Clinical implications of genomic alterations in the tumour and circulation of pancreatic cancer patients.
Clinical implications of genomic alterations in the tumour and circulation of pancreatic cancer patients.
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DOI：
10.1038/ncomms8686
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发表时间：
2015-07-07
影响因子：
16.6
通讯作者：
Velculescu VE
中科院分区：
文献类型：
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作者：
Sausen M;Phallen J;Adleff V;Jones S;Leary RJ;Barrett MT;Anagnostou V;Parpart-Li S;Murphy D;Kay Li Q;Hruban CA;Scharpf R;White JR;O'Dwyer PJ;Allen PJ;Eshleman JR;Thompson CB;Klimstra DS;Linehan DC;Maitra A;Hruban RH;Diaz LA Jr;Von Hoff DD;Johansen JS;Drebin JA;Velculescu VE
胰腺癌是所有实体癌症中死亡率最高的。在这项研究中，为了评估基因组改变在这种肿瘤类型中的临床意义，我们对24个肿瘤进行了全外显子分析，对77个肿瘤进行了有针对性的基因组分析，并使用非侵入性方法检查了这些患者循环中的肿瘤特异性突变。这些分析显示，在20%的患者中，染色质调节基因MLL、ML12、ML3和ARID1A发生了体细胞突变，这与提高存活率有关。我们在超过三分之一的病例中观察到具有潜在治疗效用的基因的变化。液体活检分析表明，43%的局部疾病患者在诊断时有可检测到的循环肿瘤DNA(CtDNA)。切除后检测ctDNA可预测临床复发和不良预后，ctDNA检测的复发时间比CT成像早6.5个月。这些观察结果提供了胰腺癌预后的遗传预测因子，并为治疗干预的新途径提供了启示。
Pancreatic adenocarcinoma has the worst mortality of any solid cancer. In this study, to evaluate the clinical implications of genomic alterations in this tumour type, we perform whole-exome analyses of 24 tumours, targeted genomic analyses of 77 tumours, and use non-invasive approaches to examine tumour-specific mutations in the circulation of these patients. These analyses reveal somatic mutations in chromatin-regulating genes MLL, MLL2, MLL3 and ARID1A in 20% of patients that are associated with improved survival. We observe alterations in genes with potential therapeutic utility in over a third of cases. Liquid biopsy analyses demonstrate that 43% of patients with localized disease have detectable circulating tumour DNA (ctDNA) at diagnosis. Detection of ctDNA after resection predicts clinical relapse and poor outcome, with recurrence by ctDNA detected 6.5 months earlier than with CT imaging. These observations provide genetic predictors of outcome in pancreatic cancer and have implications for new avenues of therapeutic intervention.