Germline polygenic risk scores are associated with immune gene expression signature and immune cell infiltration in breast cancer,American Journal of Human Genetics

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Germline polygenic risk scores are associated with immune gene expression signature and immune cell infiltration in breast cancer
American Journal of Human Genetics ( IF 8.1 ) Pub Date : 2024-09-12 , DOI: 10.1016/j.ajhg.2024.08.009
Yuxi Liu ₁ , Cheng Peng ₂ , Ina S Brorson ₃ , Denise G O'Mahony ₃ , Rebecca L Kelly ₄ , Yujing J Heng ₅ , Gabrielle M Baker ₅ , Grethe I Grenaker Alnæs ₆ , Clara Bodelon ₇ , Daniel G Stover ₈ , Eliezer M Van Allen ₉ , A Heather Eliassen ₁₀ , Vessela N Kristensen ₁₁ , Rulla M Tamimi ₁₂ , Peter Kraft ₁₃

Affiliation

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
Cancer Prevention Fellowship Program, National Cancer Institute, Rockville, MD, USA; Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway.
Department of Population Science, American Cancer Society, Atlanta, GA, USA.
Division of Medical Oncology, Stefanie Spielman Comprehensive Breast Center, Columbus, OH, USA; Department of Biomedical Informatics, Ohio State University, Columbus, OH, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway.
Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, USA.
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

The tumor immune microenvironment (TIME) plays key roles in tumor progression and response to immunotherapy. Previous studies have identified individual germline variants associated with differences in TIME. Here, we hypothesize that common variants associated with breast cancer risk or cancer-related traits, represented by polygenic risk scores (PRSs), may jointly influence immune features in TIME. We derived 154 immune traits from bulk gene expression profiles of 764 breast tumors and 598 adjacent normal tissue samples from 825 individuals with breast cancer in the Nurses’ Health Study (NHS) and NHSII. Immunohistochemical staining of four immune cell markers were available for a subset of 205 individuals. Germline PRSs were calculated for 16 different traits including breast cancer, autoimmune diseases, type 2 diabetes, ages at menarche and menopause, body mass index (BMI), BMI-adjusted waist-to-hip ratio, alcohol intake, and tobacco smoking. Overall, we identified 44 associations between germline PRSs and immune traits at false discovery rate q < 0.25, including 3 associations with q < 0.05. We observed consistent inverse associations of inflammatory bowel disease (IBD) and Crohn disease (CD) PRSs with interferon signaling and STAT1 scores in breast tumor and adjacent normal tissue; these associations were replicated in a Norwegian cohort. Inverse associations were also consistently observed for IBD PRS and B cell abundance in normal tissue. We also observed positive associations between CD PRS and endothelial cell abundance in tumor. Our findings suggest that the genetic mechanisms that influence immune-related diseases are also associated with TIME in breast cancer.

中文翻译：

种系多基因风险评分与乳腺癌患者的免疫基因表达特征和免疫细胞浸润相关

肿瘤免疫微环境（TIME）在肿瘤进展和对免疫治疗的反应中起关键作用。以前的研究已经确定了与 TIME 差异相关的单个种系变异。在这里，我们假设与乳腺癌风险或癌症相关特征相关的常见变异，由多基因风险评分（PRS）表示，可能共同影响 TIME 中的免疫特征。我们从护士健康研究（NHS）和 NHSII 中 764 例乳腺肿瘤和 598 例相邻正常组织样本的大量基因表达谱中获得了 825 例免疫特征。4 种免疫细胞标志物的免疫组织化学染色可用于 205 个个体的子集。计算 16 种不同特征的种系 PRS，包括乳腺癌、自身免疫性疾病、2 型糖尿病、初潮和绝经年龄、体重指数（BMI）、BMI 调整后的腰臀比、酒精摄入量和吸烟。总体而言，我们以错误发现率 q < 0.25 确定了种系 PRS 与免疫性状之间的 44 个关联，其中 3 个与 q < 0.05 的关联。我们观察到炎症性肠病（IBD）和克罗恩病（CD） PRSs 与乳腺肿瘤和邻近正常组织中的干扰素信号传导和 STAT1 评分呈一致的负相关;这些关联在挪威队列中被复制。也一致观察到 IBD PRS 和正常组织中 B 细胞丰度的负相关。我们还观察到 CD PRS 与肿瘤内皮细胞丰度之间的正相关。我们的研究结果表明，影响免疫相关疾病的遗传机制也与乳腺癌的 TIME 有关。

更新日期：2024-09-12

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