Differential Burden of Rare and Common Variants on Tumor Characteristics, Survival, and Mode of Detection in Breast Cancer

Differential Burden of Rare and Common Variants on Tumor Characteristics, Survival, and Mode of Detection in Breast Cancer
Title:
Differential Burden of Rare and Common Variants on Tumor Characteristics, Survival, and Mode of Detection in Breast Cancer
Other Titles:
Cancer Research
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Publication Date:
01 November 2018
Citation:
Cancer Res November 1 2018 (78) (21) 6329-6338; DOI: 10.1158/0008-5472.CAN-18-1018
Abstract:
Genetic variants that increase breast cancer risk can be rare or common. This study tests whether the genetic risk stratification of breast cancer by rare and common variants in established loci can discriminate tumors with different biology, patient survival, and mode of detection. Multinomial logistic regression tested associations between genetic risk load [protein-truncating variant (PTV) carriership in 31 breast cancer predisposition genes—or polygenic risk score (PRS) using 162 single-nucleotide polymorphisms], tumor characteristics, and mode of detection (OR). Ten-year breast cancer–specific survival (HR) was estimated using Cox regression models. In this unselected cohort of 5,099 patients with breast cancer diagnosed in Sweden between 2001 and 2008, PTV carriers (n = 597) were younger and associated with more aggressive tumor phenotypes (ER-negative, large size, high grade, high proliferation, luminal B, and basal-like subtype) and worse outcome (HR, 1.65; 1.16–2.36) than noncarriers. After excluding 92 BRCA1/2 carriers, PTV carriership remained associated with high grade and worse survival (HR, 1.76; 1.21–2.56). In 5,007 BRCA1/2 noncarriers, higher PRS was associated with less aggressive tumor characteristics (ER-positive, PR-positive, small size, low grade, low proliferation, and luminal A subtype). Among patients with low mammographic density (<25%), non-BRCA1/2 PTV carriers were more often interval than screen-detected breast cancer (OR, 1.89; 1.12–3.21) than noncarriers. In contrast, higher PRS was associated with lower risk of interval compared with screen-detected cancer (OR, 0.77; 0.64–0.93) in women with low mammographic density. These findings suggest that rare and common breast cancer susceptibility loci are differentially associated with tumor characteristics, survival, and mode of detection.
License type:
PublisherCopyrights
Funding Info:
J. Li is a recipient of a National Research Foundation Singapore Fellowship (NRF-NRFF2017-02).
Description:
The full paper is available for download at the publisher's URL: https://doi.org/10.1158/0008-5472.CAN-18-1018
ISSN:
0008-5472
1538-7445
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