Immunogenetics

, Volume 58, Issue 1, pp 1–8

The pattern of clinical breast cancer metastasis correlates with a single nucleotide polymorphism in the C1qA component of complement

  • Emilian Racila
  • Doina M. Racila
  • Justine M. Ritchie
  • Christiana Taylor
  • Christopher Dahle
  • George J. Weiner
Original Paper

Abstract

Complement is one of primary defense mechanisms against intravascular microorganisms and could play a role in the immune response to malignancy and hence its clinical behavior. We evaluated if the sole coding polymorphism of C1qA associates with outcome in patients with breast carcinoma. Genotyping for C1qA[276A/G] was performed in 63 breast cancer subjects with localized tumor and compared with that in 38 breast cancer subjects with metastasis. Established risk factors for clinical outcome were considered and evaluated in multivariable analysis. Breast cancer subjects with heterozygous or homozygous C1qA[276G] genotype had a higher rate of metastasis than subjects with the homozygous C1qA[276A] genotype [hazard ratio (HR) 2.4, 95% confidence interval (CI) 1.1–4.1]. This association was stronger when only metastatic sites associated with hematogenous spread, i.e., to the bone, liver, and brain, were considered (HR 3.5, 95% CI 1.4–5.6) and remained statistically significant after adjustment for the number of positive lymph nodes, estrogen receptor status, and progesterone receptor status. There was no statistical difference in the C1qA[276A/G] allelic distribution between all subjects with breast cancer and controls. These results suggest there could be an association of a single nucleotide polymorphism at position 276 of the C1qA component of complement with breast cancer metastasis to sites linked to hematogenous spread of disease. The C1qA polymorphism associated with decreased distant metastasis has also been correlated with an increased incidence of subcutaneous systemic lupus and C1q deficiencies, suggesting that an altered immune response may play a role in the observed association.

Keywords

Complement Single nucleotide polymorphism (SNP) Breast cancer Metastasis 

References

  1. Abu-Shakra M, Buskila D, Ehrenfeld M, Conrad K, Shoenfeld Y (2001) Cancer and autoimmunity: autoimmune and rheumatic features in patients with malignancies. Ann Rheum Dis 60:433–441PubMedCrossRefGoogle Scholar
  2. Baldwin WM III, Qian Z, Wasowska B, Sanfilippo F (1999) Complement causes allograft injury by cell activation rather than lysis. Transplantation 67:1498–1499PubMedCrossRefGoogle Scholar
  3. Balkwill F (2004) Cancer and the chemokine network. Nat Rev Cancer 4:540–550PubMedCrossRefGoogle Scholar
  4. Boedefeld WM II, Bland KI, Heslin MJ (2003) Recent insights into angiogenesis, apoptosis, invasion, and metastasis in colorectal carcinoma. Ann Surg Oncol 10:839–851PubMedCrossRefGoogle Scholar
  5. Caragine TA, Okada N, Frey AB, Tomlinson S (2002) A tumor-expressed inhibitor of the early but not late complement lytic pathway enhances tumor growth in a rat model of human breast cancer. Cancer Res 62:1110–1115PubMedGoogle Scholar
  6. Carlini DB, Chen Y, Stephan W (2001) The relationship between third-codon position nucleotide content, codon bias, mRNA secondary structure and gene expression in the drosophilid alcohol dehydrogenase genes Adh and Adhr. Genetics 159:623–633PubMedGoogle Scholar
  7. Conrad K (2000) Autoantibodies in cancer patients and in persons with a higher risk of cancer development. Elsevier, AmsterdamGoogle Scholar
  8. Cox DR (1972) Regression models and life tables (with discussion). J R Stat Soc B 34:187–220Google Scholar
  9. Duan J, Wainwright MS, Comeron JM, Saitou N, Sanders AR, Gelernter J, Gejman PV (2003) Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor. Hum Mol Genet 12:205–216PubMedCrossRefGoogle Scholar
  10. Eccles SA (2001) Monoclonal antibodies targeting cancer: ‘magic bullets’ or just the trigger? Breast Cancer Res 3:86–90PubMedCrossRefGoogle Scholar
  11. Emmert S, Schneider TD, Khan SG, Kraemer KH (2001) The human XPG gene: gene architecture, alternative splicing and single nucleotide polymorphisms. Nucleic Acids Res 29:1443–1452PubMedCrossRefGoogle Scholar
  12. Erichsen HC, Chanock SJ (2004) SNPs in cancer research and treatment. Br J Cancer 90:747–751PubMedCrossRefGoogle Scholar
  13. Fishelson Z, Donin N, Zell S, Schultz S, Kirschfink M (2003) Obstacles to cancer immunotherapy: expression of membrane complement regulatory proteins (mCRPs) in tumors. Mol Immunol 40:109–123PubMedCrossRefGoogle Scholar
  14. Gelderman KA, Tomlinson S, Ross GD, Gorter A (2004) Complement function in mAb-mediated cancer immunotherapy. Trends Immunol 25:158–164PubMedCrossRefGoogle Scholar
  15. Golay J, Zaffaroni L, Vaccari T, Lazzari M, Borleri GM, Bernasconi S, Tedesco F, Rambaldi A, Introna M (2000) Biologic response of B lymphoma cells to anti-CD20 monoclonal antibody rituximab in vitro: CD55 and CD59 regulate complement-mediated cell lysis. Blood 95:3900–3908PubMedGoogle Scholar
  16. Hakulinen J, Meri S (1998) Complement-mediated killing of microtumors in vitro. Am J Pathol 153:845–855PubMedGoogle Scholar
  17. Hansen MH, Ostenstad B, Sioud M (2001) Antigen-specific IgG antibodies in stage IV long-time survival breast cancer patients. Mol Med 7:230–239PubMedGoogle Scholar
  18. Harjunpaa A, Junnikkala S, Meri S (2000) Rituximab (anti-CD20) therapy of B-cell lymphomas: direct complement killing is superior to cellular effector mechanisms. Scand J Immunol 51:634–641PubMedCrossRefGoogle Scholar
  19. Jager D, Jager E, Knuth A (2001) Immune responses to tumour antigens: implications for antigen specific immunotherapy of cancer. J Clin Pathol 54:669–674PubMedGoogle Scholar
  20. Jurianz K, Maslak S, Garcia-Schuler H, Fishelson Z, Kirschfink M (1999) Neutralization of complement regulatory proteins augments lysis of breast carcinoma cells targeted with rhumAb anti-HER2. Immunopharmacology 42:209–218PubMedCrossRefGoogle Scholar
  21. Kaplan E, Meier P (1958) Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481CrossRefGoogle Scholar
  22. Kauppi M, Pukkala E, Isomaki H (1997) Elevated incidence of hematologic malignancies in patients with Sjogren's syndrome compared with patients with rheumatoid arthritis (Finland). Cancer Causes Control 8:201–204PubMedCrossRefGoogle Scholar
  23. Khan SG, Muniz-Medina V, Shahlavi T, Baker CC, Inui H, Ueda T, Emmert S, Schneider TD, Kraemer KH (2002) The human XPC DNA repair gene: arrangement, splice site information content and influence of a single nucleotide polymorphism in a splice acceptor site on alternative splicing and function. Nucleic Acids Res 30:3624–3631PubMedCrossRefGoogle Scholar
  24. Kishore U, Reid KB (2000) C1q: structure, function, and receptors. Immunopharmacology 49:159–170PubMedCrossRefGoogle Scholar
  25. Korb LC, Ahearn JM (1997) C1q binds directly and specifically to surface blebs of apoptotic human keratinocytes: complement deficiency and systemic lupus erythematosus revisited. J Immunol 158:4525–4528PubMedGoogle Scholar
  26. Mellemkjaer L, Andersen V, Linet MS, Gridley G, Hoover R, Olsen JH (1997) Non-Hodgkin’s lymphoma and other cancers among a cohort of patients with systemic lupus erythematosus. Arthritis Rheum 40:761–768PubMedCrossRefGoogle Scholar
  27. Modrek B, Resch A, Grasso C, Lee C (2001) Genome-wide detection of alternative splicing in expressed sequences of human genes. Nucleic Acids Res 29:2850–2859PubMedCrossRefGoogle Scholar
  28. Onoe K, Iwabuchi K, Iwabuchi C, Tone S, Konishi J, Kawakami Y, Nishimura M (2002) Enhanced complement sensitivity of NK-T cells in murine thymus and spleen associated with presence of serum immunoglobulin. Immunobiology 206:377–391PubMedCrossRefGoogle Scholar
  29. Pantel K, Brakenhoff RH (2004) Dissecting the metastatic cascade. Nat Rev Cancer 4:448–456PubMedCrossRefGoogle Scholar
  30. Pardoll DM (1999) Inducing autoimmune disease to treat cancer. Proc Natl Acad Sci U S A 96:5340–5342PubMedCrossRefGoogle Scholar
  31. Peters-Golden M, Wise RA, Hochberg M, Stevens MB, Wigley FM (1985) Incidence of lung cancer in systemic sclerosis. J Rheumatol 12:1136–1139PubMedGoogle Scholar
  32. Petry F, Loos M (2005) Common silent mutations in all types of hereditary complement C1q deficiencies. Immunogenetics 57:566–571PubMedCrossRefGoogle Scholar
  33. Posner JB (2003) Immunology of paraneoplastic syndromes: overview. Ann N Y Acad Sci 998:178–186PubMedCrossRefGoogle Scholar
  34. Racila E, Scheuermann RH, Picker LJ, Yefenof E, Tucker T, Chang W, Marches R, Street NE, Vitetta ES, Uhr JW (1995) Tumor dormancy and cell signaling. II. Antibody as an agonist in inducing dormancy of a B cell lymphoma in SCID mice. J Exp Med 181:1539–1550PubMedCrossRefGoogle Scholar
  35. Racila DM, Sontheimer CJ, Sheffield A, Wisnieski JJ, Racila E, Sontheimer RD (2003) Homozygous single nucleotide polymorphism of the complement C1QA gene is associated with decreased levels of C1q in patients with subacute cutaneous lupus erythematosus. Lupus 12:124–132PubMedCrossRefGoogle Scholar
  36. Ramsey-Goldman R, Mattai SA, Schilling E, Chiu YL, Alo CJ, Howe HL, Manzi S (1998) Increased risk of malignancy in patients with systemic lupus erythematosus. J Investig Med 46:217–222PubMedGoogle Scholar
  37. Reid KB (1983) Proteins involved in the activation and control of the two pathways of human complement. Biochem Soc Trans 11:1–12PubMedGoogle Scholar
  38. Roodman GD (2004) Mechanisms of bone metastasis. N Engl J Med 350:1655–1664PubMedCrossRefGoogle Scholar
  39. Sigurgeirsson B, Lindelof B, Edhag O, Allander E (1992) Risk of cancer in patients with dermatomyositis or polymyositis. A population-based study. N Engl J Med 326:363–367PubMedCrossRefGoogle Scholar
  40. Tan EM (2001) Autoantibodies as reporters identifying aberrant cellular mechanisms in tumorigenesis. J Clin Invest 108:1411–1415PubMedCrossRefGoogle Scholar
  41. Tan EM, Shi FD (2003) Relative paradigms between autoantibodies in lupus and autoantibodies in cancer. Clin Exp Immunol 134:169–177PubMedCrossRefGoogle Scholar
  42. Tazawa H, Okada F, Kobayashi T, Tada M, Mori Y, Une Y, Sendo F, Kobayashi M, Hosokawa M (2003) Infiltration of neutrophils is required for acquisition of metastatic phenotype of benign murine fibrosarcoma cells: implication of inflammation-associated carcinogenesis and tumor progression. Am J Pathol 163:2221–2232PubMedGoogle Scholar
  43. von Ahsen N, Oellerich M (2004) The intronic prothrombin 19911A>G polymorphism influences splicing efficiency and modulates effects of the 20210G>A polymorphism on mRNA amount and expression in a stable reporter gene assay system. Blood 103:586–593CrossRefGoogle Scholar
  44. Walport MJ (2001) Complement. First of two parts. N Engl J Med 344:1058–1066PubMedCrossRefGoogle Scholar
  45. Webb KE, Martin JF, Cotton J, Erusalimsky JD, Humphries SE (2003) The 4830C>A polymorphism within intron 5 affects the pattern of alternative splicing occurring within exon 6 of the thrombopoietin gene. Exp Hematol 31:488–494PubMedCrossRefGoogle Scholar
  46. Zeng G, Li Y, El-Gamil M, Sidney J, Sette A, Wang RF, Rosenberg SA, Robbins PF (2002) Generation of NY-ESO-1-specific CD4+ and CD8+ T cells by a single peptide with dual MHC class I and class II specificities: a new strategy for vaccine design. Cancer Res 62:3630–3635PubMedGoogle Scholar
  47. Zhu Y, Spitz MR, Amos CI, Lin J, Schabath MB, Wu X (2004) An evolutionary perspective on single-nucleotide polymorphism screening in molecular cancer epidemiology. Cancer Res 64:2251–2257PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Emilian Racila
    • 1
  • Doina M. Racila
    • 2
  • Justine M. Ritchie
    • 3
  • Christiana Taylor
    • 1
  • Christopher Dahle
    • 1
  • George J. Weiner
    • 1
    • 2
  1. 1.Holden Comprehensive Cancer Center at the University of Iowa, 5216MERFUniversity of IowaIowaUSA
  2. 2.Department of Internal MedicineUniversity of IowaIowaUSA
  3. 3.Department of BiostatisticsUniversity of IowaIowa CityUSA

Personalised recommendations