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Common variants in breast cancer risk loci predispose to distinct tumor subtypes

Common variants in breast cancer risk loci predispose to distinct tumor subtypes
Common variants in breast cancer risk loci predispose to distinct tumor subtypes
Background: genome-wide association studies have identified over 170 common breast cancer susceptibility loci, many of them with differential associations by estrogen receptor (ER). How these variants are related to other tumor features is unclear. 

Methods: analyses included 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 178 genotyped or imputed single nucleotide polymorphisms (SNPs). We used two-stage polytomous logistic regression models to evaluate SNPs in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and in relation to molecular subtypes. 

Results: nearly half of the SNPs (85 out of 178) were associated with at least one tumor feature (false discovery rate <5%). Case-case comparisons identified ER and grade as the most common heterogeneity sources, followed by PR and HER2. Case-control comparisons among these 85 SNPs with molecular subtypes identified four main clusters of SNPs: two clusters most strongly or exclusively (P<0.05) associated with luminal-like subtypes (65 SNPs), one cluster associated with all subtypes at various strengths (5 SNPs), and one cluster primarily associated with non-luminal tumors, especially triple-negative (TN) disease (15 SNPs). A CHEK2 variant (rs17879961) showed significant risk associations with luminal A-like (P=9.26x10-14) and TN (P=2.55x10-4) subtypes in opposite directions.

Conclusion: breast cancer susceptibility loci have complex associations with multiple tumor features. ER and tumor grade are the most common sources of heterogeneity. These findings provide insights into the genetic predisposition of breast cancer subtypes and can inform subtype-specific risk predictions.
0002-9297
Ahearn, Thomas
c3ee2477-53ca-4e2a-bc56-9d75e567155f
Eccles, Diana
5b59bc73-11c9-4cf0-a9d5-7a8e523eee23
Breast Cancer Association Consortium
Ahearn, Thomas
c3ee2477-53ca-4e2a-bc56-9d75e567155f
Eccles, Diana
5b59bc73-11c9-4cf0-a9d5-7a8e523eee23

Ahearn, Thomas and Eccles, Diana , Breast Cancer Association Consortium (2020) Common variants in breast cancer risk loci predispose to distinct tumor subtypes. The American Journal of Human Genetics. (doi:10.1101/733402).

Record type: Article

Abstract

Background: genome-wide association studies have identified over 170 common breast cancer susceptibility loci, many of them with differential associations by estrogen receptor (ER). How these variants are related to other tumor features is unclear. 

Methods: analyses included 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 178 genotyped or imputed single nucleotide polymorphisms (SNPs). We used two-stage polytomous logistic regression models to evaluate SNPs in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and in relation to molecular subtypes. 

Results: nearly half of the SNPs (85 out of 178) were associated with at least one tumor feature (false discovery rate <5%). Case-case comparisons identified ER and grade as the most common heterogeneity sources, followed by PR and HER2. Case-control comparisons among these 85 SNPs with molecular subtypes identified four main clusters of SNPs: two clusters most strongly or exclusively (P<0.05) associated with luminal-like subtypes (65 SNPs), one cluster associated with all subtypes at various strengths (5 SNPs), and one cluster primarily associated with non-luminal tumors, especially triple-negative (TN) disease (15 SNPs). A CHEK2 variant (rs17879961) showed significant risk associations with luminal A-like (P=9.26x10-14) and TN (P=2.55x10-4) subtypes in opposite directions.

Conclusion: breast cancer susceptibility loci have complex associations with multiple tumor features. ER and tumor grade are the most common sources of heterogeneity. These findings provide insights into the genetic predisposition of breast cancer subtypes and can inform subtype-specific risk predictions.

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Known SNPs Manuscript text 7Jun2019 - Accepted Manuscript
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More information

Submitted date: 2019
Accepted/In Press date: 21 January 2020
e-pub ahead of print date: 4 June 2020
Published date: 11 June 2020

Identifiers

Local EPrints ID: 437411
URI: http://eprints.soton.ac.uk/id/eprint/437411
ISSN: 0002-9297
PURE UUID: 68b634a4-9cbd-4610-ad56-0bc937e58384
ORCID for Diana Eccles: ORCID iD orcid.org/0000-0002-9935-3169

Catalogue record

Date deposited: 29 Jan 2020 17:34
Last modified: 19 Feb 2021 02:33

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Contributors

Author: Thomas Ahearn
Author: Diana Eccles ORCID iD
Corporate Author: Breast Cancer Association Consortium

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