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. 2016 Jan;135(1):137-54.
doi: 10.1007/s00439-015-1616-8. Epub 2015 Nov 30.

Genetic Variation in the Immunosuppression Pathway Genes and Breast Cancer Susceptibility: A Pooled Analysis of 42,510 Cases and 40,577 Controls From the Breast Cancer Association Consortium

Jieping Lei  1 Anja Rudolph  1 Kirsten B Moysich  2 Sabine Behrens  1 Ellen L Goode  3 Manjeet K Bolla  4 Joe Dennis  4 Alison M Dunning  5 Douglas F Easton  4   5 Qin Wang  4 Javier Benitez  6   7 John L Hopper  8 Melissa C Southey  9 Marjanka K Schmidt  10 Annegien Broeks  10 Peter A Fasching  11   12 Lothar Haeberle  11 Julian Peto  13 Isabel Dos-Santos-Silva  13 Elinor J Sawyer  14 Ian Tomlinson  15 Barbara Burwinkel  16   17 Frederik Marmé  16   18 Pascal Guénel  19   20 Thérèse Truong  19   20 Stig E Bojesen  21   22   23 Henrik Flyger  24 Sune F Nielsen  22 Børge G Nordestgaard  22   23 Anna González-Neira  6 Primitiva Menéndez  25 Hoda Anton-Culver  26 Susan L Neuhausen  27 Hermann Brenner  28   29   30 Volker Arndt  28 Alfons Meindl  31 Rita K Schmutzler  32   33   34 Hiltrud Brauch  30   35   36 Ute Hamann  37 Heli Nevanlinna  38 Rainer Fagerholm  38 Thilo Dörk  39 Natalia V Bogdanova  40 Arto Mannermaa  41   42   43 Jaana M Hartikainen  41   42   43 Australian Ovarian Study GroupkConFab InvestigatorsLaurien Van Dijck  44 Ann Smeets  45 Dieter Flesch-Janys  46   47 Ursula Eilber  1 Paolo Radice  48 Paolo Peterlongo  49 Fergus J Couch  50 Emily Hallberg  3 Graham G Giles  8   51 Roger L Milne  8   51 Christopher A Haiman  52 Fredrick Schumacher  52 Jacques Simard  53 Mark S Goldberg  54   55 Vessela Kristensen  56   57   58 Anne-Lise Borresen-Dale  56   57 Wei Zheng  59 Alicia Beeghly-Fadiel  59 Robert Winqvist  60   61 Mervi Grip  62 Irene L Andrulis  63   64 Gord Glendon  63 Montserrat García-Closas  65   66 Jonine Figueroa  66 Kamila Czene  67 Judith S Brand  67 Hatef Darabi  67 Mikael Eriksson  67 Per Hall  67 Jingmei Li  67 Angela Cox  68 Simon S Cross  69 Paul D P Pharoah  4   5 Mitul Shah  5 Maria Kabisch  37 Diana Torres  37   70 Anna Jakubowska  71 Jan Lubinski  71 Foluso Ademuyiwa  72 Christine B Ambrosone  72 Anthony Swerdlow  73   74 Michael Jones  73 Jenny Chang-Claude  75   76
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Free PMC article

Genetic Variation in the Immunosuppression Pathway Genes and Breast Cancer Susceptibility: A Pooled Analysis of 42,510 Cases and 40,577 Controls From the Breast Cancer Association Consortium

Jieping Lei et al. Hum Genet. .
Free PMC article

Abstract

Immunosuppression plays a pivotal role in assisting tumors to evade immune destruction and promoting tumor development. We hypothesized that genetic variation in the immunosuppression pathway genes may be implicated in breast cancer tumorigenesis. We included 42,510 female breast cancer cases and 40,577 controls of European ancestry from 37 studies in the Breast Cancer Association Consortium (2015) with available genotype data for 3595 single nucleotide polymorphisms (SNPs) in 133 candidate genes. Associations between genotyped SNPs and overall breast cancer risk, and secondarily according to estrogen receptor (ER) status, were assessed using multiple logistic regression models. Gene-level associations were assessed based on principal component analysis. Gene expression analyses were conducted using RNA sequencing level 3 data from The Cancer Genome Atlas for 989 breast tumor samples and 113 matched normal tissue samples. SNP rs1905339 (A>G) in the STAT3 region was associated with an increased breast cancer risk (per allele odds ratio 1.05, 95 % confidence interval 1.03-1.08; p value = 1.4 × 10(-6)). The association did not differ significantly by ER status. On the gene level, in addition to TGFBR2 and CCND1, IL5 and GM-CSF showed the strongest associations with overall breast cancer risk (p value = 1.0 × 10(-3) and 7.0 × 10(-3), respectively). Furthermore, STAT3 and IL5 but not GM-CSF were differentially expressed between breast tumor tissue and normal tissue (p value = 2.5 × 10(-3), 4.5 × 10(-4) and 0.63, respectively). Our data provide evidence that the immunosuppression pathway genes STAT3, IL5, and GM-CSF may be novel susceptibility loci for breast cancer in women of European ancestry.

Figures

Fig. 1
Fig. 1
Linkage disequilibrium plot showing r 2 values and color schemes for the genotyped SNP rs1905339 and seven independent imputed SNPs as well as imputed SNP rs181888151 within ±50 kb of STAT3. The linkage disequilibrium (LD) plot shows that SNP rs1905339 is in strong LD with the imputed SNP rs8074296 (r 2 = 0.99), and independent of the other six imputed SNPs (r 2 ≤ 0.01) at STAT3. LD was estimated based on control data
Fig. 2
Fig. 2
Regional association plot for the genotyped SNP rs1905339 and 885 imputed SNPs within ±50 kb of STAT3 and PTRF. Each dot represents an SNP. The color of each dot reflects the extent of linkage disequilibrium (r 2) with SNP rs1032070 (in purple diamond). Genomic positions of SNPs were plotted based on hg19/1000 Genomes Mar 2012 European. Association is represented at the −log10 scale. cM/Mb centiMorgans/megabase
Fig. 3
Fig. 3
UCSC genome browser graphic for SNPs at the STAT3/PTRF region. The UCSC genome browser graphic shows functional annotations for the SNPs rs1905339 (red), correlated SNPs (r 2 > 0.80, green), as well as the other independent imputed SNPs (black) in or near the STAT3/PTRF region

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