Goglia Alexander G, Alshalalfa Mohammed, Khan Anwar, Isakov Danielle R, Hougen Helen Y, Swami Nishwant, Kannikal Jasmine, Mcbride Sean M, Gomez Daniel R, Punnen Sanoj, Nguyen Paul L, Iyengar Puneeth, Antonarakis Emmanuel S, Mahal Brandon A, Dee Edward Christopher
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Radiation Oncology, University of Miami Miller School of Medicine/Sylvester Comprehensive Cancer Center, Miami, FL, USA.
J Natl Cancer Inst. 2025 Jan 1;117(1):188-197. doi: 10.1093/jnci/djae224.
Alterations in forkhead box A1 (FOXA1), a pioneer transcription factor, are associated with poor prognosis in breast cancer and prostate cancer. We characterized FOXA1 genomic alterations and their clinical impacts in a large pan-cancer cohort from the American Association for Cancer Research Genomics, Evidence, Neoplasia, Information, Exchange database.
FOXA1 alterations were characterized across more than 87 000 samples from more than 30 cancer types for primary and metastatic tumors alongside patient characteristics and clinical outcomes. FOXA1 alterations were queried in the Memorial Sloan Kettering - Metastatic Events and Tropisms (MSK-MET) cohort (a GENIE subset), allowing definition of hazard ratios (HRs) and survival estimates based on Cox proportional hazard models.
FOXA1 was altered in 1869 (2.1%) samples, with distinct patterns across different cancers: prostate cancer enriched with indel-inframe alterations, breast cancer with missense mutations, and lung cancers with copy number amplifications. Of 74 715 samples with FOXA1 copy number profiles, amplification was detected in 834 (1.1%). Amplification was most common in non-small cell lung cancer (NSCLC; 3% in primary; 6% in metastatic) and small cell lung cancer (4.1% primary; 3.5% metastatic), followed by breast cancer (2% primary; 1.6% metastatic) and prostate cancer (2.2% primary; 1.6% metastatic). Copy number amplifications were associated with decreased overall survival in NSCLC (HR = 1.45, 95% confidence interval [CI] = 1.06 to 1.99; P = .02), breast cancer (HR = 3.04, 95% CI = 1.89 to 4.89; P = 4e-6), and prostate cancer (HR = 1.94, 95% CI = 1.03 to 3.68; P = .04). Amplifications were associated with widespread metastases in NSCLC, breast cancer, and prostate cancer.
FOXA1 demonstrates distinct alteration profiles across cancer sites. Our findings suggest an association between FOXA1 amplification and enhanced metastatic potential and decreased survival, highlighting prognostic and therapeutic potential in breast cancer, prostate cancer, and NSCLC.
先驱转录因子叉头框A1（FOXA1）的改变与乳腺癌和前列腺癌的不良预后相关。我们在美国癌症研究协会基因组学、证据、肿瘤学、信息、交换数据库的一个大型泛癌队列中，对FOXA1基因组改变及其临床影响进行了特征分析。
在来自30多种癌症类型的87000多个原发性和转移性肿瘤样本中，对FOXA1改变以及患者特征和临床结局进行了特征分析。在纪念斯隆凯特琳癌症中心 - 转移事件和趋向性（MSK-MET）队列（GENIE的一个子集）中查询FOXA1改变，从而基于Cox比例风险模型定义风险比（HRs）和生存估计值。
1869个（2.1%）样本中FOXA1发生改变，不同癌症呈现出不同模式：前列腺癌富含框内插入缺失改变，乳腺癌存在错义突变，肺癌存在拷贝数扩增。在74715个有FOXA1拷贝数图谱的样本中，检测到834个（1.1%）存在扩增。扩增在非小细胞肺癌（NSCLC；原发性为3%；转移性为6%）和小细胞肺癌（原发性为4.1%；转移性为3.5%）中最为常见，其次是乳腺癌（原发性为2%；转移性为1.6%）和前列腺癌（原发性为2.2%；转移性为1.6%）。拷贝数扩增与NSCLC（HR = 1.45，95%置信区间[CI] = 1.06至1.99；P = 0.02）、乳腺癌（HR = 3.04，95% CI = 1.89至4.89；P = 4×10⁻⁶）和前列腺癌（HR = 1.94，95% CI = 1.03至3.68；P = 0.04）的总生存期降低相关。扩增与NSCLC、乳腺癌和前列腺癌的广泛转移相关。
FOXA1在不同癌症部位表现出不同的改变模式。我们的研究结果提示FOXA1扩增与转移潜能增强及生存期降低之间存在关联，突出了其在乳腺癌、前列腺癌和NSCLC中的预后及治疗潜力。
