TP53-based interaction analysis identifies cis-eQTL variants for TP53BP2, FBXO28, and FAM53A that associate with survival and treatment outcome in breast cancer

TY - JOUR

T1 - TP53-based interaction analysis identifies cis-eQTL variants for TP53BP2, FBXO28, and FAM53A that associate with survival and treatment outcome in breast cancer

AU - Fagerholm, Rainer

AU - Khan, Sofia

AU - Schmidt, Marjanka K

AU - García-Closas, Montserrat

AU - Heikkilä, Päivi

AU - Saarela, Jani

AU - Beesley, Jonathan

AU - Jamshidi, Maral

AU - Aittomäki, Kristiina

AU - Liu, Jianjun

AU - Ali, H Raza

AU - Andrulis, Irene L

AU - Beckmann, Matthias W

AU - Behrens, Sabine

AU - Blows, Fiona M

AU - Brenner, Hermann

AU - Chang-Claude, Jenny

AU - Couch, Fergus J

AU - Czene, Kamila

AU - Fasching, Peter A

AU - Figueroa, Jonine

AU - Floris, Giuseppe

AU - Glendon, Gord

AU - Guo, Qi

AU - Hall, Per

AU - Hallberg, Emily

AU - Hamann, Ute

AU - Holleczek, Bernd

AU - Hooning, Maartje J

AU - Hopper, John L

AU - Jager, Agnes

AU - Kabisch, Maria

AU - Keeman, Renske

AU - Kosma, Veli-Matti

AU - Lambrechts, Diether

AU - Lindblom, Annika

AU - Mannermaa, Arto

AU - Margolin, Sara

AU - Provenzano, Elena

AU - Shah, Mitul

AU - Southey, Melissa C

AU - Dennis, Joe

AU - Lush, Michael

AU - Michailidou, Kyriaki

AU - Wang, Qin

AU - Bolla, Manjeet K

AU - Dunning, Alison M

AU - Easton, Douglas F

AU - Pharoah, Paul P D

AU - Chenevix-Trench, Georgia

AU - Blomqvist, Carl

AU - Nevanlinna, Heli

AU - kConFab/AOCS Investigators

PY - 2017/3/14

Y1 - 2017/3/14

N2 - TP53 overexpression is indicative of somatic TP53 mutations and associates with aggressive tumors and poor prognosis in breast cancer. We utilized a two-stage SNP association study to detect variants associated with breast cancer survival in a TP53-dependent manner. Initially, a genome-wide study (n = 575 cases) was conducted to discover candidate SNPs for genotyping and validation in the Breast Cancer Association Consortium (BCAC). The SNPs were then tested for interaction with tumor TP53 status (n = 4,610) and anthracycline treatment (n = 17,828). For SNPs interacting with anthracycline treatment, siRNA knockdown experiments were carried out to validate candidate genes.In the test for interaction between SNP genotype and TP53 status, we identified one locus, represented by rs10916264 (p(interaction) = 3.44 × 10-5; FDR-adjusted p = 0.0011) in estrogen receptor (ER) positive cases. The rs10916264 AA genotype associated with worse survival among cases with ER-positive, TP53-positive tumors (hazard ratio [HR] 2.36, 95% confidence interval [C.I] 1.45 - 3.82). This is a cis-eQTL locus for FBXO28 and TP53BP2; expression levels of these genes were associated with patient survival specifically in ER-positive, TP53-mutated tumors. Additionally, the SNP rs798755 was associated with survival in interaction with anthracycline treatment (p(interaction) = 9.57 × 10-5, FDR-adjusted p = 0.0130). RNAi-based depletion of a predicted regulatory target gene, FAM53A, indicated that this gene can modulate doxorubicin sensitivity in breast cancer cell lines.If confirmed in independent data sets, these results may be of clinical relevance in the development of prognostic and predictive marker panels for breast cancer.

AB - TP53 overexpression is indicative of somatic TP53 mutations and associates with aggressive tumors and poor prognosis in breast cancer. We utilized a two-stage SNP association study to detect variants associated with breast cancer survival in a TP53-dependent manner. Initially, a genome-wide study (n = 575 cases) was conducted to discover candidate SNPs for genotyping and validation in the Breast Cancer Association Consortium (BCAC). The SNPs were then tested for interaction with tumor TP53 status (n = 4,610) and anthracycline treatment (n = 17,828). For SNPs interacting with anthracycline treatment, siRNA knockdown experiments were carried out to validate candidate genes.In the test for interaction between SNP genotype and TP53 status, we identified one locus, represented by rs10916264 (p(interaction) = 3.44 × 10-5; FDR-adjusted p = 0.0011) in estrogen receptor (ER) positive cases. The rs10916264 AA genotype associated with worse survival among cases with ER-positive, TP53-positive tumors (hazard ratio [HR] 2.36, 95% confidence interval [C.I] 1.45 - 3.82). This is a cis-eQTL locus for FBXO28 and TP53BP2; expression levels of these genes were associated with patient survival specifically in ER-positive, TP53-mutated tumors. Additionally, the SNP rs798755 was associated with survival in interaction with anthracycline treatment (p(interaction) = 9.57 × 10-5, FDR-adjusted p = 0.0130). RNAi-based depletion of a predicted regulatory target gene, FAM53A, indicated that this gene can modulate doxorubicin sensitivity in breast cancer cell lines.If confirmed in independent data sets, these results may be of clinical relevance in the development of prognostic and predictive marker panels for breast cancer.

KW - Journal Article

U2 - 10.18632/oncotarget.15110

DO - 10.18632/oncotarget.15110

M3 - SCORING: Journal article

C2 - 28179588

VL - 8

SP - 18381

EP - 18398

JO - ONCOTARGET

JF - ONCOTARGET

SN - 1949-2553

IS - 11

ER -