title: The rs11515 Polymorphism Is More Frequent and Associated With Aggressive Breast Tumors with Increased ANRIL and Decreased p16 (INK4a) Expression.
abstract: Chromosome position 9p21 encodes three-tumor suppressors p16(INK4a), p14(ARF), and p15(INK4b) and the long non-coding RNA ANRIL (antisense non-coding RNA in the INK4 locus). The rs11515 single-nucleotide polymorphism in the p16 (INK4a) /p14 (ARF) 3'-untranslated region is associated with glioblastoma, melanoma, and other cancers. This study investigated the frequency and effect of rs11515 genotypes in breast cancer. Genomic DNA samples from 400 women (200 with and 200 without a diagnosis of breast cancer) were genotyped for the rs11515 major (C) and minor (G) alleles. The rs11515 polymorphism was also investigated in 108 heart tissues to test for tissue-specific effects. Four 9p21 transcripts, p16 (INK4a) , p14 (ARF) , p15 (INK4b) , and ANRIL were measured in breast tumors and myocardium using quantitative PCR. Heterozygotes (CG genotype) were more frequent in women with breast cancer compared to the control population (P = 0.0039). In those with breast cancer, the CG genotype was associated with an older age (P = 0.016) and increased lymph node involvement (P = 0.007) compared to homozygotes for the major allele (CC genotype). In breast tumors, the CG genotype had higher ANRIL (P = 0.031) and lower p16 (INK4a) (P = 0.006) expression compared to the CC genotype. The CG genotype was not associated with altered 9p21 transcripts in heart tissue. In breast cancer, the rs11515 CG genotype is more frequent and associated with a more aggressive tumor that could be due to increased ANRIL and reduced p16 (INK4a) expression. The absence of association between rs11515 genotypes and 9p21 transcripts in heart tissue suggests this polymorphism has tissue- or disease-specific functions.
authors.affiliation: Department of Pathology, Dunedin School of Medicine, University of Otago , Dunedin , New Zealand.
authors.forename: Janice A
authors.initials: JA
authors.lastname: Royds
authors.affiliation: Department of Medicine, University of Otago , Christchurch , New Zealand.
authors.forename: Anna P
authors.initials: AP
authors.lastname: Pilbrow
authors.affiliation: Department of Pathology, Dunedin School of Medicine, University of Otago , Dunedin , New Zealand.
authors.forename: Antonio
authors.initials: A
authors.lastname: Ahn
authors.affiliation: Department of Pathology, University of Otago , Christchurch , New Zealand.
authors.forename: Helen R
authors.initials: HR
authors.lastname: Morrin
authors.affiliation: Department of Medicine, University of Otago , Christchurch , New Zealand.
authors.forename: Chris
authors.initials: C
authors.lastname: Frampton
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge , Cambridge , UK.
authors.forename: I Alasdair
authors.initials: IA
authors.lastname: Russell
authors.affiliation: Department of Cardiovascular Medicine, Kaufman Center for Heart Failure, Cleveland Clinic , Cleveland, OH , USA.
authors.forename: Christine S
authors.initials: CS
authors.lastname: Moravec
authors.affiliation: Department of Cardiovascular Medicine, Kaufman Center for Heart Failure, Cleveland Clinic , Cleveland, OH , USA.
authors.forename: Wendy E
authors.initials: WE
authors.lastname: Sweet
authors.affiliation: Department of Cardiovascular Medicine, Kaufman Center for Heart Failure, Cleveland Clinic , Cleveland, OH , USA.
authors.forename: W H Wilson
authors.initials: WH
authors.lastname: Tang
authors.affiliation: Department of Pathology, University of Otago , Christchurch , New Zealand.
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: Currie
authors.affiliation: Department of Pathology, Dunedin School of Medicine, University of Otago , Dunedin , New Zealand.
authors.forename: Noelyn A
authors.initials: NA
authors.lastname: Hung
authors.affiliation: Department of Pathology, Dunedin School of Medicine, University of Otago , Dunedin , New Zealand.
authors.forename: Tania L
authors.initials: TL
authors.lastname: Slatter
keywords: 9p21; ANRIL; breast cancer; p16INK4a; rs11515; single-nucleotide polymorphisms
references.citation: Cell Immunol. 2014 May-Jun;289(1-2):91-6
references.pmid: 24747824
references.citation: Nat Genet. 2010 Jun;42(6):492-4
references.pmid: 20453839
references.citation: PLoS Genet. 2010 Apr 08;6(4):e1000899
references.pmid: 20386740
references.citation: Carcinogenesis. 2014 Dec;35(12):2698-705
references.pmid: 25239644
references.citation: Genes Chromosomes Cancer. 2000 Aug;28(4):404-14
references.pmid: 10862049
references.citation: Oncogene. 2011 Apr 21;30(16):1956-62
references.pmid: 21151178
references.citation: PLoS Genet. 2009 Feb;5(2):e1000378
references.pmid: 19214202
references.citation: Atherosclerosis. 2012 Feb;220(2):449-55
references.pmid: 22178423
references.citation: Nat Genet. 2009 Aug;41(8):899-904
references.pmid: 19578367
references.citation: J Natl Cancer Inst. 1999 Mar 3;91(5):446-52
references.pmid: 10070944
references.citation: Int J Cancer. 2010 Nov 15;127(10):2239-47
references.pmid: 20549699
references.citation: Science. 2007 Jun 8;316(5830):1491-3
references.pmid: 17478679
references.citation: Clin Cancer Res. 2007 May 15;13(10):3100-4
references.pmid: 17505013
references.citation: Nature. 2008 Jan 10;451(7175):202-6
references.pmid: 18185590
references.citation: N Z Med J. 2005 Nov 11;118(1225):U1735
references.pmid: 16286947
references.citation: PLoS Genet. 2010 Feb 19;6(2):e1000850
references.pmid: 20174566
references.citation: FASEB J. 2011 Feb;25(2):444-8
references.pmid: 20956613
references.citation: Hum Pathol. 2000 Jan;31(1):115-9
references.pmid: 10665922
references.citation: Br J Cancer. 2013 Apr 2;108(6):1378-86
references.pmid: 23361049
references.citation: PLoS Genet. 2010 Dec 02;6(12):e1001233
references.pmid: 21151960
references.citation: Hum Genet. 2012 Dec;131(12):1877-88
references.pmid: 22886559
references.citation: Sci Signal. 2013 Apr 02;6(269):pl1
references.pmid: 23550210
references.citation: DNA Cell Biol. 2008 Jan;27(1):35-43
references.pmid: 17941804
references.citation: J Invest Dermatol. 2003 Apr;120(4):676-82
references.pmid: 12648234
references.citation: J Invest Dermatol. 1998 Dec;111(6):1202-6
references.pmid: 9856841
references.citation: Int J Cancer. 2003 Mar 10;104(1):98-103
references.pmid: 12532425
references.citation: Science. 2007 Jun 8;316(5830):1488-91
references.pmid: 17478681
references.citation: PLoS One. 2009 Nov 02;4(11):e7677
references.pmid: 19888323
references.citation: Cell Res. 2005 Feb;15(2):97-8
references.pmid: 15740637
references.citation: Tumour Biol. 2016 Mar;37(3):2933-40
references.pmid: 26409453
references.citation: PLoS One. 2011;6(10):e26737
references.pmid: 22046342
references.citation: Nat Genet. 2009 Aug;41(8):920-5
references.pmid: 19578364
references.citation: N Engl J Med. 2007 Aug 2;357(5):443-53
references.pmid: 17634449
references.citation: Cancer Res. 2007 Apr 15;67(8):3963-9
references.pmid: 17440112
references.citation: Mol Cancer Res. 2014 Feb;12(2):167-83
references.pmid: 24136988
references.citation: Cancer Discov. 2012 May;2(5):401-4
references.pmid: 22588877
references.citation: Nat Genet. 2010 Jun;42(6):504-7
references.pmid: 20453838
references.citation: Mol Cell. 2010 Jun 11;38(5):662-74
references.pmid: 20541999
references.citation: Int J Oncol. 2004 Nov;25(5):1447-52
references.pmid: 15492837
references.citation: Cancer Res. 2004 Aug 1;64(15):5245-50
references.pmid: 15289330
references.citation: PLoS One. 2012;7(6):e39574
references.pmid: 22768093
references.citation: Breast Cancer Res Treat. 2001 May;67(1):61-70
references.pmid: 11518467
references.citation: PLoS Genet. 2013;9(7):e1003588
references.pmid: 23861667
references.citation: BMC Med Genomics. 2008 Dec 29;1:64
references.pmid: 19114010
references.citation: Biomarkers. 2014 Mar;19(2):121-7
references.pmid: 24491138