Genomic Features of Muscle-invasive Bladder Cancer Arising After Prostate Radiotherapy.
Genomic Features of Muscle-invasive Bladder Cancer Arising After Prostate Radiotherapy.
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DOI：
10.1016/j.eururo.2021.12.004
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发表时间：
2022-05
期刊：
影响因子：
23.4
通讯作者：
Mouw, Kent W.
中科院分区：
文献类型：
--
作者：
Mossanen, Matthew;Carvalho, Filipe L. F.;Muralidhar, Vinayak;Preston, Mark A.;Reardon, Brendan;Conway, Jake R.;Curran, Catherine;Freeman, Dory;Sha, Sybil;Sonpavde, Guru;Hirsch, Michelle;Kibel, Adam S.;Van Allen, Eliezer M.;Mouw, Kent W.
关键词：
肌层浸润性膀胱癌（MIBC）是前列腺癌明确放射治疗后的一种罕见但严重的事件。鉴于对先前受过辐射的骨盆进行确定性治疗的挑战，放射相关的 MIBC (RA-MIBC) 可能难以管理。 RA-MIBC 的基因组图谱以及它是否与非 RA-MIBC 不同尚不清楚。定义 RA-MIBC 的突变特征，并将 RA-MIBC 的基因组图谱与非 RA-MIBC 的基因组图谱进行比较。我们确定了我们机构中接受前列腺癌放射治疗并随后患上 MIBC 的患者。我们对 RA-MIBC 患者的膀胱肿瘤进行了全外显子组测序。鉴定了肿瘤遗传改变，包括突变、拷贝数改变和突变特征，并与非 RA-MIBC 的遗传特征进行了比较。我们使用 Kaplan-Meier 方法来估计无复发 (RFS) 和总 (OS) 生存率。我们确定了 19 名具有可用肿瘤组织（n = 22 个肿瘤）和临床数据的 RA-MIBC 患者。中位年龄为 76 岁，从前列腺癌放疗到 RA-MIBC 的中位时间为 12 岁。中位 RFS 为 14.5 个月，中位 OS 为 22.0 个月。与平行分析的非 RA-MIBC 队列相比，肿瘤突变负荷没有差异，但 RA-MIBC 的短插入和缺失 (indels) 数量显着增加，与之前的辐射暴露一致。我们鉴定了 APOBEC 介导的诱变、衰老和同源重组缺陷的突变特征。 RA-MIBC 中许多已知膀胱癌基因（包括 TP53、KDM6A 和 RB1）的突变频率以及拷贝数改变（例如 CDKN2A 丢失）与非 RA-MIBC 相似。我们发现了独特的突变特性，这些特性可能导致 RA-MIBC 独特的生物学和临床特征。膀胱癌是前列腺癌放射治疗后罕见但严重的诊断。我们表征了前列腺放疗后出现的膀胱肿瘤的遗传特征，并确定了与既往未接受放疗的患者膀胱肿瘤的相似之处和差异。前列腺癌放疗后出现的与辐射相关的肌肉浸润性膀胱癌具有辐射暴露的突变证据，但与非辐射相关的肌肉浸润性膀胱癌有许多共同的驱动因素改变。
Muscle-invasive bladder cancer (MIBC) is a rare but serious event following definitive radiation for prostate cancer. Radiation-associated MIBC (RA-MIBC) can be difficult to manage given the challenges of delivering definitive therapy to a previously irradiated pelvis. The genomic landscape of RA-MIBC and whether it is distinct from non–RA-MIBC are unknown. To define mutational features of RA-MIBC and compare the genomic landscape of RA-MIBC with that of non–RA-MIBC. We identified patients from our institution who received radiotherapy for prostate cancer and subsequently developed MIBC. We performed whole exome sequencing of bladder tumors from RA-MIBC patients. Tumor genetic alterations including mutations, copy number alterations, and mutational signatures were identified and were compared with genetic features of non–RA-MIBC. We used the Kaplan-Meier method to estimate recurrence-free (RFS) and overall (OS) survival. We identified 19 RA-MIBC patients with available tumor tissue (n = 22 tumors) and clinical data. The median age was 76 yr, and the median time from prostate cancer radiation to RA-MIBC was 12 yr. The median RFS was 14.5 mo and the median OS was 22.0 mo. Compared with a cohort of non–RA-MIBC analyzed in parallel, there was no difference in tumor mutational burden, but RA-MIBCs had a significantly increased number of short insertions and deletions (indels) consistent with previous radiation exposure. We identified mutation signatures characteristic of APOBEC-mediated mutagenesis, aging, and homologous recombination deficiency. The frequency of mutations in many known bladder cancer genes, including TP53, KDM6A, and RB1, as well as copy number alterations such as CDKN2A loss in RA-MIBC was similar to that in non–RA-MIBC. We identified unique mutational properties that likely contribute to the distinct biological and clinical features of RA-MIBC. Bladder cancer is a rare but serious diagnosis following radiation for prostate cancer. We characterized genetic features of bladder tumors arising after prostate radiotherapy, and identify similarities with and differences from bladder tumors from patients without previous radiation. Radiation-associated muscle-invasive bladder cancers arising after prostate cancer radiotherapy have mutational evidence of radiation exposure but share many driver alterations with non–radiation-associated muscle-invasive bladder cancers.
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影响因子：
2.1
作者：
Nguyen, Daniel P.;Al Awamlh, Bashir Al Hussein;Scherr, Douglas S.
通讯作者：
Scherr, Douglas S.
影响因子：
6.6
作者：
Bostrom, Peter J.;Soloway, Mark S.;Samavedi, Srinivas
通讯作者：
Samavedi, Srinivas
影响因子：
16.6
作者：
Behjati, Sam;Gundem, Gunes;Wedge, David C.;Roberts, Nicola D.;Tarpey, Patrick S.;Cooke, Susanna L.;Van Loo, Peter;Alexandrov, Ludmil B.;Ramakrishna, Manasa;Davies, Helen;Nik-Zainal, Serena;Hardy, Claire;Latimer, Calli;Raine, Keiran M.;Stebbings, Lucy;Menzies, Andy;Jones, David;Shepherd, Rebecca;Butler, Adam P.;Teague, Jon W.;Jorgensen, Mette;Khatri, Bhavisha;Pillay, Nischalan;Shlien, Adam;Futreal, P. Andrew;Badie, Christophe;McDermott, Ultan;Bova, G. Steven;Richardson, Andrea L.;Flanagan, Adrienne M.;Stratton, Michael R.;Campbell, Peter J.
通讯作者：
Campbell, Peter J.
影响因子：
3.2
作者：
Iyer G;Tully CM;Zabor EC;Bochner BH;Dalbagni G;Herr HW;Donat SM;Russo P;Ostrovnaya I;Regazzi AM;Milowsky MI;Rosenberg JE;Bajorin DF
通讯作者：
Bajorin DF
影响因子：
12.3
作者：
Fisher S;Barry A;Abreu J;Minie B;Nolan J;Delorey TM;Young G;Fennell TJ;Allen A;Ambrogio L;Berlin AM;Blumenstiel B;Cibulskis K;Friedrich D;Johnson R;Juhn F;Reilly B;Shammas R;Stalker J;Sykes SM;Thompson J;Walsh J;Zimmer A;Zwirko Z;Gabriel S;Nicol R;Nusbaum C
通讯作者：
Nusbaum C