JC: Blockade of the insulin-like growth factor-1 receptor inhibits growth of human colorectal cancer cells: Evidence of a functional IGF-II-mediated autocrine loop. Int J Cancer 1994;58:452–459.
28.
Kinouchi Y, Iwatashi N, Higashioka S, Nagashima F, Chida M, Toyota T: Relaxation of imprinting of the insulin-like growth factor II gene in colorectal cancer. Cancer Lett 1996;107:105–108.
© 2000 S. Karger AG, Basel
2000
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