Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia PA, 19104.
Division of Oncology, Department of Medicine, University of Washington, Seattle, WA, USA; Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Eur Urol. 2022 Mar;81(3):243-250. doi: 10.1016/j.eururo.2021.10.036. Epub 2021 Dec 1.
Inherited germline TP53 pathogenic and likely pathogenic variants (gTP53) cause autosomal dominant multicancer predisposition including Li-Fraumeni syndrome (LFS). However, there is no known association of prostate cancer with gTP53.
To determine whether gTP53 predisposes to prostate cancer.
DESIGN, SETTING, AND PARTICIPANTS: This multi-institutional retrospective study characterizes prostate cancer incidence in a cohort of LFS males and gTP53 prevalence in a prostate cancer cohort.
We evaluated the spectrum of gTP53 variants and clinical features associated with prostate cancer.
We identified 31 prostate cancer cases among 163 adult LFS males, including 26 of 54 aged ≥50 yr. Among 117 LFS males without prostate cancer at the time of genetic testing, six were diagnosed with prostate cancer over a median (interquartile range [IQR]) of 3.0 (1.3-7.2) yr of follow-up, a 25-fold increased risk (95% confidence interval [CI] 9.2-55; p < 0.0001). We identified gTP53 in 38 of 6850 males (0.6%) in the prostate cancer cohort, a relative risk 9.1-fold higher than that of population controls (95% CI 6.2-14; p < 0.0001; gnomAD). We observed hotspots at the sites of attenuated variants not associated with classic LFS. Two-thirds of available gTP53 prostate tumors had somatic inactivation of the second TP53 allele. Among gTP53 prostate cancer cases in this study, the median age at diagnosis was 56 (IQR: 51-62) yr, 44% had Gleason ≥8 tumors, and 29% had advanced disease at diagnosis.
Complementary analyses of prostate cancer incidence in LFS males and gTP53 prevalence in prostate cancer cohorts suggest that gTP53 predisposes to aggressive prostate cancer. Prostate cancer should be considered as part of LFS screening protocols and TP53 considered in germline prostate cancer susceptibility testing.
Inherited pathogenic variants in the TP53 gene are likely to predispose men to aggressive prostate cancer.
遗传性种系 TP53 致病性和可能致病性变异（gTP53）导致常染色体显性遗传多种癌症易感性，包括 Li-Fraumeni 综合征（LFS）。然而，目前尚无与前列腺癌相关的 gTP53 报道。
确定 gTP53 是否会导致前列腺癌。
设计、地点和参与者：这项多机构回顾性研究描述了 LFS 男性队列中的前列腺癌发病率和前列腺癌队列中的 gTP53 患病率。
我们评估了 gTP53 变异谱和与前列腺癌相关的临床特征。
我们在 163 名成年 LFS 男性中发现了 31 例前列腺癌病例，其中 54 名年龄≥50 岁的男性中有 26 例。在 117 名进行基因检测时没有前列腺癌的 LFS 男性中，6 名在中位（四分位距 [IQR]）3.0（1.3-7.2）年的随访中被诊断为前列腺癌，风险增加 25 倍（95%置信区间 [CI] 9.2-55；p<0.0001）。我们在前列腺癌队列的 6850 名男性（0.6%）中发现了 gTP53，相对风险是人群对照的 9.1 倍（95%CI 6.2-14；p<0.0001；gnomAD）。我们观察到与经典 LFS 无关的弱化变异体的热点。三分之二的 gTP53 前列腺肿瘤存在第二个 TP53 等位基因的体细胞失活。在这项研究中，gTP53 前列腺癌病例的中位诊断年龄为 56（IQR：51-62）岁，44%的患者有 Gleason≥8 肿瘤，29%的患者在诊断时患有晚期疾病。
对 LFS 男性中前列腺癌发病率的补充分析和前列腺癌队列中 gTP53 的患病率提示 gTP53 易患侵袭性前列腺癌。前列腺癌应被视为 LFS 筛查方案的一部分，并且应考虑在种系前列腺癌易感性检测中使用 TP53。
TP53 基因的致病性变异可能使男性易患侵袭性前列腺癌。
