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

SNP-SNP interaction analysis of NF-κB signaling pathway on breast cancer survival. 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., Knight, J. A., Loehberg, C. R., Burwinkel, B., Marme, F., Hopper, J. L., Southey, M. C., Bojesen, S. E., Flyger, H., Brenner, H., Holleczek, B., Margolin, S., Mannermaa, A., Kosma, V., kConFab Investigators, Van Dyck, L., Nevelsteen, I., Couch, F. J., Olson, J. E., Giles, G. G., McLean, C., Haiman, C. A., Henderson, B. E., Winqvist, R., Pylkäs, K., Tollenaar, R. A. E. M., García-Closas, M., Figueroa, J., Hooning, M. J., Martens, J. W. M., Cox, A., Cross, S. S., Simard, J., Dunning, A. M., Easton, D. F., Pharoah, P. D. P., Hall, P., Blomqvist, C., Schmidt, M. K., & Nevanlinna, H. Oncotarget, 6(35):37979–37994, November, 2015.
doi abstract bibtex

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.

@article{jamshidi_snp-snp_2015,
	title = {{SNP}-{SNP} interaction analysis of {NF}-κ{B} signaling pathway on breast cancer survival},
	volume = {6},
	issn = {1949-2553},
	doi = {10.18632/oncotarget.4991},
	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.},
	language = {eng},
	number = {35},
	journal = {Oncotarget},
	author = {Jamshidi, Maral and Fagerholm, Rainer and Khan, Sofia and Aittomäki, Kristiina and Czene, Kamila and Darabi, Hatef and Li, Jingmei and Andrulis, Irene L. and Chang-Claude, Jenny and Devilee, Peter and Fasching, Peter A. and Michailidou, Kyriaki and Bolla, Manjeet K. and Dennis, Joe and Wang, Qin and Guo, Qi and Rhenius, Valerie and Cornelissen, Sten and Rudolph, Anja and Knight, Julia A. and Loehberg, Christian R. and Burwinkel, Barbara and Marme, Frederik and Hopper, John L. and Southey, Melissa C. and Bojesen, Stig E. and Flyger, Henrik and Brenner, Hermann and Holleczek, Bernd and Margolin, Sara and Mannermaa, Arto and Kosma, Veli-Matti and {kConFab Investigators} and Van Dyck, Laurien and Nevelsteen, Ines and Couch, Fergus J. and Olson, Janet E. and Giles, Graham G. and McLean, Catriona and Haiman, Christopher A. and Henderson, Brian E. and Winqvist, Robert and Pylkäs, Katri and Tollenaar, Rob A. E. M. and García-Closas, Montserrat and Figueroa, Jonine and Hooning, Maartje J. and Martens, John W. M. and Cox, Angela and Cross, Simon S. and Simard, Jacques and Dunning, Alison M. and Easton, Douglas F. and Pharoah, Paul D. P. and Hall, Per and Blomqvist, Carl and Schmidt, Marjanka K. and Nevanlinna, Heli},
	month = nov,
	year = {2015},
	pmid = {26317411},
	pmcid = {PMC4741978},
	keywords = {Biomarkers, Tumor, Breast Neoplasms, Female, Humans, NF-kappa B, NF-κB pathway, Neoplasm Grading, Neoplasm Invasiveness, Neoplasm Staging, Polymorphism, Single Nucleotide, Prognosis, SNP-SNP interaction, Signal Transduction, Survival Rate, breast cancer, survival analysis},
	pages = {37979--37994},
}

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