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

TY - JOUR

T1 - 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

AU - Lei, Jieping

AU - Rudolph, Anja

AU - Moysich, Kirsten B

AU - Behrens, Sabine

AU - Goode, Ellen L

AU - Bolla, Manjeet K

AU - Dennis, Joe

AU - Dunning, Alison M

AU - Easton, Douglas F

AU - Wang, Qin

AU - Benitez, Javier

AU - Hopper, John L

AU - Southey, Melissa C

AU - Schmidt, Marjanka K

AU - Broeks, Annegien

AU - Fasching, Peter A

AU - Haeberle, Lothar

AU - Peto, Julian

AU - Dos-Santos-Silva, Isabel

AU - Sawyer, Elinor J

AU - Tomlinson, Ian

AU - Burwinkel, Barbara

AU - Marmé, Frederik

AU - Guénel, Pascal

AU - Truong, Thérèse

AU - Bojesen, Stig E

AU - Flyger, Henrik

AU - Nielsen, Sune F

AU - Nordestgaard, Børge G

AU - González-Neira, Anna

AU - Menéndez, Primitiva

AU - Anton-Culver, Hoda

AU - Neuhausen, Susan L

AU - Brenner, Hermann

AU - Arndt, Volker

AU - Meindl, Alfons

AU - Schmutzler, Rita K

AU - Brauch, Hiltrud

AU - Hamann, Ute

AU - Nevanlinna, Heli

AU - Fagerholm, Rainer

AU - Dörk, Thilo

AU - Bogdanova, Natalia V

AU - Mannermaa, Arto

AU - Hartikainen, Jaana M

AU - Van Dijck, Laurien

AU - Smeets, Ann

AU - Flesch-Janys, Dieter

AU - Eilber, Ursula

AU - Radice, Paolo

AU - Peterlongo, Paolo

AU - Couch, Fergus J

AU - Hallberg, Emily

AU - Giles, Graham G

AU - Milne, Roger L

AU - Haiman, Christopher A

AU - Schumacher, Fredrick

AU - Simard, Jacques

AU - Goldberg, Mark S

AU - Kristensen, Vessela

AU - Borresen-Dale, Anne-Lise

AU - Zheng, Wei

AU - Beeghly-Fadiel, Alicia

AU - Winqvist, Robert

AU - Grip, Mervi

AU - Andrulis, Irene L

AU - Glendon, Gord

AU - García-Closas, Montserrat

AU - Figueroa, Jonine

AU - Czene, Kamila

AU - Brand, Judith S

AU - Darabi, Hatef

AU - Eriksson, Mikael

AU - Hall, Per

AU - Li, Jingmei

AU - Cox, Angela

AU - Cross, Simon S

AU - Pharoah, Paul D P

AU - Shah, Mitul

AU - Kabisch, Maria

AU - Torres, Diana

AU - Jakubowska, Anna

AU - Lubinski, Jan

AU - Ademuyiwa, Foluso

AU - Ambrosone, Christine B

AU - Swerdlow, Anthony

AU - Jones, Michael

AU - Chang-Claude, Jenny

AU - Australian Ovarian Study Group

PY - 2016/1

Y1 - 2016/1

N2 - 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.

AB - 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.

U2 - 10.1007/s00439-015-1616-8

DO - 10.1007/s00439-015-1616-8

M3 - SCORING: Journal article

C2 - 26621531

VL - 135

SP - 137

EP - 154

JO - HUM GENET

JF - HUM GENET

SN - 0340-6717

IS - 1

ER -