Diagnostic Potential of Hypermethylated DNA in Colorectal Cancer

Colorectal cancer (CRC) is one of the most common forms of cancer and the second leading cause of cancer-related deaths in the western world.
CRC mortality is related to stage of disease with a five year survival for early-stage disease of 77.0% and 50.8% for late stage disease. Methods for early detection of primary as well as recurrent CRC are therefore important to increase patient survival. Tumour biomarkers from blood, stool, or urine could aid the early diagnostics of CRC, but despite extensive research such markers have only provided limited clinical value.
Sporadic CRC develops as a result of the accumulation of genetic and epigenetic alterations. Epigenetic alterations include DNA hypermethylation, which through transcriptional silencing of tumour suppressor genes is associated with cancer development and cancer progression. The search for gene promoter regions hypermethylated in cancer has been ongoing for nearly two decades, and a number of genes have been shown to be preferentially hypermethylated in CRC. Therefore, hypermethylated DNA in plasma has been suggested as a marker for tumour-stage and survival in CRC patients. The only approved biomarker for the detection of CRC recurrence is the protein carcinoembryonic antigen (CEA). CEA is limited by its low sensitivity and therefore not recommended as a diagnostic biomarker. Hypermethylation of CRC specific genes as part of a molecular biomarker panel measured in blood could prove to be a recurrence marker in CRC patients, with elevated sensitivity and specificity.
The aims of this project are to examine if hypermethylation of specific genes measured from cell-free DNA in plasma of CRC patients can be used to detect primary CRC, to detect CRC recurrence and to be a biomarker for CRC prognosis.
Development of a reliable sensitive and specific biomarker for CRC will immensely improve the diagnostics and handling of CRC patients.

结直肠癌（Colorectal cancer, CRC）是最常见的癌症类型之一，也是西方国家癌症相关死亡的第二大诱因。结直肠癌的死亡率与疾病分期密切相关：早期患者的五年生存率可达77.0%，而晚期患者仅为50.8%。因此，实现原发性结直肠癌及复发性结直肠癌的早期检测，对提升患者生存率具有重要意义。血液、粪便或尿液来源的肿瘤生物标志物可为结直肠癌的早期诊断提供辅助，但尽管已有大量研究投入，此类标志物的临床应用价值仍较为有限。
散发性结直肠癌的发生源于遗传与表观遗传改变的累积。表观遗传改变包括DNA超甲基化，该过程通过抑癌基因的转录沉默，与癌症发生及进展紧密相关。近二十年来，学界一直在探寻癌症中发生超甲基化的基因启动子区域，且已有多个基因被证实于结直肠癌中呈现优先超甲基化状态。因此，血浆中的超甲基化DNA曾被提议作为结直肠癌患者的肿瘤分期与生存预后标志物。
目前唯一获批用于结直肠癌复发检测的生物标志物是癌胚抗原（carcinoembryonic antigen, CEA），但CEA因灵敏度较低存在显著局限性，因此并不被推荐作为诊断用生物标志物。以血液中检测的结直肠癌特异性基因超甲基化作为分子生物标志物组合，有望成为结直肠癌患者的复发检测标志物，且具备更优的灵敏度与特异性。
本项目的研究目标为：探究从结直肠癌患者血浆游离DNA（cell-free DNA）中检测得到的特定基因超甲基化，能否用于原发性结直肠癌的检测、结直肠癌复发的筛查，以及作为结直肠癌预后的生物标志物。
开发一款可靠、灵敏且特异的结直肠癌生物标志物，将极大改善结直肠癌患者的诊断与临床管理。