前列腺癌中基因融合的特征分析与评估：遗传不稳定性及疾病预后的衡量指标。

Characterization and evaluation of gene fusions as a measure of genetic instability and disease prognosis in prostate cancer.

机构信息

Department of Diagnostics, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany.

Department of Urology, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.

出版信息

BMC Cancer. 2023 Jun 22;23(1):575. doi: 10.1186/s12885-023-11019-6.

DOI:10.1186/s12885-023-11019-6

PMID:37349736

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10286324/

Abstract

BACKGROUND

Prostate cancer (PCa) is one of the most prevalent cancers worldwide. The clinical manifestations and molecular characteristics of PCa are highly variable. Aggressive types require radical treatment, whereas indolent ones may be suitable for active surveillance or organ-preserving focal therapies. Patient stratification by clinical or pathological risk categories still lacks sufficient precision. Incorporating molecular biomarkers, such as transcriptome-wide expression signatures, improves patient stratification but so far excludes chromosomal rearrangements. In this study, we investigated gene fusions in PCa, characterized potential novel candidates, and explored their role as prognostic markers for PCa progression.

METHODS

We analyzed 630 patients in four cohorts with varying traits regarding sequencing protocols, sample conservation, and PCa risk group. The datasets included transcriptome-wide expression and matched clinical follow-up data to detect and characterize gene fusions in PCa. With the fusion calling software Arriba, we computationally predicted gene fusions. Following detection, we annotated the gene fusions using published databases for gene fusions in cancer. To relate the occurrence of gene fusions to Gleason Grading Groups and disease prognosis, we performed survival analyses using the Kaplan-Meier estimator, log-rank test, and Cox regression.

RESULTS

Our analyses identified two potential novel gene fusions, MBTTPS2,L0XNC01::SMS and AMACR::AMACR. These fusions were detected in all four studied cohorts, providing compelling evidence for the validity of these fusions and their relevance in PCa. We also found that the number of gene fusions detected in a patient sample was significantly associated with the time to biochemical recurrence in two of the four cohorts (log-rank test, p-value < 0.05 for both cohorts). This was also confirmed after adjusting the prognostic model for Gleason Grading Groups (Cox regression, p-values < 0.05).

CONCLUSIONS

Our gene fusion characterization workflow revealed two potential novel fusions specific for PCa. We found evidence that the number of gene fusions was associated with the prognosis of PCa. However, as the quantitative correlations were only moderately strong, further validation and assessment of clinical value is required before potential application.

摘要

背景

前列腺癌（PCa）是全球最常见的癌症之一。PCa 的临床表现和分子特征具有高度变异性。侵袭性类型需要根治性治疗，而惰性类型可能适合主动监测或保留器官的局部治疗。根据临床或病理风险类别对患者进行分层仍然缺乏足够的准确性。纳入分子生物标志物，如转录组范围的表达特征，可以改善患者分层，但迄今为止排除了染色体重排。在这项研究中，我们研究了 PCa 中的基因融合，对潜在的新候选基因进行了特征分析，并探讨了它们作为 PCa 进展的预后标志物的作用。

方法

我们分析了四个队列中的 630 名患者，这些队列在测序方案、样本保存和 PCa 风险组方面具有不同的特征。这些数据集包括转录组范围的表达和匹配的临床随访数据，用于检测和分析 PCa 中的基因融合。我们使用融合调用软件 Arriba 进行计算预测基因融合。在检测到融合后，我们使用发表的癌症基因融合数据库对融合进行注释。为了将基因融合的发生与 Gleason 分级组和疾病预后相关联，我们使用 Kaplan-Meier 估计器、对数秩检验和 Cox 回归进行生存分析。

结果

我们的分析鉴定了两个潜在的新基因融合，即 MBTTPS2，L0XNC01::SMS 和 AMACR::AMACR。这些融合在所有四个研究队列中均被检测到，为这些融合的有效性及其在 PCa 中的相关性提供了有力证据。我们还发现，在两个队列（对数秩检验，两个队列的 p 值均<0.05）中，患者样本中检测到的基因融合数量与生化复发时间显著相关。在调整了 Gleason 分级组的预后模型后（Cox 回归，p 值均<0.05），也得到了证实。