Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
Department of Pathology, Johns Hopkins School University of Medicine, Baltimore, MD, USA.
Prostate Cancer Prostatic Dis. 2019 Mar;22(1):59-65. doi: 10.1038/s41391-018-0086-1. Epub 2018 Aug 31.
DNA repair gene mutations are present in 8-10% of localized prostate cancers. It is unknown whether this is influenced by clinicopathologic factors.
We interrogated localized prostate adenocarcinomas with tumor DNA sequencing information from the TCGA validated (n = 333) and Nature Genetics (n = 377) datasets. Homologous recombination repair genes included in our analysis were: ATM, BRCA1/2, CDK12, CHEK1/2, FANCA, FANCD2, FANCL, GEN1, NBN, PALB2, RAD51, and RAD51C. Proportions of cases with pathogenic DNA repair mutations (and in ATM/BRCA1/2 specifically) were reported by Gleason grade group, clinical T, pathologic T, and pathologic N stage. Odds ratios and Fisher's exact tests were used to compare proportions between categories.
Patients with Gleason grade groups 3 and higher were 2.2 times more likely to harbor any DNA repair mutation (95% CI: 1.2-4.2; 10.3% versus 5.0%) and were 2.7 times more likely to have BRCA1/2 or ATM mutations (95% CI: 1.3-6.6; 7.0% versus 2.7%) compared to those in Gleason grade groups 1-2. Patients with pathologic T3 and T4 stage (pT3/pT4) were 2.6 times more likely to have any DNA repair mutation (95% CI: 1.3-6.6; 13.0% versus 5.5%) and were 3.2 times more likely to have BRCA1/2 or ATM mutations (95% CI: 1.2-11.3; 9.5% versus 3.1%) compared to those with pT2 disease. There was no difference by clinical tumor or nodal stage. Among men with Gleason grade group ≥ 3 and clinical stage ≥ cT3, 21.3% (1 in 5) had a DNA repair mutation in any gene and 11.7% (1 in 9) had a mutation in ATM/BRCA1/2.
The prevalence of pathogenic DNA repair gene alterations is enriched in men with advanced tumor stages and higher Gleason grade groups, with maximal enrichment observed in those with Gleason grade group ≥ 3 and clinical stage ≥ cT3 disease. This information can be used to guide eligibility criteria for genomically targeted clinical trials in the neoadjuvant/adjuvant settings.
DNA 修复基因突变存在于 8-10%的局限性前列腺癌中。目前尚不清楚这是否受临床病理因素的影响。
我们使用 TCGA 验证的（n=333）和自然遗传学（n=377）数据集的肿瘤 DNA 测序信息对局限性前列腺腺癌进行了研究。我们分析的同源重组修复基因包括：ATM、BRCA1/2、CDK12、CHEK1/2、FANCA、FANCD2、FANCL、GEN1、NBN、PALB2、RAD51 和 RAD51C。报告了按 Gleason 分级组、临床 T、病理 T 和病理 N 分期的具有致病性 DNA 修复突变的病例比例（以及特定的 ATM/BRCA1/2）。使用优势比和 Fisher 精确检验比较类别之间的比例。
Gleason 分级组 3 及以上的患者发生任何 DNA 修复突变的可能性是 Gleason 分级组 1-2 的 2.2 倍（95%CI：1.2-4.2；10.3%与 5.0%），并且发生 BRCA1/2 或 ATM 突变的可能性是 Gleason 分级组 1-2 的 2.7 倍（95%CI：1.3-6.6；7.0%与 2.7%）。病理 T3 和 T4 期（pT3/pT4）的患者发生任何 DNA 修复突变的可能性是 pT2 疾病的 2.6 倍（95%CI：1.3-6.6；13.0%与 5.5%），发生 BRCA1/2 或 ATM 突变的可能性是 pT2 疾病的 3.2 倍（95%CI：1.2-11.3；9.5%与 3.1%）。临床肿瘤或淋巴结分期无差异。在 Gleason 分级组≥3 和临床分期≥cT3 的男性中，21.3%（1/5）在任何基因中均存在致病性 DNA 修复突变，11.7%（1/9）在 ATM/BRCA1/2 中存在突变。
在具有晚期肿瘤分期和较高 Gleason 分级组的男性中，致病性 DNA 修复基因突变的发生率更高，在 Gleason 分级组≥3 和临床分期≥cT3 的患者中观察到最大程度的富集。这些信息可用于指导新辅助/辅助治疗中基于基因组的靶向临床试验的纳入标准。
