Transcriptomic and proteomic intra-tumor heterogeneity of colorectal cancer varies depending on tumor location within the colorectum.
Transcriptomic and proteomic intra-tumor heterogeneity of colorectal cancer varies depending on tumor location within the colorectum.
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结直肠癌的转录组和蛋白质组学肿瘤内异质性因结直肠内的肿瘤位置而异。
DOI：
10.1371/journal.pone.0241148
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发表时间：
2020
期刊：
影响因子：
3.7
通讯作者：
Andersen CL
中科院分区：
文献类型：
--
作者：
Árnadóttir SS;Mattesen TB;Vang S;Madsen MR;Madsen AH;Birkbak NJ;Bramsen JB;Andersen CL
结直肠癌（CRC）的肿瘤内异质性（ITH）使分子肿瘤分类（如转录亚型）复杂化。细胞状态、活检细胞组成和肿瘤微环境的差异都可能导致ITH。在这里，我们在转录组和蛋白质组水平上分析ITH，以确定多区域活检之间的亚型不一致是否反映了相关的生物ITH或缺乏分类器稳健性。此外，我们研究了肿瘤位置对ITH的影响。通过RNA测序（41例活检，14例肿瘤）和多重免疫蛋白分析（89例活检，29例肿瘤）分析了II期和III期CRC肿瘤的多区域活检。使用共有分子亚型（CMS）、CRC内在亚型（CRIS）和TUMOR类型进行CRC亚型分型。定义了异质性评分和网络图，以确定异质性的来源。使用每个肿瘤一次活检的验证队列（162个肿瘤）。总的来说，肿瘤间转录变异超过ITH，并且多区域活检之间的分型呼叫经常是一致的。尽管如此，一些肿瘤具有高转录ITH，并且分类不一致。近端MSS肿瘤的亚型在50%的肿瘤中不一致，这种ITH与微环境的差异有关。远端MSS肿瘤的亚型不太一致，此处的ITH与癌细胞相关性更高。亚型不一致反映了肿瘤内的实际分子ITH。亚型的相关性反映在蛋白质水平上，其中几种炎症标志物在免疫相关转录亚型中显著增加，这在独立群组中得到验证（Wilcoxon秩和检验; p<0.05）。蛋白质数据的无监督分层聚类在蛋白质水平上识别出大ITH;因为多区域活检仅将29个肿瘤中的9个聚集在一起。我们的转录组学和蛋白质组学分析表明，肿瘤位置沿着结直肠影响结直肠癌的ITH，这又影响亚型的一致性。
Intra-tumor heterogeneity (ITH) of colorectal cancer (CRC) complicates molecular tumor classification, such as transcriptional subtyping. Differences in cellular states, biopsy cell composition, and tumor microenvironment may all lead to ITH. Here we analyze ITH at the transcriptomic and proteomic levels to ascertain whether subtype discordance between multiregional biopsies reflects relevant biological ITH or lack of classifier robustness. Further, we study the impact of tumor location on ITH. Multiregional biopsies from stage II and III CRC tumors were analyzed by RNA sequencing (41 biopsies, 14 tumors) and multiplex immune protein analysis (89 biopsies, 29 tumors). CRC subtyping was performed using consensus molecular subtypes (CMS), CRC intrinsic subtypes (CRIS), and TUMOR types. ITH-scores and network maps were defined to determine the origin of heterogeneity. A validation cohort was used with one biopsy per tumor (162 tumors). Overall, inter-tumor transcriptional variation exceeded ITH, and subtyping calls were frequently concordant between multiregional biopsies. Still, some tumors had high transcriptional ITH and were classified discordantly. Subtyping of proximal MSS tumors were discordant for 50% of the tumors, this ITH was related to differences in the microenvironment. Subtyping of distal MSS tumors were less discordant, here the ITH was more cancer-cell related. The subtype discordancy reflected actual molecular ITH within the tumors. The relevance of the subtypes was reflected at protein level where several inflammation markers were significantly increased in immune related transcriptional subtypes, which was verified in an independent cohort (Wilcoxon rank sum test; p<0.05). Unsupervised hierarchical clustering of the protein data identified large ITH at protein level; as the multiregional biopsies clustered together for only 9 out of 29 tumors. Our transcriptomic and proteomic analyses show that the tumor location along the colorectum influence the ITH of CRC, which again influence the concordance of subtyping.
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影响因子：
6.4
作者：
Berntsson J;Svensson MC;Leandersson K;Nodin B;Micke P;Larsson AH;Eberhard J;Jirström K
通讯作者：
Jirström K
DOI：
10.1038/nrmicro3552
发表时间：
2016-01
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
Donaldson GP;Lee SM;Mazmanian SK
通讯作者：
Mazmanian SK
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
8.8
作者：
Bramsen, Jesper Bertram;Rasmussen, Mads Heilskov;Andersen, Claus Lindbjerg
通讯作者：
Andersen, Claus Lindbjerg
影响因子：
16.6
作者：
Isella C;Brundu F;Bellomo SE;Galimi F;Zanella E;Porporato R;Petti C;Fiori A;Orzan F;Senetta R;Boccaccio C;Ficarra E;Marchionni L;Trusolino L;Medico E;Bertotti A
通讯作者：
Bertotti A