Common variants in breast cancer risk loci predispose to distinct tumor subtypes.
Breast cancer
Common breast cancer susceptibility variants
Etiologic heterogeneity
Genetic predisposition
Journal
Breast cancer research : BCR
ISSN: 1465-542X
Titre abrégé: Breast Cancer Res
Pays: England
ID NLM: 100927353
Informations de publication
Date de publication:
04 01 2022
04 01 2022
Historique:
received:
15
06
2021
accepted:
02
11
2021
entrez:
5
1
2022
pubmed:
6
1
2022
medline:
17
3
2022
Statut:
epublish
Résumé
Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions. This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.
Sections du résumé
BACKGROUND
Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear.
METHODS
Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes.
RESULTS
Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions.
CONCLUSION
This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.
Identifiants
pubmed: 34983606
doi: 10.1186/s13058-021-01484-x
pii: 10.1186/s13058-021-01484-x
pmc: PMC8725568
doi:
Substances chimiques
Biomarkers, Tumor
0
Receptors, Estrogen
0
Receptors, Progesterone
0
Receptor, ErbB-2
EC 2.7.10.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2Subventions
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA015083
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA058223
Pays : United States
Organisme : NHGRI NIH HHS
ID : 1R01 HG010480-01
Pays : United States
Investigateurs
Kristine K Sahlberg
(KK)
Lars Ottestad
(L)
Rolf Kåresen
(R)
Ellen Schlichting
(E)
Marit Muri Holmen
(MM)
Toril Sauer
(T)
Vilde Haakensen
(V)
Olav Engebråten
(O)
Bjørn Naume
(B)
Alexander Fosså
(A)
Cecile E Kiserud
(CE)
Kristin V Reinertsen
(KV)
Åslaug Helland
(Å)
Margit Riis
(M)
Jürgen Geisler
(J)
Christine Clarke
(C)
Rosemary Balleine
(R)
Robert Baxter
(R)
Stephen Braye
(S)
Jane Carpenter
(J)
Jane Dahlstrom
(J)
John Forbes
(J)
CSoon Lee
(C)
Deborah Marsh
(D)
Adrienne Morey
(A)
Nirmala Pathmanathan
(N)
Rodney Scott
(R)
Peter Simpson
(P)
Allan Spigelman
(A)
Nicholas Wilcken
(N)
Desmond Yip
(D)
Nikolajs Zeps
(N)
Stephen Fox
(S)
Ian Campbell
(I)
David Bowtell
(D)
Georgia Chenevix-Trench
(G)
Amanda Spurdle
(A)
Penny Webb
(P)
Anna de Fazio
(A)
Margaret Tassell
(M)
Judy Kirk
(J)
Geoff Lindeman
(G)
Melanie Price
(M)
Melissa Southey
(M)
Roger Milne
(R)
Sid Deb
(S)
Informations de copyright
© 2021. The Author(s).
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