SNP-SNP interaction analysis of NF-κB signaling pathway on breast cancer survival

Maral Jamshidi; Rainer Fagerholm; Sofia Khan; Kristiina Aittomäki; Kamila Czene; Hatef Darabi; Jingmei Li; Irene L Andrulis; Jenny Chang-Claude; Peter Devilee; Peter A Fasching; Kyriaki Michailidou; Manjeet K Bolla; Joe Dennis; Qin Wang; Qi Guo; Valerie Rhenius; Sten Cornelissen; Anja Rudolph; Julia A Knight; Christian R Loehberg; Barbara Burwinkel; Frederik Marme; John L Hopper; Melissa C Southey; Stig E Bojesen; Henrik Flyger; Hermann Brenner; Bernd Holleczek; Sara Margolin; Arto Mannermaa; Veli-Matti Kosma; Laurien Van Dyck; Ines Nevelsteen; Fergus J Couch; Janet E Olson; Graham G Giles; Catriona McLean; Christopher A Haiman; Brian E Henderson; Robert Winqvist; Katri Pylkäs; Rob A E M Tollenaar; Montserrat García-Closas; Jonine Figueroa; Maartje J Hooning; John W M Martens; Angela Cox; Simon S Cross; Jacques Simard; kConFab Investigators

doi:10.18632/oncotarget.4991

SNP-SNP interaction analysis of NF-κB signaling pathway on breast cancer survival

Maral Jamshidi, Rainer Fagerholm, Sofia Khan, Kristiina Aittomäki, Kamila Czene, Hatef Darabi, Jingmei Li, Irene L Andrulis, Jenny Chang-Claude, Peter Devilee, Peter A Fasching, Kyriaki Michailidou, Manjeet K Bolla, Joe Dennis, Qin Wang, Qi Guo, Valerie Rhenius, Sten Cornelissen, Anja Rudolph, Julia A KnightChristian R Loehberg, Barbara Burwinkel, Frederik Marme, John L Hopper, Melissa C Southey, Stig E Bojesen, Henrik Flyger, Hermann Brenner, Bernd Holleczek, Sara Margolin, Arto Mannermaa, Veli-Matti Kosma, Laurien Van Dyck, Ines Nevelsteen, Fergus J Couch, Janet E Olson, Graham G Giles, Catriona McLean, Christopher A Haiman, Brian E Henderson, Robert Winqvist, Katri Pylkäs, Rob A E M Tollenaar, Montserrat García-Closas, Jonine Figueroa, Maartje J Hooning, John W M Martens, Angela Cox, Simon S Cross, Jacques Simard, kConFab Investigators

Department of Clinical Medicine

16 Citations (Scopus)

Abstract

In breast cancer, constitutive activation of NF-κB has been reported, however, the impact of genetic variation of the pathway on patient prognosis has been little studied. Furthermore, a combination of genetic variants, rather than single polymorphisms, may affect disease prognosis. Here, in an extensive dataset (n = 30,431) from the Breast Cancer Association Consortium, we investigated the association of 917 SNPs in 75 genes in the NF-κB pathway with breast cancer prognosis. We explored SNP-SNP interactions on survival using the likelihood-ratio test comparing multivariate Cox' regression models of SNP pairs without and with an interaction term. We found two interacting pairs associating with prognosis: patients simultaneously homozygous for the rare alleles of rs5996080 and rs7973914 had worse survival (HRinteraction 6.98, 95% CI=3.3-14.4, P=1.42E-07), and patients carrying at least one rare allele for rs17243893 and rs57890595 had better survival (HRinteraction 0.51, 95% CI=0.3-0.6, P = 2.19E-05). Based on in silico functional analyses and literature, we speculate that the rs5996080 and rs7973914 loci may affect the BAFFR and TNFR1/TNFR3 receptors and breast cancer survival, possibly by disturbing both the canonical and non-canonical NF-κB pathways or their dynamics, whereas, rs17243893-rs57890595 interaction on survival may be mediated through TRAF2-TRAIL-R4 interplay. These results warrant further validation and functional analyses.

Original language	English
Journal	OncoTarget
Volume	6
Issue number	35
Pages (from-to)	37979-94
Number of pages	16
ISSN	1949-2553
DOIs	https://doi.org/10.18632/oncotarget.4991
Publication status	Published - 10 Nov 2015

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Jamshidi, M., Fagerholm, R., Khan, S., Aittomäki, K., Czene, K., Darabi, H., Li, J., Andrulis, I. L., Chang-Claude, J., Devilee, P., Fasching, P. A., Michailidou, K., Bolla, M. K., Dennis, J., Wang, Q., Guo, Q., Rhenius, V., Cornelissen, S., Rudolph, A., ... kConFab Investigators (2015). SNP-SNP interaction analysis of NF-κB signaling pathway on breast cancer survival. OncoTarget, 6(35), 37979-94. https://doi.org/10.18632/oncotarget.4991

Jamshidi, M, Fagerholm, R, Khan, S, Aittomäki, K, Czene, K, Darabi, H, Li, J, Andrulis, IL, Chang-Claude, J, Devilee, P, Fasching, PA, Michailidou, K, Bolla, MK, Dennis, J, Wang, Q, Guo, Q, Rhenius, V, Cornelissen, S, Rudolph, A, Knight, JA, Loehberg, CR, Burwinkel, B, Marme, F, Hopper, JL, Southey, MC, Bojesen, SE, Flyger, H, Brenner, H, Holleczek, B, Margolin, S, Mannermaa, A, Kosma, V-M, Van Dyck, L, Nevelsteen, I, Couch, FJ, Olson, JE, Giles, GG, McLean, C, Haiman, CA, Henderson, BE, Winqvist, R, Pylkäs, K, Tollenaar, RAEM, García-Closas, M, Figueroa, J, Hooning, MJ, Martens, JWM, Cox, A, Cross, SS, Simard, J & kConFab Investigators 2015, 'SNP-SNP interaction analysis of NF-κB signaling pathway on breast cancer survival', OncoTarget, vol. 6, no. 35, pp. 37979-94. https://doi.org/10.18632/oncotarget.4991

@article{492853642d0b44e5a2b29716b90659ae,

title = "SNP-SNP interaction analysis of NF-κB signaling pathway on breast cancer survival",

abstract = "In breast cancer, constitutive activation of NF-κB has been reported, however, the impact of genetic variation of the pathway on patient prognosis has been little studied. Furthermore, a combination of genetic variants, rather than single polymorphisms, may affect disease prognosis. Here, in an extensive dataset (n = 30,431) from the Breast Cancer Association Consortium, we investigated the association of 917 SNPs in 75 genes in the NF-κB pathway with breast cancer prognosis. We explored SNP-SNP interactions on survival using the likelihood-ratio test comparing multivariate Cox' regression models of SNP pairs without and with an interaction term. We found two interacting pairs associating with prognosis: patients simultaneously homozygous for the rare alleles of rs5996080 and rs7973914 had worse survival (HRinteraction 6.98, 95% CI=3.3-14.4, P=1.42E-07), and patients carrying at least one rare allele for rs17243893 and rs57890595 had better survival (HRinteraction 0.51, 95% CI=0.3-0.6, P = 2.19E-05). Based on in silico functional analyses and literature, we speculate that the rs5996080 and rs7973914 loci may affect the BAFFR and TNFR1/TNFR3 receptors and breast cancer survival, possibly by disturbing both the canonical and non-canonical NF-κB pathways or their dynamics, whereas, rs17243893-rs57890595 interaction on survival may be mediated through TRAF2-TRAIL-R4 interplay. These results warrant further validation and functional analyses.",

author = "Maral Jamshidi and Rainer Fagerholm and Sofia Khan and Kristiina Aittom{\"a}ki and Kamila Czene and Hatef Darabi and Jingmei Li and Andrulis, {Irene L} and Jenny Chang-Claude and Peter Devilee and Fasching, {Peter A} and Kyriaki Michailidou and Bolla, {Manjeet K} and Joe Dennis and Qin Wang and Qi Guo and Valerie Rhenius and Sten Cornelissen and Anja Rudolph and Knight, {Julia A} and Loehberg, {Christian R} and Barbara Burwinkel and Frederik Marme and Hopper, {John L} and Southey, {Melissa C} and Bojesen, {Stig E} and Henrik Flyger and Hermann Brenner and Bernd Holleczek and Sara Margolin and Arto Mannermaa and Veli-Matti Kosma and {Van Dyck}, Laurien and Ines Nevelsteen and Couch, {Fergus J} and Olson, {Janet E} and Giles, {Graham G} and Catriona McLean and Haiman, {Christopher A} and Henderson, {Brian E} and Robert Winqvist and Katri Pylk{\"a}s and Tollenaar, {Rob A E M} and Montserrat Garc{\'i}a-Closas and Jonine Figueroa and Hooning, {Maartje J} and Martens, {John W M} and Angela Cox and Cross, {Simon S} and Jacques Simard and {kConFab Investigators}",

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language = "English",

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T1 - SNP-SNP interaction analysis of NF-κB signaling pathway on breast cancer survival

AU - Jamshidi, Maral

AU - Fagerholm, Rainer

AU - Khan, Sofia

AU - Aittomäki, Kristiina

AU - Czene, Kamila

AU - Darabi, Hatef

AU - Li, Jingmei

AU - Andrulis, Irene L

AU - Chang-Claude, Jenny

AU - Devilee, Peter

AU - Fasching, Peter A

AU - Michailidou, Kyriaki

AU - Bolla, Manjeet K

AU - Dennis, Joe

AU - Wang, Qin

AU - Guo, Qi

AU - Rhenius, Valerie

AU - Cornelissen, Sten

AU - Rudolph, Anja

AU - Knight, Julia A

AU - Loehberg, Christian R

AU - Burwinkel, Barbara

AU - Marme, Frederik

AU - Hopper, John L

AU - Southey, Melissa C

AU - Bojesen, Stig E

AU - Flyger, Henrik

AU - Brenner, Hermann

AU - Holleczek, Bernd

AU - Margolin, Sara

AU - Mannermaa, Arto

AU - Kosma, Veli-Matti

AU - Van Dyck, Laurien

AU - Nevelsteen, Ines

AU - Couch, Fergus J

AU - Olson, Janet E

AU - Giles, Graham G

AU - McLean, Catriona

AU - Haiman, Christopher A

AU - Henderson, Brian E

AU - Winqvist, Robert

AU - Pylkäs, Katri

AU - Tollenaar, Rob A E M

AU - García-Closas, Montserrat

AU - Figueroa, Jonine

AU - Hooning, Maartje J

AU - Martens, John W M

AU - Cox, Angela

AU - Cross, Simon S

AU - Simard, Jacques

AU - kConFab Investigators

PY - 2015/11/10

Y1 - 2015/11/10

N2 - In breast cancer, constitutive activation of NF-κB has been reported, however, the impact of genetic variation of the pathway on patient prognosis has been little studied. Furthermore, a combination of genetic variants, rather than single polymorphisms, may affect disease prognosis. Here, in an extensive dataset (n = 30,431) from the Breast Cancer Association Consortium, we investigated the association of 917 SNPs in 75 genes in the NF-κB pathway with breast cancer prognosis. We explored SNP-SNP interactions on survival using the likelihood-ratio test comparing multivariate Cox' regression models of SNP pairs without and with an interaction term. We found two interacting pairs associating with prognosis: patients simultaneously homozygous for the rare alleles of rs5996080 and rs7973914 had worse survival (HRinteraction 6.98, 95% CI=3.3-14.4, P=1.42E-07), and patients carrying at least one rare allele for rs17243893 and rs57890595 had better survival (HRinteraction 0.51, 95% CI=0.3-0.6, P = 2.19E-05). Based on in silico functional analyses and literature, we speculate that the rs5996080 and rs7973914 loci may affect the BAFFR and TNFR1/TNFR3 receptors and breast cancer survival, possibly by disturbing both the canonical and non-canonical NF-κB pathways or their dynamics, whereas, rs17243893-rs57890595 interaction on survival may be mediated through TRAF2-TRAIL-R4 interplay. These results warrant further validation and functional analyses.

AB - In breast cancer, constitutive activation of NF-κB has been reported, however, the impact of genetic variation of the pathway on patient prognosis has been little studied. Furthermore, a combination of genetic variants, rather than single polymorphisms, may affect disease prognosis. Here, in an extensive dataset (n = 30,431) from the Breast Cancer Association Consortium, we investigated the association of 917 SNPs in 75 genes in the NF-κB pathway with breast cancer prognosis. We explored SNP-SNP interactions on survival using the likelihood-ratio test comparing multivariate Cox' regression models of SNP pairs without and with an interaction term. We found two interacting pairs associating with prognosis: patients simultaneously homozygous for the rare alleles of rs5996080 and rs7973914 had worse survival (HRinteraction 6.98, 95% CI=3.3-14.4, P=1.42E-07), and patients carrying at least one rare allele for rs17243893 and rs57890595 had better survival (HRinteraction 0.51, 95% CI=0.3-0.6, P = 2.19E-05). Based on in silico functional analyses and literature, we speculate that the rs5996080 and rs7973914 loci may affect the BAFFR and TNFR1/TNFR3 receptors and breast cancer survival, possibly by disturbing both the canonical and non-canonical NF-κB pathways or their dynamics, whereas, rs17243893-rs57890595 interaction on survival may be mediated through TRAF2-TRAIL-R4 interplay. These results warrant further validation and functional analyses.

U2 - 10.18632/oncotarget.4991

DO - 10.18632/oncotarget.4991

M3 - Journal article

C2 - 26317411

SN - 1949-2553

VL - 6

SP - 37979

EP - 37994

JO - OncoTarget

JF - OncoTarget

IS - 35

ER -

SNP-SNP interaction analysis of NF-κB signaling pathway on breast cancer survival

Abstract

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