Top

Published in:

01-10-2011 | Epidemiology

Genetic variation in proinflammatory cytokines IL6, IL6R, TNF-region, and TNFRSF1A and risk of breast cancer

Authors: Margaret M. Madeleine, Lisa G. Johnson, Mari Malkki, Alexa J. Resler, Effie W. Petersdorf, Barbara McKnight, Kathleen E. Malone

Published in: Breast Cancer Research and Treatment | Issue 3/2011

Abstract

Proinflammatory cytokines are associated with age-related diseases including arthritis and heart disease. IL6 and TNF also play key roles in estrogen modulation in older women. We explored whether variation in IL6 and TNF genes influenced the risk of breast cancer in samples that differed by age group: <44 years (228 cases and 271 controls), 45–64 years (426 cases and 396 controls), and 65+ years (228 cases and 239 controls). Samples were drawn from population-based case–control studies conducted in Seattle. Age-adjusted odds ratios (ORs) were calculated to evaluate the risk associated with variants in IL6, IL6R, TNF, and TNFRSF1A. There was a significantly increased risk of breast cancer associated with one or more C>T alleles at IL6 rs2069861 among subjects in the oldest age group (OR 1.8, 95% CI 1.1–2.9), but no overall increased risk of breast cancer associated with any IL6 or IL6R variants in the combined data. There were significantly elevated risks of breast cancer among women 45–64 years old associated with a UTR 5′ flanking SNP LTA rs2009658 C>G allele (OR 1.5, 95% CI 1.1–1.9) and a nonsynonomous coding SNP TNFRSF1A rs767455 T>C allele (OR 1.3, 95% CI 1.1–1.6); these two variants were also elevated in the combined data (OR 1.3, 95% CI 1.1–1.5 and OR 1.2, 95% CI 1.1–1.4, respectively). This study supports a modest association between a variant in IL6 and breast cancer among older women and TNF-related variants and breast cancer among middle-aged women. Further evaluation of these genes in other studies is warranted.

Adams EF, Rafferty B, White MC (1991) Interleukin 6 is secreted by breast fibroblasts and stimulates 17 beta-oestradiol oxidoreductase activity of MCF-7 cells: possible paracrine regulation of breast 17 beta-oestradiol levels. Int J Cancer 49:118–121PubMedCrossRef

Allinen M, Beroukhim R, Cai L, Brennan C, Lahti-Domenici J, Huang H, Porter D, Hu M, Chin L, Richardson A, Schnitt S, Sellers WR, Polyak K (2004) Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell 6:17–32PubMedCrossRef

Azmy IA, Balasubramanian SP, Wilson AG, Stephenson TJ, Cox A, Brown NJ, Reed MW (2004) Role of tumour necrosis factor gene polymorphisms (-308 and -238) in breast cancer susceptibility and severity. Breast Cancer Res 6:395–400CrossRef

Carlson CS, Eberle MA, Rieder MJ, Yi Q, Kruglyak L, Nickerson DA (2004) Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium. Am J Hum Genet 74:106–120PubMedCrossRef

Coussens LM, Werb Z (2001) Inflammatory cells and cancer: think different!. J Exp Med 193:F23–F26PubMedCrossRef

Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867PubMedCrossRef

de Jong MM, Nolte IM, de Vries EG, Schaapveld M, Kleibeuker JH, Oosterom E, Oosterwijk JC, van der Hout AH, van der Steege G, Bruinenberg M, Boezen HM, te Meerman GJ, van der Graaf WT (2003) The HLA class III subregion is responsible for an increased breast cancer risk. Hum Mol Genet 12:2311–2319PubMedCrossRef

Dorak MT, Shao W, Machulla HK, Lobashevsky ES, Tang J, Park MH, Kaslow RA (2006) Conserved extended haplotypes of the major histocompatibility complex: further characterization. Genes Immun 7:450–467PubMedCrossRef

Dudoit S, Shaffer JP, Boldrick JC (2003) Multiple hypothesis testing in microarray experiments. Stat Sci 18:71–103CrossRef

10.

Duncan LJ, Coldham NG, Reed MJ (1994) The interaction of cytokines in regulating oestradiol 17 beta-hydroxysteroid dehydrogenase activity in MCF-7 cells. J Steroid Biochem Mol Biol 49:63–68PubMedCrossRef

11.

Fanning GC, Bunce M, Black CM, Welsh KI (1997) Polymerase chain reaction haplotyping using 3’ mismatches in the forward and reverse primers: application to the biallelic polymorphisms of tumor necrosis factor and lymphotoxin alpha. Tissue Antigens 50:23–31PubMedCrossRef

12.

Ferrucci L, Izmirlian G, Leveille S, Phillips CL, Corti MC, Brock DB, Guralnik JM (1999) Smoking, physical activity, and active life expectancy. Am J Epidemiol 149:645–653PubMed

13.

Friedrichsen DM, Malone KE, Doody DR, Daling JR, Ostrander EA (2004) Frequency of CHEK2 mutations in a population-based case-control study of breast cancer in young women. Breast Cancer Res 6:629–635CrossRef

14.

Gameiro CM, Romao F, Castelo-Branco C (2010) Menopause and aging: Changes in the immune system—a review. Maturitas 67(4):316–320

15.

Gao Y, He Y, Ding J, Wu K, Hu B, Liu Y, Wu Y, Guo B, Shen Y, Landi D, Landi S, Zhou Y, Liu H (2009) An insertion/deletion polymorphism at miRNA-122-binding site in the interleukin-1alpha 3’ untranslated region confers risk for hepatocellular carcinoma. Carcinogenesis 30:2064–2069PubMedCrossRef

16.

Gaudet MM, Egan KM, Lissowska J, Newcomb PA, Brinton LA, Titus-Ernstoff L, Yeager M, Chanock S, Welch R, Peplonska B, Trentham-Dietz A, Garcia-Closas M (2007) Genetic variation in tumor necrosis factor and lymphotoxin-alpha (TNF-LTA) and breast cancer risk. Hum Genet 121:483–490PubMedCrossRef

17.

Gaudet MM, Milne RL, Cox A, Camp NJ, Goode EL, Humphreys MK, Dunning AM, Morrison J, Giles GG, Severi G, Baglietto L, English DR, Couch FJ, Olson JE, Wang X, Chang-Claude J, Flesch-Janys D, Abbas S, Salazar R, Mannermaa A, Kataja V, Kosma VM, Lindblom A, Margolin S, Heikkinen T, Kampjarvi K, Aaltonen K, Nevanlinna H, Bogdanova N, Coinac I, Schurmann P, Dork T, Bartram CR, Schmutzler RK, Tchatchou S, Burwinkel B, Brauch H, Torres D, Hamann U, Justenhoven C, Ribas G, Arias JI, Benitez J, Bojesen SE, Nordestgaard BG, Flyger HL, Peto J, Fletcher O, Johnson N, dos SS I, Fasching PA, Beckmann MW, Strick R, Ekici AB, Broeks A, Schmidt MK, van Leeuwen FE, van’t Veer LJ, Southey MC, Hopper JL, Apicella C, Haiman CA, Henderson BE, Le ML, Kolonel LN, Kristensen V, Grenaker AG, Hunter DJ, Kraft P, Cox DG, Hankinson SE, Seynaeve C, Vreeswijk MP, Tollenaar RA, Devilee P, Chanock S, Lissowska J, Brinton L, Peplonska B, Czene K, Hall P, Li Y, Liu J, Balasubramanian S, Rafii S, Reed MW, Pooley KA, Conroy D, Baynes C, Kang D, Yoo KY, Noh DY, Ahn SH, Shen CY, Wang HC, Yu JC, Wu PE, Anton-Culver H, Ziogoas A, Egan K, Newcomb P, Titus-Ernstoff L, Trentham DA, Sigurdson AJ, Alexander BH, Bhatti P, Allen-Brady K, Cannon-Albright LA, Wong J, Chenevix-Trench G, Spurdle AB, Beesley J, Pharoah PD, Easton DF, Garcia-Closas M (2009) Five polymorphisms and breast cancer risk: results from the Breast Cancer Association Consortium. Cancer Epidemiol Biomarkers Prev 18:1610–1616PubMedCrossRef

18.

Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140:883–899PubMedCrossRef

19.

Hankey BF, Ries LA, Edwards BK (1999) The surveillance, epidemiology, and end results program: a national resource. Cancer Epidemiol Biomarkers Prev 8:1117–1121PubMed

20.

Harris RE, Beebe-Donk J, Doss H, Burr DD (2005) Aspirin, ibuprofen, and other non-steroidal anti-inflammatory drugs in cancer prevention: a critical review of non-selective COX-2 blockade (review). Oncol Rep 13:559–583PubMed

21.

Hefler LA, Grimm C, Lantzsch T, Lampe D, Leodolter S, Koelbl H, Heinze G, Reinthaller A, Tong-Cacsire D, Tempfer C, Zeillinger R (2005) Interleukin-1 and interleukin-6 gene polymorphisms and the risk of breast cancer in Caucasian women. Clin Cancer Res 11:5718–5721PubMedCrossRef

22.

Iacopetta B, Grieu F, Joseph D (2004) The -174 G/C gene polymorphism in interleukin-6 is associated with an aggressive breast cancer phenotype. Br J Cancer 90:419–422PubMedCrossRef

23.

Li CI, Malone KE, Porter PL, Weiss NS, Tang MT, Daling JR (2003) Reproductive and anthropometric factors in relation to the risk of lobular and ductal breast carcinoma among women 65–79 years of age. Int J Cancer 107:647–651PubMedCrossRef

24.

Li CI, Malone KE, Porter PL, Weiss NS, Tang MT, Daling JR (2003) The relationship between alcohol use and risk of breast cancer by histology and hormone receptor status among women 65–79 years of age. Cancer Epidemiol Biomarkers Prev 12:1061–1066PubMed

25.

Malone KE, Daling JR, Doody DR, Hsu L, Bernstein L, Coates RJ, Marchbanks PA, Simon MS, McDonald JA, Norman SA, Strom BL, Burkman RT, Ursin G, Deapen D, Weiss LK, Folger S, Madeoy JJ, Friedrichsen DM, Suter NM, Humphrey MC, Spirtas R, Ostrander EA (2006) Prevalence and predictors of BRCA1 and BRCA2 mutations in a population-based study of breast cancer in White and Black American women ages 35 to 64 years. Cancer Res 66:8297–8308PubMedCrossRef

26.

Mantovani A (2010) Molecular pathways linking inflammation and cancer. Curr Mol Med 10:369–373PubMedCrossRef

27.

Marchbanks PA, McDonald JA, Wilson HG, Burnett NM, Daling JR, Bernstein L, Malone KE, Strom BL, Norman SA, Weiss LK, Liff JM, Wingo PA, Burkman RT, Folger SG, Berlin JA, Deapen DM, Ursin G, Coates RJ, Simon MS, Press MF, Spirtas R (2002) The NICHD women’s contraceptive and reproductive experiences study: methods and operational results. Ann Epidemiol 12:213–221PubMedCrossRef

28.

Matsukura H, Ikeda S, Yoshimura N, Takazoe M, Muramatsu M (2008) Genetic polymorphisms of tumour necrosis factor receptor superfamily 1A and 1B affect responses to infliximab in Japanese patients with Crohn’s disease. Aliment Pharmacol Ther 27:765–770PubMedCrossRef

29.

Moss SF, Blaser MJ (2005) Mechanisms of disease: inflammation and the origins of cancer. Nat Clin Pract Oncol 2:90–97PubMedCrossRef

30.

Pfeilschifter J, Koditz R, Pfohl M, Schatz H (2002) Changes in proinflammatory cytokine activity after menopause. Endocr Rev 23:90–119PubMedCrossRef

31.

Purohit A, Newman SP, Reed MJ (2002) The role of cytokines in regulating estrogen synthesis: implications for the etiology of breast cancer. Breast Cancer Res 4:65–69PubMedCrossRef

32.

Qi L, van Dam RM, Meigs JB, Manson JE, Hunter D, Hu FB (2006) Genetic variation in IL6 gene and type 2 diabetes: tagging-SNP haplotype analysis in large-scale case-control study and meta-analysis. Hum Mol Genet 15:1914–1920PubMedCrossRef

33.

Rodier F, Coppe JP, Patil CK, Hoeijmakers WA, Munoz DP, Raza SR, Freund A, Campeau E, Davalos AR, Campisi J (2009) Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat Cell Biol 11:973–979PubMedCrossRef

34.

Scola L, Vaglica M, Crivello A, Palmeri L, Forte GI, Macaluso MC, Giacalone A, Di NL, Bongiovanni A, Raimondi C, Accardo A, Verna R, Candore G, Caruso C, Lio D, Palmeri S (2006) Cytokine gene polymorphisms and breast cancer susceptibility. Ann N Y Acad Sci 1089:104–109PubMedCrossRef

35.

Shen C, Sun H, Sun D, Xu L, Zhang X, Liu A, Jia X, Bai J, Chen F, Yu Y, Jin Y, Yu J, Fu S (2010) Polymorphisms of tumor necrosis factor-alpha and breast cancer risk: a meta-analysis. Breast Cancer Res Treat 126:763–770PubMedCrossRef

36.

Smith KC, Bateman AC, Fussell HM, Howell WM (2004) Cytokine gene polymorphisms and breast cancer susceptibility and prognosis. Eur J Immunogenet 31:167–173PubMedCrossRef

37.

Smith BD, Smith GL, Hurria A, Hortobagyi GN, Buchholz TA (2009) Future of cancer incidence in the United States: burdens upon an aging, changing nation. J Clin Oncol 27:2758–2765PubMedCrossRef

38.

Suter NM, Malone KE, Daling JR, Doody DR, Ostrander EA (2003) Androgen receptor (CAG)n and (GGC)n polymorphisms and breast cancer risk in a population-based case-control study of young women. Cancer Epidemiol Biomarkers Prev 12:127–135PubMed

39.

Trabert B, Malone KE, Daling JR, Doody DR, Bernstein L, Ursin G, Marchbanks PA, Strom BL, Humphrey MC, Ostrander EA (2007) Vitamin D receptor polymorphisms and breast cancer risk in a large population-based case-control study of Caucasian and African-American women. Breast Cancer Res 9:R84PubMedCrossRef

40.

Volpato S, Guralnik JM, Ferrucci L, Balfour J, Chaves P, Fried LP, Harris TB (2001) Cardiovascular disease, interleukin-6, and risk of mortality in older women: the women’s health and aging study. Circulation 103:947–953PubMed

Title: Genetic variation in proinflammatory cytokines IL6, IL6R, TNF-region, and TNFRSF1A and risk of breast cancer
Authors: Margaret M. Madeleine
Lisa G. Johnson
Mari Malkki
Alexa J. Resler
Effie W. Petersdorf
Barbara McKnight
Kathleen E. Malone
Publication date: 01-10-2011
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 3/2011
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-011-1520-4

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2011

Prediction of lymph node involvement in breast cancer from primary tumor tissue using gene expression profiling and miRNAs

First-line bevacizumab in combination with weekly paclitaxel for metastatic breast cancer: efficacy and safety results from a large, open-label, single-arm Japanese study

Lack of association between hOGG1 Ser326Cys polymorphism and breast cancer susceptibility in European population

Immunohistochemically defined subtypes and outcome in occult breast carcinoma with axillary presentation

Increased SIAH expression predicts ductal carcinoma in situ (DCIS) progression to invasive carcinoma

Leptomeningeal metastases from breast cancer: intrinsic subtypes may affect unique clinical manifestations

Keynote webinar | Spotlight on antibody–drug conjugates in cancer