Zhu Qianqian, Schultz Emily, Long Jirong, Roh Janise M, Valice Emily, Laurent Cecile A, Radimer Kelly H, Yan Li, Ergas Isaac J, Davis Warren, Ranatunga Dilrini, Gandhi Shipra, Kwan Marilyn L, Bao Ping-Ping, Zheng Wei, Shu Xiao-Ou, Ambrosone Christine, Yao Song, Kushi Lawrence H
Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
NPJ Breast Cancer. 2022 Mar 23;8(1):39. doi: 10.1038/s41523-022-00401-5.
Few germline genetic variants have been robustly linked with breast cancer outcomes. We conducted trans-ethnic meta genome-wide association study (GWAS) of overall survival (OS) in 3973 breast cancer patients from the Pathways Study, one of the largest prospective breast cancer survivor cohorts. A locus spanning the UACA gene, a key regulator of tumor suppressor Par-4, was associated with OS in patients taking Par-4 dependent chemotherapies, including anthracyclines and anti-HER2 therapy, at a genome-wide significance level ([Formula: see text]). This association was confirmed in meta-analysis across four independent prospective breast cancer cohorts (combined hazard ratio = 1.84, [Formula: see text]). Transcriptome-wide association study revealed higher UACA gene expression was significantly associated with worse OS ([Formula: see text]). Our study identified the UACA locus as a genetic predictor of patient outcome following treatment with anthracyclines and/or anti-HER2 therapy, which may have clinical utility in formulating appropriate treatment strategies for breast cancer patients based on their genetic makeup.
很少有生殖系基因变异与乳腺癌预后有明确关联。我们对来自“通路研究”（Pathways Study）的3973例乳腺癌患者的总生存期（OS）进行了跨种族全基因组关联研究（GWAS），该研究是最大的前瞻性乳腺癌幸存者队列之一。一个跨越UACA基因（肿瘤抑制因子Par-4的关键调节因子）的基因座，在全基因组显著水平（[公式：见正文]）上，与接受包括蒽环类药物和抗HER2治疗在内的依赖Par-4化疗的患者的总生存期相关。这种关联在对四个独立的前瞻性乳腺癌队列进行的荟萃分析中得到了证实（合并风险比 = 1.84，[公式：见正文]）。全转录组关联研究表明，较高的UACA基因表达与较差的总生存期显著相关（[公式：见正文]）。我们的研究确定了UACA基因座是蒽环类药物和/或抗HER2治疗后患者预后的遗传预测指标，这可能在根据乳腺癌患者的基因构成制定合适的治疗策略方面具有临床应用价值。
