Williams Lindsay A, Butler Ebonee N, Sun Xuezheng, Allott Emma H, Cohen Stephanie M, Fuller Ashley M, Hoadley Katherine A, Perou Charles M, Geradts Joseph, Olshan Andrew F, Troester Melissa A
1Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA.
2Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA.
NPJ Breast Cancer. 2018 Jun 25;4:13. doi: 10.1038/s41523-018-0067-5. eCollection 2018.
Mutations in tumor suppressor have been inconsistently linked to breast cancer risk factors and survival. Immunohistochemistry (IHC) staining, a primary clinical means of mutation determination, only detects mutations that facilitate protein accumulation (e.g., missense mutations). RNA-based pathway methods capture functional status and may aid in understanding the role of TP53 function in racial disparities of breast cancer. status was assessed among invasive breast cancer cases from the Carolina Breast Cancer Study (CBCS) (2008-2013) using IHC and an established RNA-based TP53 signature (CBCS and The Cancer Genome Atlas (TCGA)). Frequency of TP53 status (IHC, RNA-based) was estimated in association with tumor characteristics, PAM50 intrinsic subtype, age, and race using relative frequency differences (RFDs) and 95% confidence intervals (95% CI) as the measure of association. Approximately 60% of basal-like tumors were TP53 protein positive (IHC), while nearly 100% were TP53 mutant-like (RNA). Luminal A tumors had low frequency of TP53 positivity (IHC: 7.9%) and mutant-like status (RNA: 1.7%). Mutant-like TP53 (RNA) was strongly associated with age ≤50 years, high tumor grade, advanced stage of disease, large tumor size, and basal-like and HER2 intrinsic subtypes. Black race was strongly associated with TP53 mutant-like status (RNA (RFD: 24.8%, 95% CI: 20.5, 29.0) even after adjusting for age, grade, stage (RFD: 11.3%; 95% CI: 7.6, 15.0). Associations were attenuated and non-significant when measured by IHC. IHC-based TP53 status is an insensitive measurement of TP53 functional status. RNA-based methods suggest a role for TP53 in tumor prognostic features and racial disparities.
肿瘤抑制基因的突变与乳腺癌风险因素及生存率之间的联系并不一致。免疫组织化学（IHC）染色作为确定突变的主要临床手段，仅能检测到促进蛋白质积累的突变（如错义突变）。基于RNA的通路方法可捕捉功能状态，可能有助于理解TP53功能在乳腺癌种族差异中的作用。利用IHC和已建立的基于RNA的TP53特征（卡罗来纳乳腺癌研究（CBCS）和癌症基因组图谱（TCGA）），对卡罗来纳乳腺癌研究（2008 - 2013年）中的浸润性乳腺癌病例进行TP53状态评估。使用相对频率差异（RFD）和95%置信区间（95%CI）作为关联度量，估计TP53状态（基于IHC、基于RNA）与肿瘤特征、PAM50内在亚型、年龄和种族的相关性。大约60%的基底样肿瘤TP53蛋白呈阳性（IHC），而近100%为TP53突变样（RNA）。管腔A型肿瘤TP53阳性频率较低（IHC：7.9%），且突变样状态频率较低（RNA：1.7%）。突变样TP53（RNA）与年龄≤50岁、高肿瘤分级、疾病晚期、肿瘤体积大以及基底样和HER2内在亚型密切相关。即使在调整年龄、分级、分期后，黑人种族仍与TP53突变样状态密切相关（RNA（RFD：24.8%，95%CI：20.5，29.0））（RFD：11.3%；95%CI：7.6，15.0）。通过IHC测量时，关联减弱且无统计学意义。基于IHC的TP53状态是对TP53功能状态的不敏感测量。基于RNA的方法表明TP53在肿瘤预后特征和种族差异中起作用。
