Abstract
The molecular basis for most non-HNPCC familial colorectal cancer cases is unknown, but there is increasing evidence that common genetic variants may play a role. We investigated the contribution of polymorphisms in two genes implicated in the pathogenesis of colorectal cancer, cyclin D1 (CCND1) and E-cadherin (CDH1), to familial and sporadic forms of the disease. The CCND1 870A/G polymorphism is thought to affect the expression of CCND1 through mRNA splicing and has been reported to modify the penetrance of HNPCC. Inactivation of E-cadherin is common in colorectal cancer, and truncating germline mutations have been reported to confer susceptibility to colorectal as well as diffuse gastric cancer. The −160A/C CDH1 polymorphism appears to affect expression of CDH1 and may therefore also confer an increased risk. We found a significantly higher frequency of CCND1 870A allele in 206 familial cases compared to 171 controls (P=0.03). Odds ratios in heterozygotes and homozygotes were 1.7 (95% CI: 1.0–2.66) and 1.8 (95% CI: 1.0–3.3) respectively. The difference was accounted for by an over-representation of A allele in non-HNPCC familial cases (P=0.007). Over-representation of the CCND1 A allele was also seen in sporadic colorectal cancer cases compared to controls but this did not attain statistical significance (P=0.08). No significant differences between the frequency of CDH1 −160A/C genotypes in familial, sporadic colorectal cancer cases and controls were seen, although a possible association between the low expressing A allele and right-sided tumours was detected in familial cases.
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Arber N, Hibshoosh H, Moss SF, Sutter T, Zhang Y, Begg M, Wang S, Weinstein IB, Holt PR . 1996 Gastroenterology 110: 669–674
Arber N, Doki Y, Han EK, Sgambato A, Zhou P, Kim NH, Delohery T, Klein MG, Holt PR, Weinstein IB . 1997 Cancer Res. 57: 1569–1574
Bala S, Peltomaki P . 2001 Cancer Res. 61: 6042–6045
Becker KF, Atkinson MJ, Reich U, Becker I, Nekarda H, Siewert JR, Hofler H . 1994 Cancer Res. 54: 3845–3852
Berx G, Cleton-Jansen AM, Nollet F, de Leeuw WJF, van de Vijver MJ, Cornelisse C, van Roy F . 1995 EMBO J. 14: 6107–6115
Betticher DC, Thatcher N, Altermatt HJ, Hoban P, Ryder WDJ, Heighway J . 1995 Oncogene 11: 1005–1011
Brassett C, Joyce JA, Froggatt NJ, Williams G, Furniss D, Walsh S, Miller R, Evans DG, Maher ER . 1996 J. Med. Genet. 33: 981–985
Christophori G, Semb H . 1999 Trends Biol. Sci. 24: 73–76
Frayling IM, Beck NE, Ilyas M, Dove-Edwin I, Goodman P, Pack K, Bell JA, Williams CB, Hodgson SV, Thomas HJ, Talbot IC, Bodmer WF, Tomlinson IP . 1998 Proc. Natl. Acad. Sci. USA 95: 10722–10727
Gayther SA, Gorringe KL, Ramus SJ, Huntsman D, Roviello F, Grehan N, Machado JC, Pinto E, Seruca R, Halling K, MacLeod P, Powell SM, Jackson CE, Ponder BAJ, Caldas C . 1998 Cancer Res. 58: 4086–4089
Graff JR, Herman JG, Lapidus RG, Chopra H, Xu R, Jarrard DF, Isaacs WB, Pitha PM, Davidson NE, Baylin SB . 1995 Cancer Res. 55: 5195–5199
Guilford P, Hopkins J, Harraway J, McLeod M, McLeod N, Harawira P, Taite H, Scoular R, Miller A, Reeve AE . 1998 Nature 392: 402–405
Hardy RG, Tselepis C, Hoyland J, Wallis Y, Pretlow TP, Talbot I, Sanders DSA, Matthews G, Morton D, Jankowski JA . 2002 Gut in press
Ilyas M, Tomlinson IP, Hanby A, Talbot IC, Bodmer WF . 1997 Gut 40: 654–659
Jankowski J, Bedford F, Boulton R, Cruikshank N, Hall C, Elder J, Allan R, Forbes A, Kim Y, Wright N, Sanders S . 1998 Lab. Invest. 78: 1155–1167
Kong S, Amos CI, Luthra R, Lynch PM, Levin B, Frazier ML . 2000 Cancer Res. 60: 249–252
Kong S, Wei Q, Amos CI, Lynch PM, Levin B, Zong J, Frazier ML . 2001 J. Natl. Cancer Inst. 93: 1106–1108
Laken SJ, Petersen GM, Gruber SB, Oddoux C, Ostrer H, Giardiello FM, Hamilton SR, Hampel H, Markowitz A, Klimstra D, Jhanwar S, Winawer S, Offit K, Luce MC, Kinzler KW, Vogelstein B . 1997 Nat. Genet. 17: 79–83
Li LC, Chui RM, Sasaki M, Nakajima K, Perinchery G, Au HC, Nojima D, Carroll P, Dahiya R . 2000 Cancer Res. 60: 873–876
Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M, Pukkala E, Skytthe A, Hemminki K . 2000 N. Engl. J. Med. 343: 78–84
Lynch HT, de la Chapelle A . 1999 J. Med. Genet. 36: 801–818
MacLeod SL, Plaxco JR, Shinde A, Lang NP . 2001 Proc. Amer. Assoc. Cancer Res. 42: 149–
McKay JA, Douglas JJ, Ross VG, Curran S, Murray GI, Cassidy J, McLeod HL . 2000 Int. J. Cancer 88: 77–81
Platz A, Hansson J, Ringborg U . 2000 Am. J. Hum. Genet. 67: (Suppl 2) 406–
Richards FM, Mckee SA, Rajpar MH, Cole TRP, Evans DGR, Jankowski JA, McKeown C, Sanders DSA, Maher ER . 1999 Hum. Mol. Genet. 8: 607–610
Risinger JI, Berchuck A, Kohler MF, Boyd J . 1994 Nature Genet. 7: 98–102
Shtutman M, Zhurinsky J, Simcha I, Albanese C, D'Amico M, Pestell R, Ben-Ze'ev A . 1999 Proc. Natl. Acad. Sci. USA 96: 5522–5527
van de Wetering M, Barker N, Harkes IC, van der Heyden M, Dijk NJ, Hollestelle A, Klijn JG, Clevers H, Schutte M . 2001 Cancer Res. 61: 278–284
Verma L, Maher ER, Kane MF, Schmeits J, Kolodner RD, Brassett C, Evans DGR . 1999 J. Med. Genet. 36: 678–682
Yoon KA, Ku JL, Kang HC, Park JG . 2001 Proc. Amer. Assoc. Cancer Res. 42: 343–
Acknowledgements
We thank the many patients, clinicians and scientists who contributed to this study. We are grateful to the Birmingham United Hospitals Endowment Fund (TR Porter, FM Richards, ER Maher, JA Jankowski) and The Wellcome Trust (JA Jankowski) for financial support.
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Porter, T., Richards, F., Houlston, R. et al. Contribution of cyclin d1 (CCND1) and E-cadherin (CDH1) polymorphisms to familial and sporadic colorectal cancer. Oncogene 21, 1928–1933 (2002). https://doi.org/10.1038/sj.onc.1205245
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DOI: https://doi.org/10.1038/sj.onc.1205245
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