Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.
Cancer Computational Biology Center, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.
Nat Commun. 2021 Jan 25;12(1):574. doi: 10.1038/s41467-020-20887-6.
In contrast to primary colorectal cancer (CRC) little is known about the genomic landscape of metastasized CRC. Here we present whole genome sequencing data of metastases of 429 CRC patients participating in the pan-cancer CPCT-02 study (NCT01855477). Unsupervised clustering using mutational signature patterns highlights three major patient groups characterized by signatures known from primary CRC, signatures associated with received prior treatments, and metastasis-specific signatures. Compared to primary CRC, we identify additional putative (non-coding) driver genes and increased frequencies in driver gene mutations. In addition, we identify specific genes preferentially affected by microsatellite instability. CRC-specific 1kb-10Mb deletions, enriched for common fragile sites, and LINC00672 mutations are associated with response to treatment in general, whereas FBXW7 mutations predict poor response specifically to EGFR-targeted treatment. In conclusion, the genomic landscape of mCRC shows defined changes compared to primary CRC, is affected by prior treatments and contains features with potential clinical relevance.
与原发性结直肠癌（CRC）相比，转移性 CRC 的基因组图谱知之甚少。在这里，我们展示了 429 名参与泛癌 CPCT-02 研究（NCT01855477）的 CRC 患者转移灶的全基因组测序数据。使用突变特征模式进行无监督聚类突出了三个主要的患者群体，这些群体的特征是来自原发性 CRC 的特征、与已接受的治疗相关的特征以及转移特异性特征。与原发性 CRC 相比，我们确定了更多潜在的（非编码）驱动基因，并增加了驱动基因突变的频率。此外，我们还确定了特定基因易受微卫星不稳定性影响的情况。CRC 特异性的 1kb-10Mb 缺失，富含常见脆性位点，以及 LINC00672 突变与总体治疗反应相关，而 FBXW7 突变则特异性预测 EGFR 靶向治疗的不良反应。总之，与原发性 CRC 相比，mCRC 的基因组图谱显示出明确的变化，受先前治疗的影响，并包含具有潜在临床意义的特征。
