Targeted sequencing reveals genetic variants associated with sensitivity of 79 human cancer xenografts to anticancer drugs.
Targeted sequencing reveals genetic variants associated with sensitivity of 79 human cancer xenografts to anticancer drugs.
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靶向测序揭示了与79种人类癌异种移植对抗癌药物的敏感性相关的遗传变异。
DOI：
10.3892/etm.2017.5533
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发表时间：
2018-03
影响因子：
2.7
通讯作者：
Zembutsu H
中科院分区：
文献类型：
--
作者：
Udagawa C;Sasaki Y;Suemizu H;Ohnishi Y;Ohnishi H;Tokino T;Zembutsu H
虽然已经从“一刀切”的细胞毒性方法发展到个性化的分子医学，但大多数癌症患者接受使用细胞毒性抗癌药物的化疗。在本研究中，使用从植入裸鼠体内的人癌异种移植物中提取的59个DNA序列对409个癌症相关基因进行测序分析，并检查了其中对9种细胞毒性抗癌药物[5-氟尿嘧啶、尼莫司汀、阿霉素、环磷酰胺、顺铂、丝裂霉素C（MMC）、甲氨蝶呤、长春新碱（VCR）和长春碱]的敏感性。本研究调查了异种移植物对9种抗癌药物的敏感性与单核苷酸变异（SNV）频率之间的关系。并对上述异种移植物中基因表达水平与对9种药物敏感性之间的相关性进行了估计。在使用59个异种移植物的筛选研究中，3个SNV（PMS 1同源物2，错配修复系统组分中的rs 1805321、rs62456182和LDL受体相关蛋白1B中的rs 13382825）分别与VCR和MMC敏感性相关（P<0.001）。随后进行了596个SNV的复制研究，这表明在使用20个异种移植物的独立样品的筛选研究中P<0.05。筛选和复制研究的综合结果表明，35个SNV可能与对9种抗癌药物中的一种或多种的敏感性相关（P组合=0.0011-0.035）。在35个SNV中，白血病抑制因子受体α和粘附G蛋白偶联受体A2中的rs 16903989和rs 201432181通常分别与对2种或4种抗癌药物的敏感性相关。这些发现提供了新的见解，可能有利于未来癌症患者个性化抗癌治疗的发展。
Although there has been progress moving from a ‘one-size-fits-all’ cytotoxic approach to personalized molecular medicine, the majority of patients with cancer receive chemotherapy using cytotoxic anticancer drugs. The sequencing analysis of 409 genes associated with cancer was conducted in the present study using 59 DNA sequences extracted from human cancer xenografts implanted into nude mice, of which sensitivity to 9 cytotoxic anticancer drugs [5-fluorouracil, nimustine, adriamycin, cyclophosphamide, cisplatin, mitomycin C (MMC), methotrexate, vincristine (VCR), and vinblastine] was examined. The present study investigated the association between the sensitivities of the xenografts to the 9 anticancer drugs and the frequency of single nucleotide variants (SNV). The correlation between the expression level of the genes and sensitivities to the 9 drugs in the above xenografts was also estimated. In the screening study using 59 xenografts, 3 SNVs (rs1805321, rs62456182 in PMS1 Homolog 2, Mismatch Repair System Component and rs13382825 in LDL Receptor Related Protein 1B), were associated with sensitivity to VCR and MMC, respectively (P<0.001). A replication study of 596 SNVs was subsequently performed, which indicated P<0.05 in the screening study using independent samples of 20 xenografts. A combined result of the screening and replication studies indicated that 35 SNVs were potentially associated with sensitivities to one or more of the nine anticancer drugs (Pcombined=0.0011–0.035). Of the 35 SNVs, rs16903989 and rs201432181 in Leukemia Inhibitory Factor Receptor α and Adhesion G Protein-Coupled Receptor A2 were commonly associated with sensitivity to 2 or 4 anticancer drugs, respectively. These findings provide novel insights which may benefit the development of personalized anticancer therapy for patients with cancer in the future.
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影响因子：
5.2
作者：
Loomans HA;Andl CD
通讯作者：
Andl CD
影响因子：
82.9
作者：
通讯作者：
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影响因子：
3.7
作者：
Botticelli, Andrea;Borro, Marina;Mazzuca, Federica
通讯作者：
Mazzuca, Federica
转运蛋白有机阳离子转运蛋白 2 (OCT2)、多药和毒素挤出 1 (MATE1) 和 ATP 结合盒亚家族 C 成员 2 (ABCC2) 的遗传多态性与非 SM 患者铂类化疗反应和毒性的关联
影响因子：
--
作者：
Qian CY;Zheng Y;Wang Y;Chen J;Liu JY;Zhou HH;Yin JY;Liu ZQ
通讯作者：
Liu ZQ
TGFβ 信号的背景
DOI：
10.1038/nrm3434
发表时间：
2012-10
期刊：
Nature reviews. Molecular cell biology
影响因子：
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作者：
通讯作者：
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