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无细胞核酸作为癌症患者的生物标志物

Cell-free nucleic acids as biomarkers in cancer patients

原文发布日期：2011-05-12

DOI: 10.1038/nrc3066

类型: Review Article

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要点：

要点翻译：

英文摘要：

摘要翻译：

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文章：

无细胞核酸作为癌症患者的生物标志物

Cell-free nucleic acids as biomarkers in cancer patients

原文发布日期：2011-05-12

DOI: 10.1038/nrc3066

类型: Review Article

开放获取: 否

要点：

Increased levels of circulating nucleic acids (DNA, mRNA and microRNA (miRNA)) in the blood reflect pathological processes, including malignant and benign lesions, inflammatory diseases, stroke, trauma and sepsis. During these processes nucleic acids are shed into the blood by apoptotic and necrotic cells.
In cancer patients, circulating DNA carries tumour-related genetic and epigenetic alterations that are relevant to cancer development, progression and resistance to therapy. These alterations include loss of heterozygosity (LOH) and mutations of tumour suppressor genes (such as TP53) and oncogenes (such as KRAS and BRAF).
Additional genetic alterations that are detectable on circulating DNA and used as biomarkers in cancer include the integrity of non-coding genomic DNA repeat sequences (such as ALU and LINE1). Although still in their infancy, DNA integrity assays have the potential to become a universal blood biomarker for multiple cancers.
Epigenetic alterations in genes (such as glutathione S-transferase P1 (GSTP1 and septin 9 (SEPT9)) and adenomatous polyposis coli (APC)) that are relevant to tumorigenesis and the progression of solid tumours have been detected on circulating DNA in cancer patients, and their potential clinical utility is indicated by the launch of commercial tests for cancer screening.
The detection of circulating nucleosomes in blood indicates that cell-free DNA (cfDNA) retains at least some features of the nuclear chromatin during the process of DNA release. Initial clinical studies have indicated that monitoring the abundance of nucleosomes has potential utility for monitoring the efficacy of therapy in cancer patients.
Dying tumour cells also discharge miRNAs, which circulate stably in the blood. The pivotal functions of miRNAs in cancer development and progression may explain the promising results of pilot studies on cancer patients using miRNA blood tests for tumour detection and prognosis.
The cellular source of tumour-derived circulating nucleic acids is still subject to debate. After complete removal of the primary tumour the detection of cfDNA may signal the presence of micrometastatic cells in distant organs, such as the bone marrow, which pose a risk of relapse.
Metastatic and primary tumours from the same patient can vary at the genomic, epigenomic and transcriptomic levels. Minimally invasive blood analyses of cell-free nucleic acid allow repetitive real-time monitoring of these events and will, therefore, gain clinical utility in the determination of prognosis and treatment efficacy.

要点翻译：

血液中循环核酸（DNA、mRNA及微小RNA）水平的升高反映了多种病理过程，包括恶性与良性病变、炎症性疾病、脑卒中、创伤和脓毒症。在这些过程中，核酸通过凋亡和坏死细胞释放入血液。
在癌症患者中，循环DNA携带与肿瘤发生、进展及治疗耐药性相关的遗传学和表观遗传学改变。这些改变包括杂合性缺失（LOH），以及抑癌基因（如TP53）和原癌基因（如KRAS与BRAF）的突变。
循环DNA上可检测到的其他遗传学改变包括非编码基因组DNA重复序列（如ALU和LINE1）的完整性，这些已被用作癌症生物标志物。尽管尚处于起步阶段，DNA完整性检测有望成为多种癌症的通用血液生物标志物。
在癌症患者循环DNA中，已检测到与实体瘤发生和进展相关的基因表观遗传学改变（如谷胱甘肽S-转移酶P1（GSTP1）、 septin 9（SEPT9）和腺瘤性息肉病基因（APC）），其临床潜力已通过商业癌症筛查检测产品的推出得到印证。
血液中循环核小体的检测表明，游离DNA在释放过程中至少保留了核染色质的部分特征。初步临床研究提示，监测核小体丰度对评估癌症患者疗效具有潜在价值。
濒死肿瘤细胞同时释放微小RNA，后者在血液中稳定循环。微小RNA在肿瘤发生发展中的关键作用，解释了采用微小RNA血液检测进行肿瘤识别与预后评估的初步研究获得可喜成果的原因。
肿瘤源性循环核酸的细胞来源仍存争议。在原发肿瘤完全切除后，检测到游离DNA可能预示远处器官（如骨髓）中存在微转移细胞，这些细胞可能导致复发风险。
同一患者的转移灶与原发肿瘤在基因组、表观基因组和转录组水平可能存在差异。对游离核酸进行微创血液分析可实现对这些事件的重复实时监测，因此将在预后判断和治疗效果评估方面获得临床价值。

英文摘要：

DNA, mRNA and microRNA are released and circulate in the blood of cancer patients. Changes in the levels of circulating nucleic acids have been associated with tumour burden and malignant progression. In the past decade a wealth of information indicating the potential use of circulating nucleic acids for cancer screening, prognosis and monitoring of the efficacy of anticancer therapies has emerged. In this Review, we discuss these findings with a specific focus on the clinical utility of cell-free nucleic acids as blood biomarkers.