Institute of Pathology, University Medicine of Rostock, 18055 Rostock, Germany.
Clinic for Hematology, Oncology and Palliative Care, University Medical Center Rostock, University of Rostock, D-18057 Rostock, Germany.
Hum Pathol. 2018 Apr;74:54-63. doi: 10.1016/j.humpath.2017.12.015. Epub 2018 Jan 4.
Progression of solid cancers, colorectal carcinomas among them, from their primaries to metastatic lesions traditionally is thought to proceed by a stepwise acquisition of and selection for genomic aberrations. To test if patterns of genomic aberrations would be consistent with this model, we studied 10 colorectal carcinoma primary-metastasis pairs, 9 with 1 liver metastasis each and 1 with 2 metastases. Next-generation targeted sequencing (50-gene panel) with samples obtained from different regions of the primaries and their metastases demonstrated 1-11 gene mutations per lesion. But only in 2 tumors were there seen mutations in all samples from the metastasis and not any of the primaries (BRAF and SMARCB1 mutation, respectively). However, allelotyping the multiregional samples with polymorphous microsatellite markers (17p13.1, D9S942, D9S1748, D5S346, D5S1385) and DNA methylation studies with a marker panel (MLH1, CDNK2A, NEUROG1, CRABP1, CACNA1G, IGF2, RUNX3, SOCS1) showed remarkably "insular" genomic aberrations in all cases for at least some of the analyses. The marked preponderance of mutations shared by the primaries and their metastases throughout the lesions over mutations private to metastases suggests that, at least in many cases, colorectal carcinomas might be endowed with a mutational load sufficient for fully fledged metastases even at a very early stage ("born bad"). But the very focal allelic imbalances and methylations observed here, hypothetically, could play a role in clinically metastasizing disease, a process of years rather than months and very much a matter of tumor-host interactions when tumor cells adapt to the host microenvironment.
实体瘤的进展，包括结直肠癌，传统上被认为是通过逐步获得和选择基因组异常来从原发性肿瘤转移到转移性病变。为了测试基因组异常的模式是否与该模型一致，我们研究了 10 对结直肠癌原发灶-转移灶，其中 9 对各有 1 个肝转移灶，1 对有 2 个转移灶。对原发灶和转移灶不同部位样本进行的下一代靶向测序（50 个基因panel）显示，每个病变有 1-11 个基因突变。但只有在 2 个肿瘤中，在转移灶的所有样本中都发现了突变，而在任何原发性肿瘤中都没有（分别为 BRAF 和 SMARCB1 突变）。然而，使用多态性微卫星标记（17p13.1、D9S942、D9S1748、D5S346、D5S1385）对多区域样本进行等位基因分型，以及使用标记面板（MLH1、CDNK2A、NEUROG1、CRABP1、CACNA1G、IGF2、RUNX3、SOCS1）进行 DNA 甲基化研究表明，在所有情况下，至少在某些分析中，肿瘤内的基因组异常都非常“孤立”。在所有病变中，原发性肿瘤及其转移灶共享的突变明显多于转移灶特有的突变，这表明，至少在许多情况下，结直肠癌可能具有足够的突变负荷，即使在非常早期阶段也能完全形成转移灶（“天生坏”）。但这里观察到的等位基因失衡和甲基化非常局限，假设在肿瘤细胞适应宿主微环境时，它们可能在临床上转移的疾病中发挥作用，这个过程需要数年而不是数月，而且非常依赖于肿瘤-宿主相互作用。
