Translational Medical Oncology Group (ONCOMET), Health Research Institute of Santiago de Compostela (IDIS), University Clinical Hospital of Santiago (CHUS/SERGAS), 15706, Santiago de Compostela, Spain.
Centro de Investigación Biomédica en Red Cáncer (CIBERONC), ISCIII, 28029, Madrid, Spain.
Clin Epigenetics. 2022 Jul 9;14(1):86. doi: 10.1186/s13148-022-01302-x.
Current noninvasive assays have limitations in the early detection of colorectal cancer. We evaluated the clinical utility of promoter methylation of the long noncoding RNA LINC00473 as a noninvasive biomarker to detect colorectal cancer and associated precancerous lesions.
We evaluated the epigenetic regulation of LINC00473 through promoter hypermethylation in colorectal cancer cell lines using bisulfite genomic sequencing and expression analyses. DNA methylation of LINC00473 was analyzed in primary colorectal tumors using 450K arrays and RNA-seq from The Cancer Genome Atlas (TCGA). Tissue-based findings were validated in several independent cohorts of colorectal cancer and advanced colorectal polyp patients by pyrosequencing. We explored the clinical utility of LINC00473 methylation for the early detection of colorectal cancer in plasma cell-free DNA by quantitative methylation-specific PCR and droplet digital PCR.
LINC00473 showed transcriptionally silencing due to promoter hypermethylation in colorectal cancer cell lines and primary tumors. Methylation of the LINC00473 promoter accurately detected primary colorectal tumors in two independent clinical cohorts, with areas under the receiver operating characteristic curves (AUCs) of 0.94 and 0.89. This biomarker also identified advanced colorectal polyps from two other tissue-based clinical cohorts with high diagnostic accuracy (AUCs of 0.99 and 0.78). Finally, methylation analysis of the LINC00473 promoter in plasma cell-free DNA accurately identified patients with colorectal cancer and advanced colorectal polyps (AUCs of 0.88 and 0.84, respectively), which was confirmed in an independent cohort of patients.
Hypermethylation of the LINC00473 promoter is a new promising biomarker for noninvasive early detection of colorectal cancer and related precancerous lesions.
目前的非侵入性检测方法在早期结直肠癌检测方面存在局限性。我们评估了长链非编码 RNA LINC00473 的启动子甲基化作为一种非侵入性生物标志物在检测结直肠癌和相关癌前病变中的临床应用。
我们通过亚硫酸氢盐基因组测序和表达分析评估了 LINC00473 在结直肠癌细胞系中的启动子超甲基化的表观遗传调控。使用 450K 阵列和 TCGA 的 RNA-seq 分析了原发性结直肠肿瘤中的 LINC00473 的 DNA 甲基化。通过焦磷酸测序在多个独立的结直肠癌和高级结直肠息肉患者队列中验证了组织学发现。我们通过定量甲基化特异性 PCR 和液滴数字 PCR 探索了 LINC00473 甲基化在血浆无细胞 DNA 中早期检测结直肠癌的临床应用。
LINC00473 由于启动子超甲基化在结直肠癌细胞系和原发性肿瘤中表现出转录沉默。LINC00473 启动子的甲基化准确地检测了两个独立的临床队列中的原发性结直肠肿瘤，其受试者工作特征曲线（AUC）下面积分别为 0.94 和 0.89。该生物标志物还从另外两个基于组织的临床队列中识别出高级结直肠息肉，具有很高的诊断准确性（AUC 分别为 0.99 和 0.78）。最后，血浆无细胞 DNA 中 LINC00473 启动子的甲基化分析准确地识别出结直肠癌和高级结直肠息肉患者（AUC 分别为 0.88 和 0.84），这在患者的另一个独立队列中得到了证实。
LINC00473 启动子的超甲基化是一种新的有前途的非侵入性早期检测结直肠癌和相关癌前病变的生物标志物。
