Department of Hematology and Medical Oncology, Comprehensive Cancer Center Augsburg, University Medical Center Augsburg, Augsburg, Germany.
Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany.
Colorectal Dis. 2022 Feb;24(2):157-176. doi: 10.1111/codi.15946. Epub 2021 Nov 5.
Colorectal carcinomas (CRCs) progress through heterogeneous pathways. The aim of this study was to analyse whether or not the cytogenetic evolution of CRC is linked to tumour site, level of chromosomal imbalance and metastasis.
A set of therapy-naïve pT3 CRCs comprising 26 proximal and 49 distal pT3 CRCs was studied by combining immunohistochemistry of mismatch repair (MMR) proteins, microsatellite analyses and molecular karyotyping as well as clinical parameters.
A MMR deficient/microsatellite-unstable (dMMR/MSI-H) status was associated with location of the primary tumour proximal to the splenic flexure, and dMMR/MSI-H tumours presented with significantly lower levels of chromosomal imbalances compared with MMR proficient/microsatellite-stable (pMMR/MSS) tumours. Oncogenetic tree modelling suggested two evolutionary clusters characterized by dMMR/MSI-H and chromosomal instability (CIN), respectively, for both proximal and distal CRCs. In CIN cases, +13q, -18q and +20q were predicted as preferentially early events, and -1p, -4 -and -5q as late events. Separate oncogenetic tree models of proximal and distal cases indicated similar early events independent of tumour site. However, in cases with high CIN defined by more than 10 copy number aberrations, loss of 17p occurred earlier in cytogenetic evolution than in cases showing low to moderate CIN. Differences in the oncogenetic trees were observed for CRCs with lymph node and distant metastasis. Loss of 8p was modelled as an early event in node-positive CRC, while +7p and +8q comprised early events in CRC with distant metastasis.
CRCs characterized by CIN follow multiple, interconnected genetic pathways in line with the basic 'Vogelgram' concept proposed for the progression of CRC that places the accumulation of genetic changes at centre of tumour evolution. However, the timing of specific genetic events may favour metastatic potential.
结直肠癌（CRC）的进展涉及多种途径。本研究旨在分析CRC 的细胞遗传学演变是否与肿瘤部位、染色体失衡程度和转移有关。
通过联合错配修复（MMR）蛋白免疫组化、微卫星分析和分子核型分析以及临床参数，研究了一组未经治疗的 pT3 CRC，包括 26 例近端和 49 例远端 pT3 CRC。
MMR 缺陷/微卫星不稳定（dMMR/MSI-H）状态与脾曲附近的原发肿瘤位置相关，dMMR/MSI-H 肿瘤的染色体失衡程度明显低于 MMR 功能正常/微卫星稳定（pMMR/MSS）肿瘤。肿瘤发生树模型表明，近端和远端 CRC 分别存在两种进化簇，特征分别为 dMMR/MSI-H 和染色体不稳定性（CIN）。在 CIN 病例中，+13q、-18q 和+20q 被预测为早期优先事件，而-1p、-4 和-5q 为晚期事件。近端和远端病例的独立肿瘤发生树模型表明，早期事件与肿瘤部位无关。然而，在具有高 CIN（定义为超过 10 个拷贝数异常）的病例中，与具有低至中度 CIN 的病例相比，染色体进化中较早发生 17p 缺失。在具有淋巴结和远处转移的 CRC 中观察到肿瘤发生树的差异。8p 的缺失被建模为淋巴结阳性 CRC 的早期事件，而+7p 和+8q 包括远处转移的 CRC 的早期事件。
具有 CIN 特征的 CRC 遵循多种相互关联的遗传途径，符合基本的“Vogelgram”概念，该概念将遗传变化的积累置于肿瘤进化的中心。然而，特定遗传事件的时间可能有利于转移潜力。
