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Morphological characterization of colorectal cancers in The Cancer Genome Atlas reveals distinct morphology-molecular associations: clinical and biological implications.

癌症基因组图谱中结直肠癌的形态特征揭示了明确的形态-分子关联:临床和生物学意义。

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
阅读:1104 Modern PathologyApr 2017; 30 (4): 472 - 629:599-609 

Abstract

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 constituted our study population. Upon analysis, a tight association between 'microsatellite instability-high histology' and microsatellite instability-high (P<0.001) 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<0.001 for entire cohort, P<0.03 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<0.01); (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-β pathway when compared with non-mucinous histologies (P<0.001, P=0.01, 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%, vs <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.

摘要

结直肠癌的癌症基因组图谱数据提供了有关肿瘤基因组改变与其致瘤作用间的综合探索。但是,肿瘤的形态没有被完全整合到分析中。本研究的目的是探讨结直肠癌的肿瘤形态与最近发现具有特征性基因组改变之间的相关性。207例结直肠癌患者,作为癌症基因组图谱项目的一部分已经进行了全基因组测序,且在癌症基因组学的cBioPortal上有足够的虚拟图像,构成了我们的研究人群。经分析,微卫星不稳定性高的组织学和微卫星不稳定性高之间的紧密联系(P<0.001)很明确,并帮助验证我们基于图像的组织学评价。此外,我们发现: (1)在所有的组织学类型中,非特殊类型的总突变数最低(整个队列P<0.001,微卫星不稳定组P<0.03),在微卫星不稳定的肿瘤中, 这种类型与一组编码单核苷酸重复基因所定义移码突变较少具有相关性 (P<0.01); (2)胞嘧啶-磷酸鸟嘌呤岛甲基化表型高的结直肠癌,伴或不伴微卫星不稳定性,往往有不同的组织学类型:前者常为黏液性的,而后者常为非特殊类型的; (3)与非粘液性组织学相比,粘液性的组织学常与BRAF、PIK3CA和转化生长因子-β通路突变较多有关(P值分别为P<0.001,P = 0.01,P<0.001);(4)少数结直肠癌(<9%)显示包括主要免疫检查点在内的免疫抑制基因上调;这些肿瘤主要是微卫星不稳定的(高达43%,微卫星稳定组<3%)和具有实性生长模式的、组织学明显为非粘液性的肿瘤。这些形态-分子相关性是有趣的,并具有重要的临床意义。与免疫检查点基因改变相关的形态模式对患者选择免疫检查点靶向治疗的临床试验具有潜在指导作用, 并为今后的研究提供了方向。

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