背景:以扩张型筛状(EC)模式为特征的前列腺癌与根治性前列腺切除术(RP)后较差的临床结果相关。然而,对Gleason模式4亚型基因组特征的研究有限。
目的:探索Gleason模式4亚型(融合/形成不良,肾小球,小筛形,EC/导管内癌[IDC])以及与生化复发(BCR)无生存的关联。
方法:这是一项回顾性队列研究,包括165名2-4级前列腺癌患者,他们在单一学术机构接受RP(2016-2020)和RP标本的解密测试。排除Gleason模式5的患者。对IDC和EC模式进行分组。无BCR患者RP后中位随访时间为2.5年。
方法:通过探索性分析确定的模式4亚型内的异质性提示,我们使用围绕medoids和标志基因集评分的分区研究了转录组共识簇.主要临床结果为BCR,定义为RP后至少8周连续两次前列腺特异性抗原测量>0.2ng/ml,或任何额外的治疗。多变量Cox比例风险模型用于确定与无BCR生存相关的因素。
结论:在这个队列中,99/165例患者(60%)有EC,67例经历BCR。探索性分析和聚类证明了每个Gleason模式4亚型中的转录组异质性。在为模式4亚型控制的多变量模型中,边距状态,前列腺癌术后风险评估评分,和破译得分,新发现的类固醇激素驱动簇(风险比2.3595%置信区间1.01-5.47)与较差的无BCR生存率相关.这项研究受到中间随访的限制,无验证队列,缺乏对瘤内和前列腺内异质性的考虑。
结论:转录组异质性存在于每个格里森模式4亚型之内和之间,证明有额外的生物多样性未被组织学亚型捕获。这种异质性可用于开发新的签名和分类转录组亚型,这可能有助于完善RP后的风险分层,以进一步指导辅助和抢救治疗的决策。
结果:我们研究了前列腺切除术标本,发现具有相似微观外观的肿瘤可能具有遗传差异,这可能有助于预测前列腺切除术后前列腺癌的预后。我们的结果表明,前列腺癌亚型的进一步基因表达分析可能会改善前列腺切除术后的风险分层。未来的研究需要开发新的基因表达特征,并在独立的患者组中验证这些发现。
BACKGROUND: Prostate cancers featuring an expansile
cribriform (EC) pattern are associated with worse clinical outcomes following radical prostatectomy (RP). However, studies of the genomic characteristics of Gleason pattern 4 subtypes are limited.
OBJECTIVE: To explore transcriptomic characteristics and heterogeneity within Gleason pattern 4 subtypes (fused/poorly formed, glomeruloid, small
cribriform, EC/intraductal carcinoma [IDC]) and the association with biochemical recurrence (BCR)-free survival.
METHODS: This was a retrospective cohort study including 165 men with grade group 2-4 prostate cancer who underwent RP at a single academic institution (2016-2020) and Decipher testing of the RP specimen. Patients with Gleason pattern 5 were excluded. IDC and EC patterns were grouped. Median follow-up was 2.5 yr after RP for patients without BCR.
METHODS: Prompted by heterogeneity within pattern 4 subtypes identified via exploratory analyses, we investigated transcriptomic consensus clusters using partitioning around medoids and hallmark gene set scores. The primary clinical outcome was BCR, defined as two consecutive prostate-specific antigen measurements >0.2 ng/ml at least 8 wk after RP, or any additional treatment. Multivariable Cox proportional-hazards models were used to determine factors associated with BCR-free survival.
CONCLUSIONS: In this cohort, 99/165 patients (60%) had EC and 67 experienced BCR. Exploratory analyses and clustering demonstrated transcriptomic heterogeneity within each Gleason pattern 4 subtype. In the multivariable model controlled for pattern 4 subtype, margin status, Cancer of the Prostate Risk Assessment Post-Surgical score, and Decipher score, a newly identified steroid hormone-driven cluster (hazard ratio 2.35 95% confidence interval 1.01-5.47) was associated with worse BCR-free survival. The study is limited by intermediate follow-up, no validation cohort, and lack of accounting for intratumoral and intraprostatic heterogeneity.
CONCLUSIONS: Transcriptomic heterogeneity was present within and across each Gleason pattern 4 subtype, demonstrating there is additional biologic diversity not captured by histologic subtypes. This heterogeneity can be used to develop novel signatures and to classify transcriptomic subtypes, which may help in refining risk stratification following RP to further guide decision-making on adjuvant and salvage treatments.
RESULTS: We studied prostatectomy specimens and found that tumors with similar microscopic appearance can have genetic differences that may help to predict outcomes after prostatectomy for prostate cancer. Our results demonstrate that further gene expression analysis of prostate cancer subtypes may improve risk stratification after prostatectomy. Future studies are needed to develop novel gene expression signatures and validate these findings in independent sets of patients.