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Association of Germline Genetic Variants with Breast Cancer-Specific Survival in Patient Subgroups Defined by Clinic-Pathological Variables Related to Tumor Biology and Type of Systemic Treatment

Citation

Morra, Anna; Escala-Garcia, Maria; Beesley, Jonathan; Keeman, Renske; Canisius, Sander; Ahearn, Thomas U.; Andrulis, Irene L.; Anton-Culver, Hoda; Arndt, Volker; & Auer, Paul L., et al. (2021). Association of Germline Genetic Variants with Breast Cancer-Specific Survival in Patient Subgroups Defined by Clinic-Pathological Variables Related to Tumor Biology and Type of Systemic Treatment. Breast Cancer Research, 23(1), 86. PMCID: PMC8371820

Abstract

BACKGROUND: Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients.
METHODS: We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP < 0.15).
RESULTS: Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E-08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E-07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E-08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E-08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy.
CONCLUSIONS: We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on breast cancer-specific survival might be limited.

URL

http://dx.doi.org/10.1186/s13058-021-01450-7

Reference Type

Journal Article

Year Published

2021

Journal Title

Breast Cancer Research

Author(s)

Morra, Anna
Escala-Garcia, Maria
Beesley, Jonathan
Keeman, Renske
Canisius, Sander
Ahearn, Thomas U.
Andrulis, Irene L.
Anton-Culver, Hoda
Arndt, Volker
Auer, Paul L.
Augustinsson, Annelie
Beane Freeman, Laura E.
Becher, Heiko
Beckmann, Matthias W.
Behrens, Sabine
Bojesen, Stig Egil
Bolla, Manjeet K.
Brenner, Hermann
Brüning, Thomas
Buys, Saundra S.
Caan, Bette
Campa, Daniele
Canzian, Federico
Castelao, Jose E.
Chang-Claude, Jenny
Chanock, Stephen J.
Cheng, Ting-Yuan David
Clarke, Christine L.
NBCS Collaborators,
Colonna, Sarah V.
Couch, Fergus J.
Cox, Angela
Cross, Simon S.
Czene, Kamila
Daly, Mary B.
Dennis, Joe
Dörk, Thilo
Dossus, Laure
Dunning, Alison M.
Dwek, Miriam
Eccles, Diana M.
Ekici, Arif B.
Eliassen, A. Heather
Eriksson, Mikael
Evans, D. Gareth
Fasching, Peter A.
Flyger, Henrik
Fritschi, Lin
Gago-Dominguez, Manuela
García-Sáenz, José A.
Giles, Graham G.
Grip, Mervi
Guénel, Pascal
Gündert, Melanie
Hahnen, Eric
Haiman, Christopher A.
Håkansson, Niclas
Hall, Per
Hamann, Ute
Hart, Steven N.
Hartikainen, Jaana M.
Hartmann, Arndt
He, Wei
Hooning, Maartje J.
Hoppe, Reiner
Hopper, John L.
Howell, Anthony
Hunter, David J.
ABCTB Investigators,
kConFab Investigators,
Jager, Agnes
Jakubowska, Anna
Janni, Wolfgang
John, Esther M.
Jung, Audrey
Kaaks, Rudolf
Keupers, Machteld
Kitahara, Cari M.
Koutros, Stella
Kraft, Peter
Kristensen, Vessela N.
Kurian, Allison W.
Lacey, James V.
Lambrechts, Diether
Le Marchand, Loic
Lindblom, Annika
Linet, Martha
Luben, Robert
Lubi
ński, Jan
Lush, Michael
Mannermaa, Arto
Manoochehri, Mehdi
Margolin, Sara
Martens, John W
.
M
.
Martinez, Maria Elena
Mavroudis, Dimitrios
Michailidou, Kyriaki
Milne, Roger L
.
Mulligan, Anna Marie
Muranen, Taru A
.
Nevanlinna, Heli
Newman, William G
.
Nielsen, Sune F
.
Nordestgaard, Børge G
.
Olshan, Andrew F
.
Olsson, Håkan
Orr, Nick
Park-Simon, Tjoung-Won
Patel, Alpa
v.
Peissel, Bernard
Peterlongo, Paolo
Plaseska-Karanfilska, Dijana
Prajzendanc, Karolina
Prentice, Ross
L.
Presneau, Nadege
Rack, Brigitte
Rennert, Gad
Rennert, Hedy S
.
Rhenius, Valerie
Romero, Atocha
Roylance, Rebecca
Ruebner, Matthias
Saloustros, Emmanouil
Sawyer, Elinor J
.
Schmutzler, Rita K
.
Schneeweiss, Andreas
Scott, Christopher
Shah, Mitul
Smichkoska, Snezhana
Southey, Melissa C
.
Stone, Jennifer
Surowy, Harald
Swerdlow, Anthony J
.
Tamimi, Rulla M
.
Tapper, William J
.
Teras, Lauren
R.
Terry, Mary Beth
Tollenaar, Rob

A
.
E
.
M
.
Tomlinson, Ian
Troester, Melissa A
.
Truong, Thérèse
Vachon, Celine M
.
Wang, Qin
Hurson, Amber N
.
Winqvist, Robert
Wolk, Alicja
Ziogas, Argyrios
Brauch, Hiltrud
García-Closas, Montserrat
Pharoah, Paul D
.
P
.
Easton, Douglas F
.
Chenevix-Trench, Georgia
Schmidt, Marjanka K
.

Article Type

Regular

PMCID

PMC8371820

Data Set/Study

Breast Cancer Association Consortium (BCAC)

Continent/Country

United States of America

State

Nonspecific

Race/Ethnicity

European Ancestry

Sex/Gender

Ciswomen

ORCiD

Olshan - 0000-0001-9115-5128