Arnoff Taylor E, El-Deiry Wafik S
Laboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School, Brown University Providence, RI, USA.
Hematology/Oncology Division, Department of Medicine, Lifespan Health System and The Warren Alpert Medical School, Brown University Providence, RI, USA.
Am J Cancer Res. 2021 Nov 15;11(11):5452-5471. eCollection 2021.
Bladder carcinoma has a 6% 5-year survival-rate for metastatic disease, with poorly understood links between genetic and environmental drivers of disease development, progression, and treatment response. Rhode Island has among the highest annual age-adjusted incidence rate of bladder cancer at 26.0/100,000, compared to 20.0 in the US, with a paucity of known driver genes for targeted therapies or predictive biomarkers. Bladder carcinomas have the highest frequency of alterations in CDKN1A/p21 (10%) across all cancer types analyzed in The Cancer Genome Atlas (TCGA) PanCancer Atlas Studies, displaying a predominance of truncating mutations (86%). We found that lung carcinomas lack CDKN1A truncating mutations, despite the shared role of tobacco as a risk factor for bladder cancer. Bladder carcinomas also have the highest frequency of RB1 alterations in TCGA (25%). We find that chromophobe renal cell carcinomas with CDKN1A and RB1 mutations are 100% truncating. Analysis of 1,868 bladder tumors demonstrated that truncating CDKN1A mutations co-occur with truncating RB1 mutations, suggesting an environmental exposure signature. Moreover, we found that HRNR and FLG mutations are enriched in tumors with CDKN1A alteration, suggesting potential novel roles in promoting bladder tumorigenesis. Association of HRNR with AKT activation offers possible therapeutic avenues, and FLG may provide insight into carcinogen exposure within the bladder. We suggest that because APOBEC mutations largely shape the bladder cancer mutational landscape, these events likely contribute to dysfunctional DNA repair genes, leading to frameshifts and the predominance of truncations in CDKN1A, RB1, ARID1A, or other drivers. We propose that patients with co-occurrence of CDKN1A and RB1 truncations may display enhanced responsiveness to targeted therapies combining cisplatin with ATR, ATM, CHK1, and CHK2 inhibitors, expanding therapeutic options for patients in need of improved precision treatments.
转移性膀胱癌的5年生存率为6%，其疾病发生、发展和治疗反应的遗传与环境驱动因素之间的联系尚不清楚。罗德岛州的膀胱癌年龄调整后年发病率高达26.0/10万，高于美国的20.0/10万，且缺乏用于靶向治疗的已知驱动基因或预测性生物标志物。在《癌症基因组图谱》（TCGA）泛癌图谱研究分析的所有癌症类型中，膀胱癌中CDKN1A/p21的改变频率最高（10%），显示出截断突变占主导（86%）。我们发现，尽管烟草是膀胱癌的共同危险因素，但肺癌缺乏CDKN1A截断突变。膀胱癌在TCGA中RB1改变的频率也最高（25%）。我们发现，携带CDKN1A和RB1突变的嫌色性肾细胞癌100%为截断突变。对1868例膀胱肿瘤的分析表明，截断性CDKN1A突变与截断性RB1突变同时出现，提示存在环境暴露特征。此外，我们发现HRNR和FLG突变在发生CDKN1A改变的肿瘤中富集，提示它们在促进膀胱肿瘤发生中可能具有新作用。HRNR与AKT激活的关联提供了可能的治疗途径，而FLG可能有助于深入了解膀胱内的致癌物暴露情况。我们认为，由于APOBEC突变在很大程度上塑造了膀胱癌的突变格局，这些事件可能导致DNA修复基因功能失调，从而导致CDKN1A、RB１、ARID1A或其他驱动基因出现移码突变和截断突变占主导。我们提出，同时发生CDKN1A和RB1截断突变的患者可能对顺铂与ATR、ATM、CHK1和CHK2抑制剂联合的靶向治疗表现出更高的反应性，从而为需要改进精准治疗的患者扩展治疗选择。
