Translational Gastrointestinal Oncology, Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Oncoproteomics Laboratory, Department of Medical Oncology, VU University Medical Centre, Amsterdam, The Netherlands.
J Pathol. 2018 Nov;246(3):266-276. doi: 10.1002/path.5129. Epub 2018 Aug 31.
Consensus molecular subtyping is an RNA expression-based classification system for colorectal cancer (CRC). Genomic alterations accumulate during CRC pathogenesis, including the premalignant adenoma stage, leading to changes in RNA expression. Only a minority of adenomas progress to malignancies, a transition that is associated with specific DNA copy number aberrations or microsatellite instability (MSI). We aimed to investigate whether colorectal adenomas can already be stratified into consensus molecular subtype (CMS) classes, and whether specific CMS classes are related to the presence of specific DNA copy number aberrations associated with progression to malignancy. RNA sequencing was performed on 62 adenomas and 59 CRCs. MSI status was determined with polymerase chain reaction-based methodology. DNA copy number was assessed by low-coverage DNA sequencing (n = 30) or array-comparative genomic hybridisation (n = 32). Adenomas were classified into CMS classes together with CRCs from the study cohort and from The Cancer Genome Atlas (n = 556), by use of the established CMS classifier. As a result, 54 of 62 (87%) adenomas were classified according to the CMS. The CMS3 'metabolic subtype', which was least common among CRCs, was most prevalent among adenomas (n = 45; 73%). One of the two adenomas showing MSI was classified as CMS1 (2%), the 'MSI immune' subtype. Eight adenomas (13%) were classified as the 'canonical' CMS2. No adenomas were classified as the 'mesenchymal' CMS4, consistent with the fact that adenomas lack invasion-associated stroma. The distribution of the CMS classes among adenomas was confirmed in an independent series. CMS3 was enriched with adenomas at low risk of progressing to CRC, whereas relatively more high-risk adenomas were observed in CMS2. We conclude that adenomas can be stratified into the CMS classes. Considering that CMS1 and CMS2 expression signatures may mark adenomas at increased risk of progression, the distribution of the CMS classes among adenomas is consistent with the proportion of adenomas expected to progress to CRC. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
共识分子亚型是一种基于 RNA 表达的结直肠癌（CRC）分类系统。在 CRC 发病过程中，包括癌前腺瘤阶段，基因组改变会导致 RNA 表达发生变化。只有少数腺瘤会发展为恶性肿瘤，这种转变与特定的 DNA 拷贝数异常或微卫星不稳定性（MSI）有关。我们旨在研究结直肠腺瘤是否已经可以分为共识分子亚型（CMS）类别，以及特定的 CMS 类别是否与与进展为恶性肿瘤相关的特定 DNA 拷贝数异常有关。对 62 个腺瘤和 59 个 CRC 进行了 RNA 测序。MSI 状态通过聚合酶链反应为基础的方法确定。通过低覆盖度 DNA 测序（n=30）或阵列比较基因组杂交（n=32）评估 DNA 拷贝数。通过使用已建立的 CMS 分类器，将腺瘤与研究队列和癌症基因组图谱（n=556）中的 CRC 一起分类为 CMS 类别。结果，62 个腺瘤中有 54 个（87%）根据 CMS 进行了分类。CMS3“代谢亚型”在 CRC 中最不常见，但在腺瘤中最为常见（n=45；73%）。两个 MSI 中的一个被分类为 CMS1（2%），“MSI 免疫”亚型。8 个腺瘤（13%）被分类为“经典”CMS2。没有腺瘤被分类为“间质”CMS4，这与腺瘤缺乏侵袭相关的基质一致。CMS 类别的分布在独立系列中得到了证实。CMS3 中腺瘤进展为 CRC 的风险较低，而 CMS2 中观察到相对更多的高危腺瘤。我们得出的结论是，腺瘤可以分为 CMS 类别。考虑到 CMS1 和 CMS2 表达特征可能标志着进展为 CRC 的风险增加的腺瘤，CMS 类别的分布与预期进展为 CRC 的腺瘤比例一致。
