VIB Center for Cancer Biology, VIB, Herestraat 49, 3000, Leuven, Belgium.
Department of Human Genetics, University of Leuven (KULeuven), Herestraat 49, 3000, Leuven, Belgium.
Nat Commun. 2018 Oct 5;9(1):4112. doi: 10.1038/s41467-018-06567-6.
Increased copy number alterations (CNAs) indicative of chromosomal instability (CIN) have been associated with poor cancer outcome. Here, we study CNAs as potential biomarkers of bevacizumab (BVZ) response in metastatic colorectal cancer (mCRC). We cluster 409 mCRCs in three subclusters characterized by different degrees of CIN. Tumors belonging to intermediate-to-high instability clusters have improved outcome following chemotherapy plus BVZ versus chemotherapy alone. In contrast, low instability tumors, which amongst others consist of POLE-mutated and microsatellite-instable tumors, derive no further benefit from BVZ. This is confirmed in 81 mCRC tumors from the phase 2 MoMa study involving BVZ. CNA clusters overlap with CRC consensus molecular subtypes (CMS); CMS2/4 xenografts correspond to intermediate-to-high instability clusters and respond to FOLFOX chemotherapy plus mouse avastin (B20), while CMS1/3 xenografts match with low instability clusters and fail to respond. Overall, we identify copy number load as a novel potential predictive biomarker of BVZ combination therapy.
提示染色体不稳定性（CIN）的拷贝数改变（CNAs）增加与癌症不良预后相关。在此，我们研究了 CNA 作为转移性结直肠癌（mCRC）贝伐珠单抗（BVZ）反应的潜在生物标志物。我们将 409 例 mCRC 聚类为三个亚群，这些亚群的 CIN 程度不同。与单独化疗相比，化疗加 BVZ 治疗后，具有中等至高不稳定性聚类的肿瘤具有更好的预后。相比之下，低不稳定性肿瘤（其中包括 POLE 突变和微卫星不稳定肿瘤）不会从 BVZ 中获得进一步获益。这在 MoMa 研究中涉及 BVZ 的 81 例 mCRC 肿瘤中得到了证实。CNA 聚类与 CRC 共识分子亚型（CMS）重叠；CMS2/4 异种移植物对应于中等至高不稳定性聚类，对 FOLFOX 化疗加小鼠阿瓦斯汀（B20）有反应，而 CMS1/3 异种移植物与低不稳定性聚类相匹配，并且没有反应。总的来说，我们确定了拷贝数负荷作为 BVZ 联合治疗的一种新的潜在预测生物标志物。
