Discovery of methylated circulating DNA biomarkers for comprehensive non-invasive monitoring of treatment response in metastatic colorectal cancer.
Discovery of methylated circulating DNA biomarkers for comprehensive non-invasive monitoring of treatment response in metastatic colorectal cancer.
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DOI：
10.1136/gutjnl-2016-313372
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发表时间：
2018-11
期刊：
影响因子：
24.5
通讯作者：
Di Nicolantonio F
中科院分区：
文献类型：
--
作者：
Barault L;Amatu A;Siravegna G;Ponzetti A;Moran S;Cassingena A;Mussolin B;Falcomatà C;Binder AM;Cristiano C;Oddo D;Guarrera S;Cancelliere C;Bustreo S;Bencardino K;Maden S;Vanzati A;Zavattari P;Matullo G;Truini M;Grady WM;Racca P;Michels KB;Siena S;Esteller M;Bardelli A;Sartore-Bianchi A;Di Nicolantonio F
无细胞循环DNA（cfDNA）中突变的评估最近已用于跟踪结直肠癌（CRC）中的疾病复发。由于缺乏普遍突变的基因，这种方法需要个性化的测定设计。相比之下，早期甲基化改变仅限于限定的基因组基因座，从而允许用于群体研究的全面测定设计。我们的目的是鉴定可以在cfDNA中纵向测量的癌症特异性甲基化生物标志物，以监测转移性CRC患者（mCRC）的治疗结果。全基因组甲基化微阵列鉴定了一组高度癌症特异性的5个甲基化基因座（EYA 4、GRIA 4、ITGA 4、MAP 3 K14-AS 1、MSC）。针对这些基因设计了数字PCR检测。在来自mCRC患者（N=182）的组织DNA（N=85）和cfDNA中回顾性地评价标记物流行率。对接受化疗或靶向治疗的患者子集进行了纵向评估。159例mCRC患者（87%）至少有一种标志物呈阳性。EYA 4、GRIA 4、ITGA 4、MAP 3 K14-AS 1和MSC的阳性率分别为67%、71.3%、69.2%、69.8%和62.1%。甲基化标志物随时间的动态变化不受治疗类型的影响，与客观肿瘤缓解和无进展生存期相关。甲基化可用作通用测试，以规避患者特异性突变的缺失，用于通过液体活检监测肿瘤负荷动力学。选择的生物标志物允许监测不同治疗方案下的肿瘤负荷。该方法可用于临床试验中的药效学评估或常规成像有局限性时。
The evaluation of mutations in cell free circulating DNA (cfDNA) has recently been used for tracking disease relapse in colorectal cancer (CRC). This approach requires personalized assay design due to the lack of universally mutated genes. In contrast, early methylation alterations are restricted to defined genomic loci allowing comprehensive assay design for population studies. Our objective was to identify cancer specific methylated biomarkers which could be measured longitudinally in cfDNA to monitor therapeutic outcome in metastatic CRC patients (mCRC). Genome wide methylation microarrays identified a highly cancer specific panel of five methylated loci (EYA4, GRIA4, ITGA4, MAP3K14-AS1, MSC). Digital PCR assays were designed for these genes. Marker prevalence was retrospectively evaluated in tissue DNA (N=85) and cfDNA from mCRC patients (N=182). Longitudinal assessment was performed in a subset of patients treated with chemotherapy or targeted therapy. One hundred and fifty-nine mCRC patients (87%) showed positivity in at least one marker. Positivity was observed in 67% for EYA4, 71.3% for GRIA4, 69.2% for ITGA4, 69.8% for MAP3K14-AS1 and 62.1% for MSC. Dynamics of methylation markers over time was not affected by treatment type and correlated with objective tumor response and progression-free survival. Methylation can be used as a universal test to circumvent the absence of patient specific mutations for monitoring tumor burden dynamics via liquid biopsy. The selected biomarkers allowed monitoring of tumor burden under different therapeutic regimens. This method might be proposed for assessing pharmacodynamics in clinical trials or when conventional imaging has limitations.
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影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
影响因子：
50.3
作者：
De Carvalho DD;Sharma S;You JS;Su SF;Taberlay PC;Kelly TK;Yang X;Liang G;Jones PA
通讯作者：
Jones PA
影响因子：
24.5
作者：
Hardy T;Zeybel M;Day CP;Dipper C;Masson S;McPherson S;Henderson E;Tiniakos D;White S;French J;Mann DA;Anstee QM;Mann J
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Mann J
影响因子：
28.2
作者：
Bardelli A;Corso S;Bertotti A;Hobor S;Valtorta E;Siravegna G;Sartore-Bianchi A;Scala E;Cassingena A;Zecchin D;Apicella M;Migliardi G;Galimi F;Lauricella C;Zanon C;Perera T;Veronese S;Corti G;Amatu A;Gambacorta M;Diaz LA Jr;Sausen M;Velculescu VE;Comoglio P;Trusolino L;Di Nicolantonio F;Giordano S;Siena S
通讯作者：
Siena S
影响因子：
11.5
作者：
Garlan, Fanny;Laurent-Puig, Pierre;Zaanan, Aziz
通讯作者：
Zaanan, Aziz