Detection of circulating cell free tumour DNA in renal cancer patients for the prediction and detection of early disease recurrence

检测肾癌患者的循环游离肿瘤 DNA 以预测和检测早期疾病复发

• 批准号: MR/W030322/1
• 负责人: Alexander Laird
• 金额: $ 31.56万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW030322%2F1
• 关键词: Detection; circulating; cell; free; tumour

The number of patients diagnosed with kidney cancer (RCC) has been increasing over the last 10 years and accounts for 4% of all cancers in the UK. Clear cell RCC (ccRCC) is the predominate subtype accounting for approximately 75% of all cases. Surgery is often curative if the disease is identified at an early stage. However approximately 1/3 of patients who undergo surgery with the aim of removing all the kidney cancer, develop recurrence of their disease in the future, which is often incurable. Because of this, RCC is recognised as the most lethal cancer of the urinary tract with up to 50% of patients dying of their disease. Cancer cells shed DNA into the blood of patients with the disease. It is anticipated that liquid biopsy, through study of the patients' blood and identification of this circulating cell free tumour DNA (ctDNA) will provide useful information for predicting disease recurrence and monitoring for this disease recurrence. This would then allow tailored interventions to improve patient outcomes. However, this ctDNA is a small fraction of the overall cell free DNA found in the circulation, which also has cell free DNA derived from healthy cells within the body. The small fraction of cell-free tumour DNA makes this difficult to detect. Nonetheless, studies in other cancers, such as lung, breast and colon cancer, have shown promising results for the detection of tumour specific DNA changes in the blood of patients with those respective cancers, which could have clinically meaningful implications. Unfortunately using the same approaches to identify ctDNA in RCC has been more difficult and disappointing. Previous work in our own lab has shown significant changes in a DNA modification called methylation, in ccRCC. Furthermore, very recent small-scale studies have demonstrated much higher levels of ctDNA in ccRCC patients than previously reported, when methylation changes are used to interrogate the cfDNA in both blood and urine. We therefore hypothesis that using RCC specific methylation changes (rather than DNA mutational changes) to identify ctDNA in the blood of patients with RCC will improve the detection of ctDNA in RCC patients. We have performed a large-scale study with publicly available data to develop a ccRCC specific methylated ctDNA profile, which will be validated in tumour samples from our own cohort. Thereafter using innovative technology, that allows the detection of up to 10000 methylation changes in the blood or urine of patients, we will study the blood from a large number of patients with ccRCC both at diagnosis and throughout follow-up as well as healthy controls. Patients will have RCC representative of the spectrum of disease. All samples have high quality well annotated clinical data which will be correlated with ctDNA findings to identify the utility of this profile for predicting and detecting disease recurrence following surgery. This will potentially lead to the development of clinically applicable tests to improve patient outcomes.

在过去的10年里，被诊断患有肾癌（RCC）的患者人数一直在增加，占英国所有癌症的4%。透明细胞肾细胞癌（ccRCC）是占主导地位的亚型，约占所有病例的75%。如果疾病在早期被发现，手术通常是治愈性的。然而，大约三分之一的患者接受手术以去除所有肾癌，在未来发展他们的疾病复发，这通常是无法治愈的。因此，RCC被认为是最致命的泌尿道癌症，高达50%的患者死于这种疾病。癌细胞将DNA释放到患者的血液中。预计通过研究患者的血液和鉴定这种循环无细胞肿瘤DNA（ctDNA）的液体活检将为预测疾病复发和监测这种疾病复发提供有用的信息。这将允许量身定制的干预措施，以改善患者的结果。然而，这种ctDNA是在循环中发现的整体无细胞DNA的一小部分，其也具有来自体内健康细胞的无细胞DNA。小部分的无细胞肿瘤DNA使其难以检测。尽管如此，对其他癌症，如肺癌、乳腺癌和结肠癌的研究表明，在检测这些癌症患者血液中肿瘤特异性DNA变化方面取得了可喜的成果，这可能具有临床意义。不幸的是，使用相同的方法来鉴定RCC中的ctDNA更加困难和令人失望。我们实验室以前的工作已经显示了ccRCC中称为甲基化的DNA修饰的显著变化。此外，最近的小规模研究表明，当甲基化变化用于询问血液和尿液中的cfDNA时，ccRCC患者中的ctDNA水平比先前报道的要高得多。因此，我们假设使用RCC特异性甲基化变化（而不是DNA突变变化）来鉴定RCC患者血液中的ctDNA将改善RCC患者中ctDNA的检测。我们利用公开数据进行了一项大规模研究，以开发ccRCC特异性甲基化ctDNA谱，该谱将在我们自己队列的肿瘤样本中进行验证。此后，使用创新技术，允许检测患者血液或尿液中多达10000个甲基化变化，我们将研究大量ccRCC患者的血液，包括诊断和整个随访以及健康对照。患者将患有代表疾病谱的RCC。所有样品都具有高质量的良好注释的临床数据，其将与ctDNA发现相关，以鉴定该谱用于预测和检测手术后疾病复发的效用。这将可能导致临床适用的测试，以改善患者的结果的发展。