The molecular landscape of synchronous colorectal cancer reveals genetic heterogeneity.
The molecular landscape of synchronous colorectal cancer reveals genetic heterogeneity.
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同时结直肠癌的分子景观揭示了遗传异质性
DOI：
10.1093/carcin/bgy040
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发表时间：
2018-05-03
期刊：
影响因子：
4.7
通讯作者：
Liu B
中科院分区：
文献类型：
--
作者：
Wang X;Fang H;Cheng Y;Li L;Sun X;Fu T;Huang P;Zhang A;Feng Z;Li C;Huang X;Li G;Du P;Yang H;Fang X;Li F;Gao Q;Liu B
摘要同时性结直肠癌（synchronous colorectal cancers，syCRCs）是一种罕见的肿瘤，临床治疗面临着巨大的挑战。虽然一些与syCRCs相关的诱发因素已经在有限的登记中进行了研究，但是个体内病变中的基因组事件的全部谱和syCRCs的原因仍然不清楚。我们对来自20名患者的40个配对病变的手术肿瘤样本进行了全外显子组测序，以表征遗传改变。来自同一患者的病变显示出不同的体细胞畸变景观，并且共享很少的突变，这表明它们独立地起源和发展，尽管它们具有相似的遗传背景。典型基因如APC、KRAS、TP 53和PIK 3CA在syCRC中频繁突变，且大多数与孤立性结直肠癌的突变谱不同。我们在25%的syCRC中鉴定了RPL 22中的复发性体细胞改变（K15 fs）。功能分析表明，突变的RPL 22可以抑制细胞凋亡，促进上皮-间质转化（EMT）。在几个信号通路中确定了潜在的药物靶点，并且它们在同一患者的病变之间存在很大差异。我们的数据表明，同一患者体内的syCRCs存在很大的遗传异质性，它们可能由不同的分子事件驱动并独立发展。同一患者病变中潜在药物靶点和突变负荷的差异为syCRC患者的临床管理提供了有价值的信息。
Abstract Synchronous colorectal cancers (syCRCs), which present two or more lesions at diagnosis, are rare and pose a great challenge for clinical management. Although some predisposing factors associated with syCRCs have been studied with limited accession, the full repertoire of genomic events among the lesions within an individual and the causes of syCRCs remain unclear. We performed whole-exome sequencing of 40 surgical tumour samples of paired lesions from 20 patients to characterize the genetic alterations. Lesions from same patient showed distinct landscapes of somatic aberrations and shared few mutations, which suggests that they originate and develop independently, although they shared the similar genetic background. Canonical genes, such as APC, KRAS, TP53 and PIK3CA, were frequently mutated in the syCRCs, and most of them show different mutation profile compared with solitary colorectal cancer. We identified a recurrent somatic alteration (K15fs) in RPL22 in 25% of the syCRCs. Functional analysis indicated that mutated RPL22 may suppress cell apoptosis and promote the epithelial–mesenchymal transition (EMT). Potential drug targets were identified in several signalling pathways, and they present great discrepancy between lesions from the same patient. Our data show that the syCRCs within the same patient present great genetic heterogeneity, and they may be driven by distinct molecular events and develop independently. The discrepancy of potential drug targets and mutation burden in lesions from one patient provides valuable information in clinical management for patients with syCRCs.
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影响因子：
14.9
作者：
An O;Dall'Olio GM;Mourikis TP;Ciccarelli FD
通讯作者：
Ciccarelli FD
影响因子：
3.2
作者：
Kato T;Alonso S;Muto Y;Noda H;Miyakura Y;Suzuki K;Tsujinaka S;Saito M;Perucho M;Rikiyama T
通讯作者：
Rikiyama T
DOI：
10.1093/bioinformatics/btp698
发表时间：
2010-03-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Li H;Durbin R
通讯作者：
Durbin R
影响因子：
4.4
作者：
Nariai N;Kojima K;Saito S;Mimori T;Sato Y;Kawai Y;Yamaguchi-Kabata Y;Yasuda J;Nagasaki M
通讯作者：
Nagasaki M
DOI：
10.1084/jem.20131448
发表时间：
2013-10-21
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Fabbri G;Khiabanian H;Holmes AB;Wang J;Messina M;Mullighan CG;Pasqualucci L;Rabadan R;Dalla-Favera R
通讯作者：
Dalla-Favera R