Human Genetics, Genome Institute of Singapore, Singapore, Singapore.
Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Cancer Res. 2018 Nov 1;78(21):6329-6338. doi: 10.1158/0008-5472.CAN-18-1018.
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 genesor 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 ( = 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 carriers, PTV carriership remained associated with high grade and worse survival (HR, 1.76; 1.21-2.56). In 5,007 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- 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. These findings offer the potential to improve screening practices for breast cancer by providing a deeper understanding of how risk variants affect disease progression and mode of detection. .
遗传变异可以增加乳腺癌的风险，这些遗传变异既可以是罕见的，也可以是常见的。本研究旨在检验通过已确定的遗传风险位点中的罕见和常见变异对乳腺癌进行遗传风险分层，是否可以区分具有不同生物学特性、患者生存和检测方式的肿瘤。多变量逻辑回归检验了遗传风险负荷[31 个乳腺癌易感性基因中的蛋白质截断变异（PTV）携带者或使用 162 个单核苷酸多态性的多基因风险评分（PRS）]、肿瘤特征和检测方式（OR）之间的相关性。使用 Cox 回归模型估计了 10 年乳腺癌特异性生存率（HR）。在这项未选择的队列研究中，纳入了 2001 年至 2008 年期间在瑞典诊断为乳腺癌的 5099 名患者，其中 PTV 携带者（ = 597）年龄较小，与更具侵袭性的肿瘤表型（ER-阴性、较大肿瘤大小、高级别、高增殖、管腔 B 和基底样亚型）和更差的预后相关（HR，1.65；1.16-2.36），而非携带者则没有。在排除 92 名 PTV 携带者后，PTV 携带者仍与高级别和较差的生存相关（HR，1.76；1.21-2.56）。在 5007 名非携带者中，更高的 PRS 与侵袭性较低的肿瘤特征相关（ER-阳性、PR-阳性、较小肿瘤大小、低级别、低增殖和管腔 A 亚型）。在低乳房 X 线密度（<25%）的患者中，非 PTV 携带者比非携带者更常为间隔期乳腺癌（OR，1.89；1.12-3.21），而非携带者为筛查期乳腺癌。相反，在乳房 X 线密度低的女性中，较高的 PRS 与间隔期乳腺癌相比，筛查期乳腺癌的风险较低（OR，0.77；0.64-0.93）。这些发现表明，罕见和常见的乳腺癌易感性基因座与肿瘤特征、生存和检测方式存在差异关联。这些发现为通过深入了解风险变异如何影响疾病进展和检测方式来改善乳腺癌筛查实践提供了潜力。
