Genomic characterization of high-risk non-muscle invasive bladder cancer.
Genomic characterization of high-risk non-muscle invasive bladder cancer.
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DOI：
10.18632/oncotarget.12661
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发表时间：
2016-11-15
期刊：
影响因子：
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通讯作者：
Giles FJ
中科院分区：
文献类型：
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作者：
Meeks JJ;Carneiro BA;Pai SG;Oberlin DT;Rademaker A;Fedorchak K;Balasubramanian S;Elvin J;Beaubier N;Giles FJ
与高危非肌层浸润性膀胱癌（HR-NMIBC）进展相关的遗传机制尚未描述。我们对HR-NMIBC进行了选择性下一代测序（NGS），并比较了对膀胱内治疗有反应的癌症和进展为肌肉浸润性或晚期疾病的癌症的基因组谱。从25例HR-NMIBC的石蜡包埋切片中提取DNA（22例T1 HG; 3例TaHG伴或不伴原位癌）。10名患有HR-NMIBC的患者发生进展（pT 2+或N+）（“进展者”）。15名患者没有进展（“非进展者”）。分析了11例转移性膀胱癌（BC）患者的组织进行比较。我们发现与非进展者和转移性肿瘤相比，进展者的原发性肿瘤之间TP 53、PIK 3CA或KMT 2D的突变频率没有差异。与非进展者（6%）相比，在进展的肿瘤（37%）中鉴定到CDKN 2A/B缺失的频率增加（p = 0.10）。我们发现与免疫治疗反应相关的总突变负荷（TMB）显著降低，分别在15、10.1和5.1个突变/MB下比较非进展者、进展者和转移性肿瘤（p = 0.02）。这种关联表明，更晚期的肿瘤具有降低的新抗原负荷，并且可以解释非进展者中BCG应答的机制。我们发现进展者中没有新的遗传驱动因素，HR-NMIBC具有许多与转移性BC相似的遗传特征。CDKN 2 A/B的丢失可能发生在BC侵袭的晚期，并且可能代表进展的重要步骤。TMB和CDKN 2 A/B基因座缺失作为NMIBC进展的生物标志物的价值有待进一步研究。
The genetic mechanisms associated with progression of high-risk non-muscle-invasive bladder cancer (HR-NMIBC) have not been described. We conducted selective next-generation sequencing (NGS) of HR-NMIBC and compared the genomic profiles of cancers that responded to intravesical therapy and those that progressed to muscle-invasive or advanced disease. DNA was extracted from paraffin-embedded sections from 25 HR-NMIBCs (22 with T1HG; 3 with TaHG with or without carcinoma in situ). Ten patients with HR-NMIBC developed progression (pT2+ or N+) (“progressors”). Fifteen patients had no progression (“non-progressors”). Tissue from 11 patients with metastatic bladder cancer (BC) were analyzed for comparison. We found no difference in frequency of mutations of TP53, PIK3CA, or KMT2D between the primary tumors of progressors compared to non-progressors and metastatic tumors. An increased frequency of deletions of CDKN2A/B was identified in tumors at progression (37%) compared to non-progressors (6%) (p = 0.10). We found a significant decrease in total mutational burden (TMB) that has been associated with immunotherapy response comparing non-progressors, progressors and metastatic tumors at 15, 10.1 and 5.1 mutations/MB respectively (p = 0.02). This association suggests more advanced tumors have decreased neoantigen burden and may explain the mechanism of BCG response in non-progressors. We found no novel genetic drivers in progressors and HR-NMIBC had many genetic features similar to metastatic BC. Loss of CDKN2A/B may occur late during invasion of BC and may represent an important step in progression. Further research is necessary to evaluate TMB and loss of CDKN2A/B locus as a biomarker for progression of NMIBC.