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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.

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.

SUBMITTER: Lei J

PROVIDER: S-EPMC4698282 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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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.

Lei Jieping J Rudolph Anja A Moysich Kirsten B KB Behrens Sabine S Goode Ellen L EL Bolla Manjeet K MK Dennis Joe J Dunning Alison M AM Easton Douglas F DF Wang Qin Q Benitez Javier J Hopper John L JL Southey Melissa C MC Schmidt Marjanka K MK Broeks Annegien A Fasching Peter A PA Haeberle Lothar L Peto Julian J Dos-Santos-Silva Isabel I Sawyer Elinor J EJ Tomlinson Ian I Burwinkel Barbara B Marmé Frederik F Guénel Pascal P Truong Thérèse T Bojesen Stig E SE Flyger Henrik H Nielsen Sune F SF Nordestgaard Børge G BG González-Neira Anna A Menéndez Primitiva P Anton-Culver Hoda H Neuhausen Susan L SL Brenner Hermann H Arndt Volker V Meindl Alfons A Schmutzler Rita K RK Brauch Hiltrud H Hamann Ute U Nevanlinna Heli H Fagerholm Rainer R Dörk Thilo T Bogdanova Natalia V NV Mannermaa Arto A Hartikainen Jaana M JM Van Dijck Laurien L Smeets Ann A Flesch-Janys Dieter D Eilber Ursula U Radice Paolo P Peterlongo Paolo P Couch Fergus J FJ Hallberg Emily E Giles Graham G GG Milne Roger L RL Haiman Christopher A CA Schumacher Fredrick F Simard Jacques J Goldberg Mark S MS Kristensen Vessela V Borresen-Dale Anne-Lise AL Zheng Wei W Beeghly-Fadiel Alicia A Winqvist Robert R Grip Mervi M Andrulis Irene L IL Glendon Gord G García-Closas Montserrat M Figueroa Jonine J Czene Kamila K Brand Judith S JS Darabi Hatef H Eriksson Mikael M Hall Per P Li Jingmei J Cox Angela A Cross Simon S SS Pharoah Paul D P PD Shah Mitul M Kabisch Maria M Torres Diana D Jakubowska Anna A Lubinski Jan J Ademuyiwa Foluso F Ambrosone Christine B CB Swerdlow Anthony A Jones Michael M Chang-Claude Jenny J

Human genetics 20151130 1

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 gene ...[more]

PMID: 26621531

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Project description:BackgroundPrevious studies have suggested that breast cancer risk factors are associated with estrogen receptor (ER) and progesterone receptor (PR) expression status of the tumors.MethodsWe pooled tumor marker and epidemiological risk factor data from 35,568 invasive breast cancer case patients from 34 studies participating in the Breast Cancer Association Consortium. Logistic regression models were used in case-case analyses to estimate associations between epidemiological risk factors and tumor subtypes, and case-control analyses to estimate associations between epidemiological risk factors and the risk of developing specific tumor subtypes in 12 population-based studies. All statistical tests were two-sided.ResultsIn case-case analyses, of the epidemiological risk factors examined, early age at menarche (?12 years) was less frequent in case patients with PR(-) than PR(+) tumors (P = .001). Nulliparity (P = 3 × 10(-6)) and increasing age at first birth (P = 2 × 10(-9)) were less frequent in ER(-) than in ER(+) tumors. Obesity (body mass index [BMI] ? 30 kg/m(2)) in younger women (?50 years) was more frequent in ER(-)/PR(-) than in ER(+)/PR(+) tumors (P = 1 × 10(-7)), whereas obesity in older women (>50 years) was less frequent in PR(-) than in PR(+) tumors (P = 6 × 10(-4)). The triple-negative (ER(-)/PR(-)/HER2(-)) or core basal phenotype (CBP; triple-negative and cytokeratins [CK]5/6(+) and/or epidermal growth factor receptor [EGFR](+)) accounted for much of the heterogeneity in parity-related variables and BMI in younger women. Case-control analyses showed that nulliparity, increasing age at first birth, and obesity in younger women showed the expected associations with the risk of ER(+) or PR(+) tumors but not triple-negative (nulliparity vs parity, odds ratio [OR] = 0.94, 95% confidence interval [CI] = 0.75 to 1.19, P = .61; 5-year increase in age at first full-term birth, OR = 0.95, 95% CI = 0.86 to 1.05, P = .34; obesity in younger women, OR = 1.36, 95% CI = 0.95 to 1.94, P = .09) or CBP tumors.ConclusionsThis study shows that reproductive factors and BMI are most clearly associated with hormone receptor-positive tumors and suggest that triple-negative or CBP tumors may have distinct etiology.

Dataset Information

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.

Publications

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.

Similar Datasets

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