Breast Cancer Research and Treatment

, Volume 128, Issue 2, pp 467–472

Current evidence on the relationship between HRAS1 polymorphism and breast cancer risk: a meta-analysis

  • Chun Zhang
  • Guo-Qiang Lv
  • Xian-Ming Yu
  • Yuan-Long Gu
  • Jian-Ping Li
  • Liang-Feng Du
  • Ping Zhou


Rare alleles at the HRAS1 variable number of tandem repeats (VNTRs) locus have been implicated in breast cancer risk. Although many studies have showed that rare HRAS1 alleles may be associated with breast cancer risk, this relationship remains controversial. A meta-analysis was conducted to investigate the potential association between rare HRAS1 alleles and breast cancer risk. A database search found a total of 13 studies involving 1926 breast cancer cases and 2800 controls. Crude odds ratios (OR) and 95% confidence intervals (CI) were used to test the strength of association. When all the studies were combined into the meta-analysis, we found that breast cancer cases had a significantly higher frequency of rare alleles (OR = 2.03, 95% CI = 1.34, 3.10). In the subgroup analysis by race, we found that breast cancer cases had a significantly higher frequency of rare alleles (OR = 2.14, 95% CI = 1.37, 3.36) among Caucasians. In the subgroup analysis by study design, we found that breast cancer cases had a significantly higher frequency of rare alleles (OR = 2.47, 95% CI = 1.62, 3.79) among groups with hospital-based controls. In conclusion, this meta-analysis suggested that rare alleles at the HRAS1 VNTRs may contribute to breast cancer susceptibility. More population-based case–control studies were needed especially in Asians in the future.


HRAS1 Breast cancer Polymorphism Meta-analysis 


  1. 1.
    Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55(2):74–108PubMedCrossRefGoogle Scholar
  2. 2.
    Muss HB, Berry DA, Cirrincione CT, Theodoulou M, Mauer AM, Kornblith AB, Partridge AH, Dressler LG, Cohen HJ, Becker HP, Kartcheske PA, Wheeler JD, Perez EA, Wolff AC, Gralow JR, Burstein HJ, Mahmood AA, Magrinat G, Parker BA, Hart RD, Grenier D, Norton L, Hudis CA, Winer EP (2009) Adjuvant chemotherapy in older women with early-stage breast cancer. N Engl J Med 360(20):2055–2065PubMedCrossRefGoogle Scholar
  3. 3.
    Chlebowski RT, Blackburn GL, Thomson CA, Nixon DW, Shapiro A, Hoy MK, Goodman MT, Giuliano AE, Karanja N, McAndrew P, Hudis C, Butler J, Merkel D, Kristal A, Caan B, Michaelson R, Vinciguerra V, Del Prete S, Winkler M, Hall R, Simon M, Winters BL, Elashoff RM (2006) Dietary fat reduction and breast cancer outcome: interim efficacy results from the Women’s Intervention Nutrition Study. J Natl Cancer Inst 98(24):1767–1776PubMedCrossRefGoogle Scholar
  4. 4.
    Sotiriou C, Pusztai L (2009) Gene-expression signatures in breast cancer. N Engl J Med 360(8):790–800PubMedCrossRefGoogle Scholar
  5. 5.
    Dunning AM, Healey CS, Pharoah PD, Teare MD, Ponder BA, Easton DF (1999) A systematic review of genetic polymorphisms and breast cancer risk. Cancer Epidemiol Biomarkers Prev 8(10):843–854PubMedGoogle Scholar
  6. 6.
    Krontiris TG, DiMartino NA, Colb M, Parkinson DR (1985) Unique allelic restriction fragments of the human Ha-ras locus in leukocyte and tumour DNAs of cancer patients. Nature 313(6001):369–374PubMedCrossRefGoogle Scholar
  7. 7.
    Theillet C, Lidereau R, Escot C, Hutzell P, Brunet M, Gest J, Schlom J, Callahan R (1986) Loss of a c-H-ras-1 allele and aggressive human primary breast carcinomas. Cancer Res 46(9):4776–4781PubMedGoogle Scholar
  8. 8.
    Pluzhnikova GF, Serova OM, Kniazev PG, Fedorov SN, Novikov LB (1987) Joint amplification of c-myc and c-Ha-ras oncogenes in human breast and thyroid cancer cells. Eksp Onkol 9(2):15–17PubMedGoogle Scholar
  9. 9.
    Peto TE, Thein SL, Wainscoat JS (1988) Statistical methodology in the analysis of relationships between DNA polymorphisms and disease: putative association of Ha-ras-I hypervariable alleles and cancer. Am J Hum Genet 42(4):615–617PubMedGoogle Scholar
  10. 10.
    Nikiforova IF (1988) Amplification, rearrangement and expression of the c-myc and c-Ha-ras1 proto-oncogenes in patients with breast cancer. Eksp Onkol 10(1):17–20PubMedGoogle Scholar
  11. 11.
    White GR, Heighway J, Williams GT, Scott D (1988) Constitutional frequency of rare alleles of c-Ha-ras in breast cancer patients. Br J Cancer 57(5):526PubMedCrossRefGoogle Scholar
  12. 12.
    Garcia I, Dietrich PY, Aapro M, Vauthier G, Vadas L, Engel E (1989) Genetic alterations of c-myc, c-erbB-2, and c-Ha-ras protooncogenes and clinical associations in human breast carcinomas. Cancer Res 49(23):6675–6679PubMedGoogle Scholar
  13. 13.
    Kniazev PG, Serova OM, Babenko VI, Nikiforova IF, Gol’tseva AA, Pluzhnikova GF, Plutalov OV, Berlin Iu A, Shvarts EI (1990) Molecular nature of oncogene HRAS1 damage in human breast carcinoma: G—T transversion in codon 12 of one allele during deletion of other allele. Bioorg Khim 16(3):419–423PubMedGoogle Scholar
  14. 14.
    Nefedov MD, Gar’kavtsev IV, Rogaev EI (1990) Analysis of the association of inherited predisposition to breast cancer with c-Ha-ras-1 oncogene alleles. Genetika 26(12):2226–2231PubMedGoogle Scholar
  15. 15.
    Watson DM, Elton RA, Jack WJ, Dixon JM, Chetty U, Miller WR (1991) The H-ras oncogene product p21 and prognosis in human breast cancer. Breast Cancer Res Treat 17(3):161–169PubMedCrossRefGoogle Scholar
  16. 16.
    Bland KI, Konstadoulakis MM, Vezeridis MP, Wanebo HJ (1995) Oncogene protein co-expression. Value of Ha-ras, c-myc, c-fos, and p53 as prognostic discriminants for breast carcinoma. Ann Surg 221(6):706–718 discussion 718–720PubMedCrossRefGoogle Scholar
  17. 17.
    Conway K, Edmiston S, Fried DB, Hulka BS, Garrett PA, Liu ET (1995) Ha-ras rare alleles in breast cancer susceptibility. Breast Cancer Res Treat 35(1):97–104PubMedCrossRefGoogle Scholar
  18. 18.
    Weston A, Godbold JH (1997) Polymorphisms of H-ras-1 and p53 in breast cancer and lung cancer: a meta-analysis. Environ Health Perspect 105(Suppl 4):919–926PubMedCrossRefGoogle Scholar
  19. 19.
    Ding S, Larson GP, Foldenauer K, Zhang G, Krontiris TG (1999) Distinct mutation patterns of breast cancer-associated alleles of the HRAS1 minisatellite locus. Hum Mol Genet 8(3):515–521PubMedCrossRefGoogle Scholar
  20. 20.
    Schondorf T, Andrack A, Niederacher D, Scharl A, Becker M, Engel H, Gohring UJ (1999) H-ras gene amplification or mutation is not common in human primary breast cancer. Oncol Rep 6(5):1029–1033PubMedGoogle Scholar
  21. 21.
    Kannan K, Krishnamurthy J, Feng J, Nakajima T, Tsuchida N, Shanmugam G (2000) Mutation profile of the p53, fhit, p16INK4a/p19ARF and H-ras genes in Indian breast carcinomas. Int J Oncol 17(5):1031–1035PubMedGoogle Scholar
  22. 22.
    Ozer E, Sis B, Ozen E, Sakizli M, Canda T, Sarioglu S (2000) BRCA1, C-erbB-2, and H-ras gene expressions in young women with breast cancer. An immunohistochemical study. Appl Immunohistochem Mol Morphol 8(1):12–18PubMedCrossRefGoogle Scholar
  23. 23.
    Kotsinas A, Gorgoulis VG, Zacharatos P, Mariatos G, Kokotas S, Liloglou T, Ikonomopoulos J, Zoumpourlis V, Kyroudi A, Field JK, Asimacopoulos PJ, Kittas C (2001) Additional characterization of a hexanucleotide polymorphic site in the first intron of human H-ras gene: comparative study of its alterations in non-small cell lung carcinomas and sporadic invasive breast carcinomas. Cancer Genet Cytogenet 126(2):147–154PubMedCrossRefGoogle Scholar
  24. 24.
    Schondorf T, Rutzel S, Andrack A, Becker M, Hoopmann M, Breidenbach M, Gohring UJ (2002) Immunohistochemical analysis reveals a protective effect of H-ras expression mediated via apoptosis in node-negative breast cancer patients. Int J Oncol 20(2):273–277PubMedGoogle Scholar
  25. 25.
    Papadakis EN, Dokianakis DN, Spandidos DA (2003) Genetic analysis of H-ras intron-1 polymorphic and variable tandem repeat regions in human breast cancer. Int J Biol Markers 18(3):195–199PubMedGoogle Scholar
  26. 26.
    Tamimi RM, Hankinson SE, Ding S, Gagalang V, Larson GP, Spiegelman D, Colditz GA, Krontiris TG, Hunter DJ (2003) The HRAS1 variable number of tandem repeats and risk of breast cancer. Cancer Epidemiol Biomarkers Prev 12(12):1528–1530PubMedGoogle Scholar
  27. 27.
    Gosse-Brun S, Sauvaigo S, Daver A, Page M, Lortholary A, Larra F, Bignon YJ, Bernard-Gallon D (1999) Specific H-Ras minisatellite alleles in breast cancer susceptibility. Anticancer Res 19(6B):5191–5196PubMedGoogle Scholar
  28. 28.
    Firgaira FA, Seshadri R, McEvoy CR, Dite GS, Giles GG, McCredie MR, Southey MC, Venter DJ, Hopper JL (1999) HRAS1 rare minisatellite alleles and breast cancer in Australian women under age forty years. J Natl Cancer Inst 91(24):2107–2111PubMedCrossRefGoogle Scholar
  29. 29.
    Krontiris TG, Devlin B, Karp DD, Robert NJ, Risch N (1993) An association between the risk of cancer and mutations in the HRAS1 minisatellite locus. N Engl J Med 329(8):517–523PubMedCrossRefGoogle Scholar
  30. 30.
    Garrett PA, Hulka BS, Kim YL, Farber RA (1993) HRAS protooncogene polymorphism and breast cancer. Cancer Epidemiol Biomarkers Prev 2(2):131–138PubMedGoogle Scholar
  31. 31.
    Hall JM, Huey B, Morrow J, Newman B, Lee M, Jones E, Carter C, Buehring GC, King MC (1990) Rare HRAS alleles and susceptibility to human breast cancer. Genomics 6(1):188–191PubMedCrossRefGoogle Scholar
  32. 32.
    Barkardottir RB, Johannsson OT, Arason A, Gudnason V, Egilsson V (1989) Polymorphism of the c-Ha-ras-1 proto-oncogene in sporadic and familial breast cancer. Int J Cancer 44(2):251–255PubMedCrossRefGoogle Scholar
  33. 33.
    Sheng ZM, Guerin M, Gabillot M, Spielmann M, Riou G (1988) c-Ha-ras-1 polymorphism in human breast carcinomas: evidence for a normal distribution of alleles. Oncogene Res 2(3):245–250PubMedGoogle Scholar
  34. 34.
    Saglio G, Camaschella C, Giai M, Serra A, Guerrasio A, Peirone B, Gasparini P, Mazza U, Ceppellini R, Biglia N et al (1988) Distribution of Ha-RAS-1 proto-oncogene alleles in breast cancer patients and in a control population. Breast Cancer Res Treat 11(2):147–153PubMedCrossRefGoogle Scholar
  35. 35.
    Mackay J, Elder PA, Porteous DJ, Steel CM, Hawkins RA, Going JJ, Chetty U (1988) Partial deletion of chromosome 11p in breast cancer correlates with size of primary tumour and oestrogen receptor level. Br J Cancer 58(6):710–714PubMedCrossRefGoogle Scholar
  36. 36.
    Honda K, Ishizaki K, Ikenaga M, Toguchida J, Inamoto T, Tanaka K, Ozawa K (1988) Increased frequency of specific alleles of the c-Ha-ras gene in Japanese cancer patients. Hum Genet 79(4):297–300PubMedCrossRefGoogle Scholar
  37. 37.
    Corell B, Zoll B (1988) Comparison between the allelic frequency distribution of the Ha-ras 1 locus in normal individuals and patients with lymphoma, breast, and ovarian cancer. Hum Genet 79(3):255–259PubMedCrossRefGoogle Scholar
  38. 38.
    Lidereau R, Escot C, Theillet C, Champeme MH, Brunet M, Gest J, Callahan R (1986) High frequency of rare alleles of the human c-Ha-ras-1 proto-oncogene in breast cancer patients. J Natl Cancer Inst 77(3):697–701PubMedGoogle Scholar
  39. 39.
    Robins J, Greenland S, Breslow NE (1986) A general estimator for the variance of the Mantel-Haenszel odds ratio. Am J Epidemiol 124(5):719–723PubMedGoogle Scholar
  40. 40.
    Lee SA, Lee KM, Park SK, Choi JY, Kim B, Nam J, Yoo KY, Noh DY, Ahn SH, Kang D (2007) Genetic polymorphism of XRCC3 Thr241Met and breast cancer risk: case-control study in Korean women and meta-analysis of 12 studies. Breast Cancer Res Treat 103(1):71–76PubMedCrossRefGoogle Scholar
  41. 41.
    Lu C, Dong J, Ma H, Jin G, Hu Z, Peng Y, Guo X, Wang X, Shen H (2009) CCND1 G870A polymorphism contributes to breast cancer susceptibility: a meta-analysis. Breast Cancer Res Treat 116(3):571–575PubMedCrossRefGoogle Scholar
  42. 42.
    Tang C, Chen N, Wu M, Yuan H, Du Y (2009) Fok1 polymorphism of vitamin D receptor gene contributes to breast cancer susceptibility: a meta-analysis. Breast Cancer Res Treat 117(2):391–399PubMedCrossRefGoogle Scholar
  43. 43.
    Tao W, Wang C, Han R, Jiang H (2009) HER2 codon 655 polymorphism and breast cancer risk: a meta-analysis. Breast Cancer Res Treat 114(2):371–376PubMedCrossRefGoogle Scholar
  44. 44.
    Ryberg D, Tefre T, Ovrebo S, Skaug V, Stangeland L, Naalsund A, Baera R, Borresen AL, Haugen A (1990) Ha-ras-1 alleles in Norwegian lung cancer patients. Hum Genet 86(1):40–44PubMedCrossRefGoogle Scholar
  45. 45.
    Pierce LM, Sivaraman L, Chang W, Lum A, Donlon T, Seifried A, Wilkens LR, Lau AF, Le Marchand L (2000) Relationships of TP53 codon 72 and HRAS1 polymorphisms with lung cancer risk in an ethnically diverse population. Cancer Epidemiol Biomarkers Prev 9(11):1199–1204PubMedGoogle Scholar
  46. 46.
    Klingel R, Mittelstaedt P, Dippold WG, Meyer zum Buschenfelde KH (1991) Distribution of Ha-ras alleles in patients with colorectal cancer and Crohn’s disease. Gut 32(12):1508–1513PubMedCrossRefGoogle Scholar
  47. 47.
    Wyllie FS, Wynford-Thomas V, Lemoine NR, Williams GT, Williams ED, Wynford-Thomas D (1988) Ha-ras restriction fragment length polymorphisms in colorectal cancer. Br J Cancer 57(2):135–138PubMedCrossRefGoogle Scholar
  48. 48.
    Weitzel JN, Ding S, Larson GP, Nelson RA, Goodman A, Grendys EC, Ball HG, Krontiris TG (2000) The HRAS1 minisatellite locus and risk of ovarian cancer. Cancer Res 60(2):259–261PubMedGoogle Scholar
  49. 49.
    Ryberg D, Heimdal K, Fossa SD, Borresen AL, Haugen A (1993) Rare Ha-ras1 alleles and predisposition to testicular cancer. Int J Cancer 53(6):938–940PubMedCrossRefGoogle Scholar
  50. 50.
    Green M, Krontiris TG (1993) Allelic variation of reporter gene activation by the HRAS1 minisatellite. Genomics 17(2):429–434PubMedCrossRefGoogle Scholar
  51. 51.
    Little J, Higgins JP, Ioannidis JP, Moher D, Gagnon F, von Elm E, Khoury MJ, Cohen B, Davey-Smith G, Grimshaw J, Scheet P, Gwinn M, Williamson RE, Zou GY, Hutchings K, Johnson CY, Tait V, Wiens M, Golding J, van Duijn C, McLaughlin J, Paterson A, Wells G, Fortier I, Freedman M, Zecevic M, King R, Infante-Rivard C, Stewart A, Birkett N (2009) Strengthening the reporting of genetic association studies (STREGA): an extension of the STROBE Statement. Hum Genet 125(2):131–151PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Chun Zhang
    • 1
    • 2
  • Guo-Qiang Lv
    • 1
  • Xian-Ming Yu
    • 1
  • Yuan-Long Gu
    • 1
  • Jian-Ping Li
    • 1
  • Liang-Feng Du
    • 2
  • Ping Zhou
    • 2
  1. 1.Department of General SurgeryThe Third Affiliated Hospital to Nantong UniversityWuxiChina
  2. 2.Department of Intensive Care UniteThe Third Affiliated Hospital to Nantong UniversityWuxiChina

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