A prognostic hypoxia gene signature with low heterogeneity within the dominant tumour lesion in prostate cancer patients.. A prognostic hypoxia gene signature with low heterogeneity within the dominant tumour lesion in prostate cancer patients.

Background: Hypoxia gene signatures measured in a biopsy are promising biomarkers in prostate cancer. We determined the ability of a previously developed signature to correctly classify tumours as more or less hypoxic and investigated how intratumour heterogeneity affected its biomarker performance. Methods: The 32-gene signature was determined from gene expression data of 141 biopsies from the dominant (index) lesion of 94 patients treated with prostatectomy. Hypoxic fraction was measured by pimonidazole immunostaining of whole-mount and biopsy sections and used as reference standard for hypoxia. Results: The signature was correlated with hypoxic fraction in whole-mount sections, and the parameters showed almost the same association with tumour aggressiveness. Gene- and pimonidazole-based classification of patients differed considerably. However, the signature had low intratumour heterogeneity compared to hypoxic fraction in biopsies and showed prognostic significance in three independent cohorts. Conclusion: The biopsy-based 32-gene signature from the index lesion reflects hypoxia-related aggressiveness in prostate cancer. Overall design: The 32-gene signature was determined from gene expression data of 141 biopsies from the dominant (index) lesion of 94 patients treated with prostatectomy. Hypoxic fraction was measured by pimonidazole immunostaining of whole-mount and biopsy sections and used as reference standard for hypoxia.

背景：活检组织检测的缺氧基因特征（hypoxia gene signatures）是前列腺癌中极具潜力的生物标志物。本研究旨在验证一款已开发的特征对肿瘤缺氧程度高低进行准确分类的能力，并探究肿瘤内异质性对其生物标志物性能的影响。
方法：本研究的32基因特征（32-gene signature）源自94例接受前列腺切除术患者的优势（索引）病灶（index lesion）处获取的141份活检组织的基因表达数据。以匹莫尼唑（pimonidazole）对全制片及活检切片进行免疫染色，以此检测缺氧分数，并将其作为缺氧状态的参考标准。
结果：该特征与全制片标本的缺氧分数呈显著相关，且二者与肿瘤侵袭性的关联程度近乎一致。基于基因特征与基于匹莫尼唑的患者分类结果差异显著。但相较于活检组织的缺氧分数，该特征的肿瘤内异质性更低，且在三个独立队列中均展现出预后价值。
结论：源自索引病灶的活检组织32基因特征可反映前列腺癌中与缺氧相关的肿瘤侵袭性。
整体实验设计：本研究的32基因特征源自94例接受前列腺切除术患者的优势（索引）病灶处获取的141份活检组织的基因表达数据。以匹莫尼唑对全制片及活检切片进行免疫染色，以此检测缺氧分数，并将其作为缺氧状态的参考标准。