Multiregion sequencing reveals the intratumor heterogeneity of driver mutations in TP53-driven non-small cell lung cancer
Multiregion sequencing reveals the intratumor heterogeneity of driver mutations in TP53-driven non-small cell lung cancer
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多区域测序揭示了 TP53 驱动的非小细胞肺癌驱动突变的瘤内异质性。
DOI：
10.1002/ijc.30437
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发表时间：
2017-01-01
影响因子：
6.4
通讯作者：
Zheng, Cui-Xia
中科院分区：
文献类型：
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作者：
Zhang, Le-Le;Kan, Mengyuan;Zheng, Cui-Xia
非小细胞肺癌（NSCLC）中的瘤内异质性（ITH）可能是靶向治疗一段时间后耐药的原因，因为药物仅破坏部分肿瘤细胞。对ITH的识别有助于识别高风险患者，以做出有效的治疗决策。然而，ITH研究受到NSCLC患者间异质性和大量乘客突变的混淆。为了解决这些问题，我们招募了携带TP 53突变的NSCLC患者，并在NSCLC中的复发突变基因中选择了驱动突变。对总共12对正常肿瘤组织进行全基因组/全外显子组测序。从中，选择367个非沉默突变作为驱动突变，并在61个肿瘤内显微解剖中进行深度测序。我们发现在所有12种肿瘤中普遍存在异质性，表明分支进化。虽然在所有12个肿瘤的单次活检中观察到TP 53突变，但大多数肿瘤由同一肿瘤内不同区域的TP 53突变和非突变细胞组成。这表明获得TP 53突变的晚期分子时间;因此，在单个活检中检测TP 53突变可能根本不能反映早期恶性潜能。此外，我们确定了肿瘤711中TP 53和CDKN 2A突变周围的杂合性丢失区域，这些区域在不同区域样本中也表现出异质性。由于驱动突变的ITH可能具有临床后果，因此需要进一步努力限制ITH的影响并提高治疗效率，这将使接受靶向治疗的NSCLC患者受益。非小细胞肺癌（NSCLC）中的瘤内异质性（ITH）可能是靶向治疗期间耐药的原因。识别ITH可以帮助做出有效的治疗决策，但ITH研究迄今为止受到混杂因素的阻碍。为了减少患者间异质性和乘客突变的干扰，作者招募了具有TP 53突变的NSCLC患者并选择了潜在的驱动突变。他们在所有NSCLC肿瘤中发现了广泛的ITH驱动突变，并证明了大多数患者在肿瘤进展期间TP 53突变的晚期分子获得。数据强调了限制ITH对NSCLC靶向治疗影响的临床潜力。
Intratumor heterogeneity (ITH) in non-small cell lung cancer (NSCLC) may account for resistance after a period of targeted therapies because drugs destroy only a portion of tumor cells. The recognition of ITH helps identify high-risk patients to make effective treatment decisions. However, ITH studies are confounded by interpatient heterogeneity in NSCLC and a large amount of passenger mutations. To address these issues, we recruited NSCLC patients carrying TP53 mutations and selected driver mutations within recurrently mutated genes in NSCLC. A total of 12-paired normal-tumor tissues were subjected to whole-genome/whole-exome sequencing. From these, 367 non-silent mutations were selected as driver mutations and deeply sequenced in 61 intratumoral microdissections. We identified a universal prevalence of heterogeneity in all 12 tumors, indicating branched evolution. Although TP53 mutations were observed in single biopsy of all 12 tumors, most tumors consist of both TP53 mutated and non-mutated cells in separate regions within the same tumor. This suggests the late molecular timing of the acquisition of TP53 mutations; therefore, the detection of TP53 mutations in a single biopsy may simply not reflect the early malignant potential. In addition, we identified regions of loss of heterozygosity surrounding TP53 and CDKN2A mutations in tumor 711, which also exhibited heterogeneity in different regional samples. Because the ITH of driver mutations likely has clinical consequences, further efforts are needed to limit the impact of ITH and to improve therapeutic efficiency, which will benefit NSCLC patients receiving targeted treatments.What's new? Intratumor heterogeneity (ITH) in non-small cell lung cancer (NSCLC) may account for resistance during targeted treatment. Identifying ITH could help make effective treatment decisions, but ITH studies have so far been hampered by confounding factors. To reduce the interference of interpatient heterogeneity and passenger mutations, the authors recruited NSCLC patients with TP53 mutations and selected potential driver mutations. They identified extensive ITH of driver mutations in all NSCLC tumors and demonstrated the late molecular acquisition of TP53 mutation during tumor progression in most patients. The data highlight the clinical potential of limiting the impact of ITH for NSCLC targeted treatment.