Characterizing CDK12-Mutated Prostate Cancers.
Characterizing CDK12-Mutated Prostate Cancers.
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表征CDK12突变的前列腺癌。
DOI：
10.1158/1078-0432.ccr-20-2371
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发表时间：
2021-01-15
期刊：
影响因子：
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通讯作者：
de Bono JS
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作者：
Rescigno P;Gurel B;Pereira R;Crespo M;Rekowski J;Rediti M;Barrero M;Mateo J;Bianchini D;Messina C;Fenor de la Maza MD;Chandran K;Carmichael J;Guo C;Paschalis A;Sharp A;Seed G;Figueiredo I;Lambros M;Miranda S;Ferreira A;Bertan C;Riisnaes R;Porta N;Yuan W;Carreira S;de Bono JS
CDK 12畸变已被报告为转移性去势抵抗性前列腺癌（mCRPC）免疫治疗反应的生物标志物。在此，我们描述了CDK 12突变的mCRPC，提供了临床、基因组和肿瘤浸润淋巴细胞数据。mCRPC患者同意接受诊断性和转移性CRPC活检的分子分析。基因组分析涉及靶向下一代（MiSeq™; Illumina）和外显子组测序（NovaSeq™; Illumina）。通过经验证的免疫细胞化学结合基于深度学习的人工智能分析评估肿瘤浸润淋巴细胞（TIL），包括评估TIL亚群的CD 4、CD 8和FOXP 3的多重免疫荧光测定。对照组包括随机选择的mCRPC队列，具有可用的测序和临床数据。2015年2月至2019年10月期间，913例患者的活检标本接受了靶向测序。43例患者（4.7%）的肿瘤CDK 12改变。CDK 12改变的癌症具有独特的特征，其中一些在外显子组测序中揭示了高染色体断裂数。双等位基因CDK 12异常mCRPC自诊断起的总生存期短于对照组（5.1年[95% CI：4.0，7.9] vs 6.4年[95% CI：5.7，7.8]; HR=1.65 [95% CI：1.07，2.53]; P=0.02）。CDK 12癌的中位瘤内CD 3+细胞密度较高，但无统计学显著性（203.7 vs 86.7 cells/mm 2，P=0.07）。这种浸润主要包括CD 4 + FOXP 3 −细胞（50.5 vs. 6.2 cells/mm 2，P<0.0001），在总体人群中，高计数往往与诊断后生存率较差相关（HR=1.64; 95% CI：[0.95，2.84]，P=0.077）。CDK 12改变的mCRPC具有更差的预后，这些肿瘤令人惊讶地主要富集CD 4 + FOXP 3 −细胞，这些细胞似乎与更差的预后相关，并且可能具有免疫抑制作用。
CDK12 aberrations have been reported as a biomarker of response to immunotherapy for metastatic castration-resistant prostate cancer (mCRPC). Herein, we characterize CDK12-mutated mCRPC, presenting clinical, genomic, and tumor-infiltrating lymphocyte data. Patients with mCRPC consented to the molecular analyses of diagnostic and metastatic CRPC biopsies. Genomic analyses involved targeted next generation (MiSeq™; Illumina) and exome sequencing (NovaSeq™; Illumina). Tumor-infiltrating lymphocytes (TIL) were assessed by validated immunocytochemistry coupled with deep learning-based artificial intelligence analyses including multiplex immunofluorescence assays for CD4, CD8, and FOXP3 evaluating TIL subsets. The control group comprised a randomly selected mCRPC cohort with sequencing and clinical data available. Biopsies from 913 patients underwent targeted sequencing between Feb/15 and Oct/19. Forty-three patients (4.7%) had tumors with CDK12 alterations. CDK12 altered cancers had distinctive features, with some revealing high chromosomal break numbers in exome sequencing. Biallelic CDK12-aberrant mCRPC had shorter overall survival from diagnosis than controls (5.1 years [95% CI: 4.0, 7.9] vs 6.4 years [95% CI: 5.7, 7.8]; HR=1.65 [95% CI: 1.07, 2.53]; P=0.02). Median intratumoral CD3+ cell density was higher in CDK12 cancers, although this was not statistically significant (203.7 versus 86.7 cells/mm2, P=0.07). This infiltrate primarily comprised CD4+FOXP3− cells (50.5 versus 6.2 cells/mm2, P<0.0001), where high counts tended to be associated with worse survival from diagnosis (HR=1.64; 95% CI: [0.95, 2.84], P=0.077) in the overall population. CDK12-altered mCRPCs have worse prognosis with these tumors surprisingly being primarily enriched for CD4+FOXP3− cells that seem to associate with worse outcome and may be immunosuppressive.