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 - Hll, 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 D.P.
AU - Chenevix-Trench, Georgia
AU - Blomqvist, Carl
AU - Nevanlinna, Heli
N1 - Funding Information:
We thank Johanna Kiiski, Kirsimari Aaltonen, Karl von Smitten, Irja Erkkilä (HEBCS-GWS and HEBCS); Swapnil Potdar, John-Patrick Mpindi, Bhagwan Yadav, and the High Thoughput Biomedicine unit (FIMM); Maggie Angelakos, Judi Maskiell, and Gillian Dite (ABCFS);; Sten Cornelissen, Frans Hogervorst, Emiel Rutgers, Annegien Broeks, (ABCS); Hartwig Ziegler, Sonja Wolf, Volker Hermann, Christa Stegmaier, Katja Butterbach (ESTHER); Eija Myöhänen, Helena Kemiläinen (KBCP); Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staffof the Family Cancer Clinics, and the Clinical Follow Up Study (which has received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia, and the National Institute of Health (USA)) for their contributions to this resource, and the many families who contribute to kConFab (kConFab/AOCS); Gilian Peuteman, Dominiek Smeets, Thomas Van Brussel and Kathleen Corthouts (LMBC); Anja Rudolph, Dieter Flesch-Janys, Petra Seibold, Judith Heinz, Nadia Obi, Alina Vrieling, Sabine Behrens, Ursula Eilber, Muhabbet Celik, and Til Olchers (MARIE); Teresa Selander, Nayana Weerasooriya (OFBCR); Louise Brinton, Mark Sherman, Neonila Szeszenia-Dabrowska, Beata Peplonska, Witold Zatonski, Pei Chao, Michael Stagner (PBCS); Petra Bos, Jannet Blom, Ellen Crepin, Elisabeth Huijskens, Annette Heemskerk, the Erasmus MC Family Cancer Clinic (RBCS); The Swedish Medical Research Counsel (SASBAC); The SEARCH and EPIC teams (SEARCH); and all study participants, clinicians, family doctors, researchers and technicians for their contributions and commitment to this study (SKKDKFZS).The BCAC iCOGS study would not have been possible without the contributions of the following: Andrew Lee, Ed Dicks, Craig Luccarini and the staffof the Centre for Genetic Epidemiology Laboratory, Javier Benitez, Anna Gonzalez Neira and the staffof the CNIO genotyping unit, Jacques Simard and Daniel C. Tessier, Francois Bacot, Daniel Vincent, Sylvie LaBoissière and Frederic Robidoux and the staffof the McGill University and Génome Québec Innovation Centre, Stig E. Bojesen, Sune F. Nielsen, Borge G. Nordestgaard, and the staffof the Copenhagen DNA laboratory, and Julie M. Cunningham, Sharon A. Windebank, Christopher A. Hilker, Jeffrey Meyer and the staffof Mayo Clinic Genotyping Core Facility. We thank all the individuals who took part in these studies and all the researchers, clinicians, technicians and administrative staffwho have enabled this work to be carried out. The Breast Cancer Association Consortium (BCAC) is funded by Cancer Research UK [C1287/A10118, C1287/A12014] and by the European Community's Seventh Framework Programme under grant agreement number 223175 (grant number HEALTH-F2-2009-223175) (COGS). Funding for the iCOGS genotyping infrastructure came from: the European Community's Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112-the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund.
PY - 2017
Y1 - 2017
N2 - TP53 overexpression is indicative of somatic TP53 mutations and associates with aggressive tumors and poor prognosis in breast cancer. We utilized a twostage 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 twostage 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 - Anthracycline
KW - Breast cancer
KW - SNP
KW - Survival
KW - TP53
UR - http://www.scopus.com/inward/record.url?scp=85015243706&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85015243706&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.15110
DO - 10.18632/oncotarget.15110
M3 - Article
AN - SCOPUS:85015243706
SN - 1949-2553
VL - 8
SP - 18381
EP - 18398
JO - Oncotarget
JF - Oncotarget
IS - 11
ER -