LBPO.PS01 · 人群科学 · Late-Breaking
三阴性乳腺癌的诊断前暴露、突变特征和免疫谱：PREMISE-TN项目概述
Pre-diagnostic exposures, mutational signatures, and immune profiles in triple-negative breast cancer: An overview of the PREMISE-TN project
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
三阴性乳腺癌（TNBC）表现出独特的演化路径，反映在异质性的突变谱和免疫谱中。为了更好地理解诊断前暴露、遗传变异、突变谱和免疫谱在TNBC中的关系，PRediagnostic Exposures, Mutations, Immune SignaturEs-Triple Negative（PREMISE-TN，诊断前暴露、突变、免疫特征-三阴性）项目对来自四项前瞻性队列研究（护士健康研究[NHS、NHS II]和癌症预防研究[CPS II、CPS3]）的322例TNBC患者的配对福尔马林固定石蜡包埋肿瘤组织和种系DNA样本进行了全外显子组测序（WES）。在排除66对肿瘤-正常样本不匹配的配对以及32对肿瘤或血液样本未达到目标覆盖度（70%碱基覆盖度达到20x）的配对后，224对样本可供分析。这些配对中肿瘤样本的中位测序深度为111.2x（范围 = 7.4x-481x）；血液样本的中位测序深度为283.4x（范围 = 156.2x-652.1x）。突变判定以及测序质量评估与控制正在进行中。患者诊断时年龄范围为34-86岁（中位数 = 58），诊断年份范围为1976-2018年（中位数 = 2004）。56例（28.7%）患者在诊断时处于绝经前。大多数肿瘤（n = 162，88.5%）为I-II期；19例（10.3%）为III期，1例（0.5%）为IV期。PREMISE-TN将体细胞突变谱与这些队列的其他数据相整合，包括：种系全基因组关联研究数据、乳腺癌风险因素、肿瘤免疫特征，以及源自数字图像的放射学和病理学表型。初步研究发现种系多基因风险评分（PRS）与乳腺肿瘤免疫特征之间存在关联，包括免疫介导疾病的PRS与乳腺肿瘤及邻近正常组织中干扰素信号传导之间的负相关。其他研究考察了生殖因素对乳腺肿瘤微环境的影响。未来工作将评估这些特征与肿瘤突变谱的关联。PREMISE-TN生成的数据资源将有助于研究遗传和非遗传风险因素如何影响乳腺肿瘤突变特征和免疫应答。
查看英文原文 English abstract
Triple negative breast cancer (TNBC) exhibits distinct evolutionary pathways reflected in heterogeneous mutational and immune profiles. To better understand the relationships between prediagnostic exposures, inherited genetic variation, mutational and immune profiles in TNBCs, the PRediagnostic Exposures, Mutations, Immune SignaturEs-Triple Negative (PREMISE-TN) project performed whole exome sequencing (WES) of matched formalin-fixed paraffin embedded tumor tissue and germline DNA samples from 322 TNBC patients from four prospective cohort studies, the Nurses' Health Study (NHS, NHS II) and the Cancer Prevention Study (CPS II, CPS3). After excluding 66 mis-matched tumor normal-pairs and 32 pairs where either the tumor or blood sample did not reach the target coverage (70% of bases covered at 20x), 224 pairs were available for analysis. The median sequencing depth for tumor samples in these pairs was 111.2x (range=7.4x-481x); the median for blood samples was 283.4x (range=156.2x-652.1x). Mutational calling and sequencing quality assessment and control is underway. Patients' age at diagnosis ranged from 34-86 years (median=58), and year of diagnosis ranged from 1976-2018 (median=2004). 56 (28.7%) of the patients were premenopausal at diagnosis. Most tumors (n=162, 88.5%) were stage I-II; 19 (10.3%) were stage III and 1 (0.5%) was stage IV. PREMISE-TN integrated somatic mutational profiles with other data from these cohorts, including: germline genome-wide association study data, breast cancer risk factors, tumor immune signatures, and radiologic and pathologic phenotypes derived from digital images. Preliminary studies identified associations between germline polygenic risk scores (PRS) and breast tumor immune features, including inverse associations between PRS for immune-mediated conditions and interferon signaling in both breast tumors and adjacent normal tissue. Other studies examined the influence of reproductive factors on the breast tumor microenvironment. Future work will assess associations of these features with tumor mutational profiles. The data resource generated by PREMISE-TN will enable the investigation of how genetic and nongenetic risk factors influence breast tumor mutational signatures and immune response.
利益披露 Disclosure
D. A. Tadesse, None..
C. Bodelon, None..
C. Peng, None..
K. D. Brantley, None..
M. Delporte, None..
Y. J. Heng, None..
L. Teras, None..
R. M. Tamimi, None..
P. Kraft, None.