Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2010

Open Access 01-12-2010 | Research article

The 4q27 locus and prostate cancer risk

Authors: Elizabeth A Tindall, Hoa N Hoang, Melissa C Southey, Dallas R English, John L Hopper, Graham G Giles, Gianluca Severi, Vanessa M Hayes

Published in: BMC Cancer | Issue 1/2010

Login to get access

Abstract

Background

Chronic inflammation is considered to be implicated in the development of prostate cancer. In this study we are the first to investigate a potential association between variants in an autoimmune related region on chromosome 4q27 and prostate cancer risk. This region harbors two cytokine genes IL-2 and the recently described IL-21.

Methods

We genotyped six variants previously associated with autoimmune disease (namely rs13151961, rs13119723, rs17388568, rs3136534, rs6822844 and rs6840978) and one functional IL-2 promoter variant (rs2069762) for possible association with prostate cancer risk using the Australian Risk Factors for Prostate Cancer case-control Study.

Results

Overall, our results do not support an association between the seven variants at position 4q27 and prostate cancer risk. Per allele odds ratios (ORs) were not significantly different from 1 (all P-values = 0.06). However, we found suggestive evidence for a significant association between the presence of the rs13119723 variant (located in a protein of unknown function) and men with a family history of prostate cancer in first-degree relatives (P-value for interaction 0.02). The per allele OR associated with this variant was significantly higher than 1 (2.37; 95% C.I. = 1.01-5.57).

Conclusions

We suggest that genetic variation within the chromosome 4q27 locus might be associated with prostate cancer susceptibility in men with a family history of the disease. Furthermore, our study alludes to a potential role of unknown protein KIAA1109 in conferring this risk.
Appendix
Available only for authorised users
Literature
1.
Baade PD, Youlden DR, Krnjacki LJ: International epidemiology of prostate cancer: geographical distribution and secular trends. Mol Nutr Food Res. 2009, 53 (2): 171-184. 10.1002/mnfr.200700511.CrossRefPubMed
2.
Fleshner NE, Lawrentschuk N: Risk of developing prostate cancer in the future: overview of prognostic biomarkers. Urology. 2009, 73 (5 Suppl): S21-27. 10.1016/j.urology.2009.02.022.CrossRefPubMed
3.
Vasto S, Carruba G, Candore G, Italiano E, Di Bona D, Caruso C: Inflammation and prostate cancer. Future Oncol. 2008, 4 (5): 637-645. 10.2217/14796694.4.5.637.CrossRefPubMed
4.
De Marzo AM, Platz EA, Sutcliffe S, Xu J, Grönberg H, Drake CG, Nakai Y, Isaacs WB, Nelson WG: Inflammation in prostate carcinogenesis. Nature Reviews Cancer. 2007, 7: 256-269. 10.1038/nrc2090.CrossRefPubMedPubMedCentral
5.
Sandhu JS: Prostate cancer and chronic prostatitis. Curr Urol Rep. 2008, 9 (4): 328-332. 10.1007/s11934-008-0056-6.CrossRefPubMed
6.
Sun J, Turner A, Xu J, Grönberg H, Isaacs W: Genetic variability in inflammation pathways and prostate cancer risk. Urological Oncology. 2007, 25 (3): 250-259.CrossRef
7.
Hoyer KK, Dooms H, Barron L, Abbas AK: Interleukin-2 in the development and control of inflammatory disease. Immunol Rev. 2008, 226: 19-28. 10.1111/j.1600-065X.2008.00697.x.CrossRefPubMed
8.
Vliet van der HJ, Koon HB, Yue SC, Uzunparmak B, Seery V, Gavin MA, Rudensky AY, Atkins MB, Balk SP, Exley MA: Effects of the administration of high-dose interleukin-2 on immunoregulatory cell subsets in patients with advanced melanoma and renal cell cancer. Clin Cancer Res. 2007, 13 (7): 2100-2108. 10.1158/1078-0432.CCR-06-1662.CrossRefPubMed
9.
Brill TH, Kubler HR, Pohla H, Buchner A, Fend F, Schuster T, von Randenborgh H, Paul R, Kummer T, Plank C, et al: Therapeutic Vaccination with an IL-2-IFNgamma-secreting Allogeneic Tumor Vaccine in Patients with Progressive Castration-Resistant Prostate Cancer - a Phase I/II Trial. Hum Gene Ther. 2009
10.
Hallett WH, Ames E, Alvarez M, Barao I, Taylor PA, Blazar BR, Murphy WJ: Combination therapy using IL-2 and anti-CD25 results in augmented natural killer cell-mediated antitumor responses. Biol Blood Marrow Transplant. 2008, 14 (10): 1088-1099. 10.1016/j.bbmt.2008.08.001.CrossRefPubMedPubMedCentral
11.
Lechleider RJ, Arlen PM, Tsang KY, Steinberg SM, Yokokawa J, Cereda V, Camphausen K, Schlom J, Dahut WL, Gulley JL: Safety and immunologic response of a viral vaccine to prostate-specific antigen in combination with radiation therapy when metronomic-dose interleukin 2 is used as an adjuvant. Clin Cancer Res. 2008, 14 (16): 5284-5291. 10.1158/1078-0432.CCR-07-5162.CrossRefPubMedPubMedCentral
12.
Wu H-C, Chang C-H, Wan L, Wu C-I, Tsai F-J, Chen W-C: IL-2 gene C/T polymorphism is associated with prostate cancer. Journal of Clinical Laboratory Analysis. 2006, 20 (6): 245-249. 10.1002/jcla.20149.CrossRefPubMed
13.
Takaki R, Hayakawa Y, Nelson A, Sivakumar PV, Hughes S, Smyth MJ, Lanier LL: IL-21 enhances tumor rejection through a NKG2D-dependent mechanism. J Immunol. 2005, 175 (4): 2167-2173.CrossRefPubMed
14.
Kim-Schulze S, Kim HS, Fan Q, Kim DW, Kaufman HL: Local IL-21 promotes the therapeutic activity of effector T cells by decreasing regulatory T cells within the tumor microenvironment. Mol Ther. 2009, 17 (2): 380-388. 10.1038/mt.2008.249.CrossRefPubMed
15.
Huber M, Brustle A, Reinhard K, Guralnik A, Walter G, Mahiny A, von Low E, Lohoff M: IRF4 is essential for IL-21-mediated induction, amplification, and stabilization of the Th17 phenotype. Proc Natl Acad Sci USA. 2008, 105 (52): 20846-20851. 10.1073/pnas.0809077106.CrossRefPubMedPubMedCentral
16.
Sfanos KS, Bruno TC, Maris CH, Xu L, Thoburn CJ, DeMarzo AM, Meeker AK, Isaacs WB, Drake CG: Phenotypic analysis of prostate-infiltrating lymphocytes reveals TH17 and Treg skewing. Clin Cancer Res. 2008, 14 (11): 3254-3261. 10.1158/1078-0432.CCR-07-5164.CrossRefPubMedPubMedCentral
17.
Derhovanessian E, Adams V, Hahnel K, Groeger A, Pandha H, Ward S, Pawelec G: Pretreatment frequency of circulating IL-17+ CD4+ T-cells, but not Tregs, correlates with clinical response to whole-cell vaccination in prostate cancer patients. Int J Cancer. 2009, 125 (6): 1372-1379. 10.1002/ijc.24497.CrossRefPubMed
18.
Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007, 447 (7145): 661-678. 10.1038/nature05911.
19.
Festen EA, Goyette P, Scott R, Annese V, Zhernakova A, Lian J, Lefebvre C, Brant SR, Cho JH, Silverberg MS, et al: Genetic variants in the region harbouring IL2/IL21 associated with ulcerative colitis. Gut. 2009, 58 (6): 799-804. 10.1136/gut.2008.166918.CrossRefPubMedPubMedCentral
20.
Liu Y, Helms C, Liao W, Zaba LC, Duan S, Gardner J, Wise C, Miner A, Malloy MJ, Pullinger CR, et al: A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci. PLoS Genet. 2008, 4 (3): e1000041-10.1371/journal.pgen.1000041.CrossRefPubMedPubMedCentral
21.
van Heel DA, Franke L, Hunt KA, Gwilliam R, Zhernakova A, Inouye M, Wapenaar MC, Barnardo MC, Bethel G, Holmes GK, et al: A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21. Nat Genet. 2007, 39 (7): 827-829. 10.1038/ng2058.CrossRefPubMedPubMedCentral
22.
Zhernakova A, Alizadeh BZ, Bevova M, van Leeuwen MA, Coenen MJ, Franke B, Franke L, Posthumus MD, van Heel DA, Steege van der G, et al: Novel association in chromosome 4q27 region with rheumatoid arthritis and confirmation of type 1 diabetes point to a general risk locus for autoimmune diseases. Am J Hum Genet. 2007, 81 (6): 1284-1288. 10.1086/522037.CrossRefPubMedPubMedCentral
23.
Fedetz M, Ndagire D, Fernandez O, Leyva L, Guerrero M, Arnal C, Lucas M, Izquierdo G, Delgado C, Alcina A, et al: Multiple sclerosis association study with the TENR-IL2-IL21 region in a Spanish population. Tissue Antigens. 2009, 74 (3): 244-247. 10.1111/j.1399-0039.2009.01298.x.CrossRefPubMed
24.
Marquez A, Orozco G, Martinez A, Palomino-Morales R, Fernandez-Arquero M, Mendoza JL, Taxonera C, Diaz-Rubio M, Gomez-Garcia M, Nieto A, et al: Novel Association of the Interleukin 2-Interleukin 21 Region With Inflammatory Bowel Disease. Am J Gastroenterol. 2009
25.
Adamovic S, Amundsen SS, Lie BA, Gudjonsdottir AH, Ascher H, Ek J, van Heel DA, Nilsson S, Sollid LM, Torinsson Naluai A: Association study of IL2/IL21 and FcgRIIa: significant association with the IL2/IL21 region in Scandinavian coeliac disease families. Genes Immun. 2008, 9 (4): 364-367. 10.1038/gene.2008.27.CrossRefPubMed
26.
Cooper JD, Smyth DJ, Smiles AM, Plagnol V, Walker NM, Allen JE, Downes K, Barrett JC, Healy BC, Mychaleckyj JC, et al: Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci. Nat Genet. 2008, 40 (12): 1399-1401. 10.1038/ng.249.CrossRefPubMedPubMedCentral
27.
Glas J, Stallhofer J, Ripke S, Wetzke M, Pfennig S, Klein W, Epplen JT, Griga T, Schiemann U, Lacher M, et al: Novel Genetic Risk Markers for Ulcerative Colitis in the IL2/IL21 Region Are in Epistasis With IL23R and Suggest a Common Genetic Background for Ulcerative Colitis and Celiac Disease. Am J Gastroenterol. 2009
28.
Romanos J, Barisani D, Trynka G, Zhernakova A, Bardella MT, Wijmenga C: Six new coeliac disease loci replicated in an Italian population confirm association with coeliac disease. J Med Genet. 2009, 46 (1): 60-63. 10.1136/jmg.2008.061457.CrossRefPubMed
29.
Garner CP, Murray JA, Ding YC, Tien Z, van Heel DA, Neuhausen SL: Replication of Celiac Disease UK Genome-Wide Association Study Results in a US Population. Hum Mol Genet. 2009
30.
Hemminki K, Li X, Sundquist J, Sundquist K: Cancer risks in ulcerative colitis patients. Int J Cancer. 2008, 123 (6): 1417-1421. 10.1002/ijc.23666.CrossRefPubMed
31.
Hemminki K, Li X, Sundquist K, Sundquist J: Cancer risk in hospitalized rheumatoid arthritis patients. Rheumatology (Oxford). 2008, 47 (5): 698-701. 10.1093/rheumatology/ken130.CrossRef
32.
Hemminki K, Li X, Sundquist J, Sundquist K: Cancer risks in Crohn disease patients. Ann Oncol. 2009, 20 (3): 574-580. 10.1093/annonc/mdn595.CrossRefPubMed
33.
Ji J, Shu X, Li X, Sundquist K, Sundquist J, Hemminki K: Cancer risk in hospitalised asthma patients. Br J Cancer. 2009, 100 (5): 829-833. 10.1038/sj.bjc.6604890.CrossRefPubMedPubMedCentral
34.
Severi G, Giles GG, Southey MC, Tesoriero A, Tilley W, Neufing P, Morris H, English DR, McCredie MR, Boyle P, et al: ELAC2/HPC2 polymorphisms, prostate-specific antigen levels, and prostate cancer. J Natl Cancer Inst. 2003, 95 (11): 818-824.CrossRefPubMed
35.
Matesanz F, Fedetz M, Leyva L, Delgado C, Fernandez O, Alcina A: Effects of the multiple sclerosis associated -330 promoter polymorphism in IL2 allelic expression. J Neuroimmunol. 2004, 148 (1-2): 212-217. 10.1016/j.jneuroim.2003.12.001.CrossRefPubMed
36.
Hoffmann SC, Stanley EM, Darrin Cox E, Craighead N, DiMercurio BS, Koziol DE, Harlan DM, Kirk AD, Blair PJ: Association of cytokine polymorphic inheritance and in vitro cytokine production in anti-CD3/CD28-stimulated peripheral blood lymphocytes. Transplantation. 2001, 72 (8): 1444-1450. 10.1097/00007890-200110270-00019.CrossRefPubMed
37.
Tindall EA, Speight G, Petersen DC, Padilla EJ, Hayes VM: Novel Plexor SNP genotyping technology: comparisons with TaqMan and homogenous MassEXTEND MALDI-TOF mass spectrometry. Hum Mutat. 2007, 28 (9): 922-927. 10.1002/humu.20533.CrossRefPubMed
38.
Sham PC: Statistics in human genetics. Applications of statistics. 1998, London: Arnold
39.
John S, Turner D, Donn R, Sinnott P, Worthington J, Ollier WE, Hutchinson IV, Hajeer AH: Two novel biallelic polymorphisms in the IL-2 gene. Eur J Immunogenet. 1998, 25 (6): 419-420. 10.1046/j.1365-2370.1998.00139.x.CrossRefPubMed
40.
Sawalha AH, Kaufman KM, Kelly JA, Adler AJ, Aberle T, Kilpatrick J, Wakeland EK, Li QZ, Wandstrat AE, Karp DR, et al: Genetic association of interleukin-21 polymorphisms with systemic lupus erythematosus. Ann Rheum Dis. 2008, 67 (4): 458-461. 10.1136/ard.2007.075424.CrossRefPubMed
41.
Asano K, Ikegami H, Fujisawa T, Nishino M, Nojima K, Kawabata Y, Noso S, Hiromine Y, Fukai A, Ogihara T: Molecular scanning of interleukin-21 gene and genetic susceptibility to type 1 diabetes. Hum Immunol. 2007, 68 (5): 384-391. 10.1016/j.humimm.2007.01.009.CrossRefPubMed
42.
Chatterjee R, Batra J, Ghosh B: A common exonic variant of interleukin21 confers susceptibility to atopic asthma. Int Arch Allergy Immunol. 2009, 148 (2): 137-146. 10.1159/000155744.CrossRefPubMed
Metadata
Title
The 4q27 locus and prostate cancer risk
Authors
Elizabeth A Tindall
Hoa N Hoang
Melissa C Southey
Dallas R English
John L Hopper
Graham G Giles
Gianluca Severi
Vanessa M Hayes
Publication date
01-12-2010
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2010
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-10-69

Other articles of this Issue 1/2010

BMC Cancer 1/2010 Go to the issue

Case report

Oligodendroglioma of the ciliary body: a unique case report and the review of literature

Research article

Characterisation of prostate cancer lesions in heterozygous Men1 mutant mice

Research article

Interference with Activator Protein-2 transcription factors leads to induction of apoptosis and an increase in chemo- and radiation-sensitivity in breast cancer cells

Research article

TIMP-1 and VEGF-165 serum concentration during first-line therapy of ovarian cancer patients

Research article

Establishment and characterization of a new human pancreatic adenocarcinoma cell line with high metastatic potential to the lung

Research article

Separate and combined analysis of successive dependent outcomes after breast-conservation surgery: recurrence, metastases, second cancer and death
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
Image Credits