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; Anja Rudolph; Kirsten B Moysich; Sabine Behrens; Ellen L Goode; Manjeet K Bolla; Joe Dennis; Alison M Dunning; Douglas F Easton; Qin Wang; Javier Benitez; John L Hopper; Melissa C Southey; Marjanka K Schmidt; Annegien Broeks; Peter A Fasching; Lothar Haeberle; Julian Peto; Isabel Dos-Santos-Silva; Elinor J Sawyer; Ian Tomlinson; Barbara Burwinkel; Frederik Marmé; Pascal Guénel; Thérèse Truong; Stig E Bojesen; Henrik Flyger; Sune F Nielsen; Børge G Nordestgaard; Anna González-Neira; Primitiva Menéndez; Hoda Anton-Culver; Susan L Neuhausen; Hermann Brenner; Volker Arndt; Alfons Meindl; Rita K Schmutzler; Hiltrud Brauch; Ute Hamann; Heli Nevanlinna; Rainer Fagerholm; Thilo Dörk; Natalia V Bogdanova; Arto Mannermaa; Jaana M Hartikainen; Laurien Van Dijck; Ann Smeets; Dieter Flesch-Janys; Ursula Eilber; Paolo Radice; Australian Ovarian Study Group

doi:10.1007/s00439-015-1616-8

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, Anja Rudolph, Kirsten B Moysich, Sabine Behrens, Ellen L Goode, Manjeet K Bolla, Joe Dennis, Alison M Dunning, Douglas F Easton, Qin Wang, Javier Benitez, John L Hopper, Melissa C Southey, Marjanka K Schmidt, Annegien Broeks, Peter A Fasching, Lothar Haeberle, Julian Peto, Isabel Dos-Santos-Silva, Elinor J SawyerIan Tomlinson, Barbara Burwinkel, Frederik Marmé, Pascal Guénel, Thérèse Truong, Stig E Bojesen, Henrik Flyger, Sune F Nielsen, Børge G Nordestgaard, Anna González-Neira, Primitiva Menéndez, Hoda Anton-Culver, Susan L Neuhausen, Hermann Brenner, Volker Arndt, Alfons Meindl, Rita K Schmutzler, Hiltrud Brauch, Ute Hamann, Heli Nevanlinna, Rainer Fagerholm, Thilo Dörk, Natalia V Bogdanova, Arto Mannermaa, Jaana M Hartikainen, Laurien Van Dijck, Ann Smeets, Dieter Flesch-Janys, Ursula Eilber, Paolo Radice, Australian Ovarian Study Group

Department of Clinical Medicine

7 Citations (Scopus)

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.

Original language	English
Journal	Human Genetics
Volume	135
Issue number	1
Pages (from-to)	137-54
Number of pages	18
ISSN	0340-6717
DOIs	https://doi.org/10.1007/s00439-015-1616-8
Publication status	Published - 1 Jan 2016

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Lei, J., Rudolph, A., Moysich, K. B., Behrens, S., Goode, E. L., Bolla, M. K., Dennis, J., Dunning, A. M., Easton, D. F., Wang, Q., Benitez, J., Hopper, J. L., Southey, M. C., Schmidt, M. K., Broeks, A., Fasching, P. A., Haeberle, L., Peto, J., Dos-Santos-Silva, I., ... Australian Ovarian Study Group (2016). 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. Human Genetics, 135(1), 137-54. https://doi.org/10.1007/s00439-015-1616-8

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; Rudolph, Anja; Moysich, Kirsten B et al.

In: Human Genetics, Vol. 135, No. 1, 01.01.2016, p. 137-54.

Research output: Contribution to journal › Journal article › Research › peer-review

Lei, J, Rudolph, A, Moysich, KB, Behrens, S, Goode, EL, Bolla, MK, Dennis, J, Dunning, AM, Easton, DF, Wang, Q, Benitez, J, Hopper, JL, Southey, MC, Schmidt, MK, Broeks, A, Fasching, PA, Haeberle, L, Peto, J, Dos-Santos-Silva, I, Sawyer, EJ, Tomlinson, I, Burwinkel, B, Marmé, F, Guénel, P, Truong, T, Bojesen, SE, Flyger, H, Nielsen, SF, Nordestgaard, BG, González-Neira, A, Menéndez, P, Anton-Culver, H, Neuhausen, SL, Brenner, H, Arndt, V, Meindl, A, Schmutzler, RK, Brauch, H, Hamann, U, Nevanlinna, H, Fagerholm, R, Dörk, T, Bogdanova, NV, Mannermaa, A, Hartikainen, JM, Van Dijck, L, Smeets, A, Flesch-Janys, D, Eilber, U, Radice, P & Australian Ovarian Study Group 2016, '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', Human Genetics, vol. 135, no. 1, pp. 137-54. https://doi.org/10.1007/s00439-015-1616-8

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title = "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.",

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T2 - 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 - Australian Ovarian Study Group

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Y1 - 2016/1/1

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 - Journal article

C2 - 26621531

SN - 0340-6717

VL - 135

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EP - 154

JO - Human Genetics

JF - Human Genetics

IS - 1

ER -

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

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