Morphological characterization of colorectal cancers in The Cancer Genome Atlas reveals distinct morphology-molecular associations: clinical and biological implications.
Morphological characterization of colorectal cancers in The Cancer Genome Atlas reveals distinct morphology-molecular associations: clinical and biological implications.
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DOI：
10.1038/modpathol.2016.198
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发表时间：
2017-04
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影响因子：
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通讯作者：
Klimstra DS
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作者：
Shia J;Schultz N;Kuk D;Vakiani E;Middha S;Segal NH;Hechtman JF;Berger MF;Stadler ZK;Weiser MR;Wolchok JD;Boland CR;Gönen M;Klimstra DS
关于结直肠癌的癌症基因组图谱数据提供了肿瘤基因组改变及其致瘤作用的全面视图。然而，肿瘤形态学尚未完全整合到分析中。本研究的目的是探讨肿瘤形态学和大肠癌新特征基因组改变之间的相关性。作为The-Cancer-Genome-Atlas项目的一部分，207例结直肠癌接受了全外显子组测序，并在cBioPortal for Cancer Genomics http://www.cbioportal.org/中拥有足够的虚拟图像，构成了我们的研究人群。分析后，很容易检测到“微卫星不稳定性-高组织学”和微卫星不稳定性-高（p<.001）之间的紧密关联，并有助于验证我们基于图像的组织学评估。此外，我们显示：1）在所有组织学类型中，未另行指定的类型具有最低的总体突变计数（整个队列p<0.001，微卫星不稳定组p<0.03），在微卫星不稳定肿瘤中，这种类型也与一组确定的相关基因编码单核苷酸重复序列中的移码突变较少相关。（p<.01）2）有或无微卫星不稳定性的胞嘧啶磷酸鸟嘌呤岛甲基化因子表型高的结直肠癌倾向于具有不同的组织学类型：前者更多地为粘液性，后者更多地为非特异性; 3）与非粘液性组织学相比，粘液性组织学与BRAF、PIK 3CA和转化生长因子β途径的更频繁的改变相关（分别为p<0.001，p= 0.01和p<0.001）;和4）少数结肠直肠癌（<9%）表现出免疫抑制基因的上调，包括主要的免疫检查点;这些肿瘤主要是微卫星不稳定的（高达43%，相比之下，微卫星稳定组中<3%），并且具有明显的非粘液性组织学和固体生长。这些形态学-分子关联是有趣的，并提出了重要的临床意义。与免疫检查点基因改变相关的形态学模式有可能指导针对结直肠癌免疫检查点的临床试验的患者选择，并为未来的研究提供方向。
The-Cancer-Genome-Atlas data on colorectal carcinoma have provided a comprehensive view of the tumor’s genomic alterations and their tumorigenic roles. Tumor morphology, however, has not been fully integrated into the analysis. The aim of this study was to explore relevant associations between tumor morphology and the newly characterized genomic alterations in colorectal carcinoma. Two-hundred-and-seven colorectal carcinomas that had undergone whole exome sequencing as part of The-Cancer-Genome-Atlas project and had adequate virtual images in the cBioPortal for Cancer Genomics http://www.cbioportal.org/ constituted our study population. Upon analysis, a tight association between “microsatellite instability-high histology” and microsatellite instability-high (p<.001) was readily detected and helped validate our image-based histology evaluation. Further, we showed: 1) among all histologies, the not-otherwise-specified type had the lowest overall mutation count (p<.001 for entire cohort, p<.03 for the microsatellite instable group), and among the microsatellite instable tumors, this type also correlated with fewer frameshift mutations in coding mononucleotide repeats of a defined set of relevant genes (p<.01); 2) cytosine-phosphate-guanine-island-methylator-phenotype-high colorectal cancers with or without microsatellite instability tended to have different histological patterns: the former more often mucinous and the latter more often not-otherwise-specified; 3) mucinous histology was associated with more frequent alterations in BRAF, PIK3CA, and the transforming-growth-factor-beta pathway when compared to non-mucinous histologies (p<.001, p=.01, and p<0.001, respectively); and 4) few colorectal cancers (<9%) exhibited upregulation of immune inhibitory genes including major immune checkpoints; these tumors were primarily microsatellite instable (up to 43%, versus <3% in microsatellite-stable group) and had distinctly non-mucinous histologies with a solid growth. These morphology-molecular associations are interesting and propose important clinical implications. The morphological patterns associated with alterations of immune checkpoint genes bear the potential to guide patient selection for clinical trials that target immune checkpoints in colorectal cancer, and provide directions for future studies.