Hurson Amber N, Abubakar Mustapha, Hamilton Alina M, Conway Kathleen, Hoadley Katherine A, Love Michael I, Olshan Andrew F, Perou Charles M, Garcia-Closas Montserrat, Troester Melissa A
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
NPJ Breast Cancer. 2022 Jun 14;8(1):74. doi: 10.1038/s41523-022-00437-7.
TP53 and estrogen receptor (ER) are essential in breast cancer development and progression, but TP53 status (by DNA sequencing or protein expression) has been inconsistently associated with survival. We evaluated whether RNA-based TP53 classifiers are related to survival. Participants included 3213 women in the Carolina Breast Cancer Study (CBCS) with invasive breast cancer (stages I-III). Tumors were classified for TP53 status (mutant-like/wildtype-like) using an RNA signature. We used Cox proportional hazards models to estimate covariate-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for breast cancer-specific survival (BCSS) among ER- and TP53-defined subtypes. RNA-based results were compared to DNA- and IHC-based TP53 classification, as well as Basal-like versus non-Basal-like subtype. Findings from the diverse (50% Black), population-based CBCS were compared to those from the largely white METABRIC study. RNA-based TP53 mutant-like was associated with BCSS among both ER-negatives and ER-positives (HR (95% CI) = 5.38 (1.84-15.78) and 4.66 (1.79-12.15), respectively). Associations were attenuated when using DNA- or IHC-based TP53 classification. In METABRIC, few ER-negative tumors were TP53-wildtype-like, but TP53 status was a strong predictor of BCSS among ER-positives. In both populations, the effect of TP53 mutant-like status was similar to that for Basal-like subtype. RNA-based measures of TP53 status are strongly associated with BCSS and may have value among ER-negative cancers where few prognostic markers have been robustly validated. Given the role of TP53 in chemotherapeutic response, RNA-based TP53 as a prognostic biomarker could address an unmet need in breast cancer.
TP53和雌激素受体（ER）在乳腺癌的发生和发展中至关重要，但TP53状态（通过DNA测序或蛋白表达）与生存率的关联并不一致。我们评估了基于RNA的TP53分类器是否与生存率相关。参与者包括卡罗来纳乳腺癌研究（CBCS）中的3213名浸润性乳腺癌（I-III期）女性。使用RNA特征将肿瘤分类为TP53状态（突变样/野生型样）。我们使用Cox比例风险模型来估计ER和TP53定义的亚型中乳腺癌特异性生存（BCSS）的协变量调整风险比（HR）和95%置信区间（CI）。将基于RNA的结果与基于DNA和免疫组化（IHC）的TP53分类以及基底样与非基底样亚型进行比较。将来自多样化（50%为黑人）的基于人群的CBCS的结果与主要为白人的METABRIC研究的结果进行比较。基于RNA的TP53突变样在ER阴性和ER阳性患者中均与BCSS相关（HR（95%CI）分别为5.38（1.84-15.78）和4.66（1.79-12.15））。使用基于DNA或IHC的TP53分类时，这种关联减弱。在METABRIC中，很少有ER阴性肿瘤为TP53野生型样，但TP53状态是ER阳性患者中BCSS的强预测指标。在这两个人群中，TP53突变样状态的影响与基底样亚型相似。基于RNA的TP53状态测量与BCSS密切相关，并且在很少有预后标志物得到充分验证的ER阴性癌症中可能具有价值。鉴于TP53在化疗反应中的作用，基于RNA的TP53作为一种预后生物标志物可以满足乳腺癌中未满足的需求。
