Oncology Research, Pfizer Worldwide Research and Development, San Diego, California, United States of America.
PLoS One. 2012;7(7):e42001. doi: 10.1371/journal.pone.0042001. Epub 2012 Jul 31.
To develop a comprehensive overview of copy number aberrations (CNAs) in stage-II/III colorectal cancer (CRC), we characterized 302 tumors from the PETACC-3 clinical trial. Microsatellite-stable (MSS) samples (n = 269) had 66 minimal common CNA regions, with frequent gains on 20 q (72.5%), 7 (41.8%), 8 q (33.1%) and 13 q (51.0%) and losses on 18 (58.6%), 4 q (26%) and 21 q (21.6%). MSS tumors have significantly more CNAs than microsatellite-instable (MSI) tumors: within the MSI tumors a novel deletion of the tumor suppressor WWOX at 16 q23.1 was identified (p<0.01). Focal aberrations identified by the GISTIC method confirmed amplifications of oncogenes including EGFR, ERBB2, CCND1, MET, and MYC, and deletions of tumor suppressors including TP53, APC, and SMAD4, and gene expression was highly concordant with copy number aberration for these genes. Novel amplicons included putative oncogenes such as WNK1 and HNF4A, which also showed high concordance between copy number and expression. Survival analysis associated a specific patient segment featured by chromosome 20 q gains to an improved overall survival, which might be due to higher expression of genes such as EEF1B2 and PTK6. The CNA clustering also grouped tumors characterized by a poor prognosis BRAF-mutant-like signature derived from mRNA data from this cohort. We further revealed non-random correlation between CNAs among unlinked loci, including positive correlation between 20 q gain and 8 q gain, and 20 q gain and chromosome 18 loss, consistent with co-selection of these CNAs. These results reinforce the non-random nature of somatic CNAs in stage-II/III CRC and highlight loci and genes that may play an important role in driving the development and outcome of this disease.
为了全面了解 II/III 期结直肠癌（CRC）中的拷贝数畸变（CNA），我们对 PETACC-3 临床试验中的 302 个肿瘤进行了特征分析。微卫星稳定（MSS）样本（n=269）有 66 个最小共同 CNA 区域，20q（72.5%）、7 号染色体（41.8%）、8q（33.1%）和 13q（51.0%）的增益较为频繁，而 18 号染色体（58.6%）、4q（26%）和 21q（21.6%）的缺失较为频繁。MSS 肿瘤的 CNA 明显多于微卫星不稳定（MSI）肿瘤：在 MSI 肿瘤中，鉴定到了位于 16q23.1 的肿瘤抑制因子 WW0X 的新型缺失（p<0.01）。GISTIC 方法确定的局灶性畸变证实了包括 EGFR、ERBB2、CCND1、MET 和 MYC 在内的癌基因的扩增，以及包括 TP53、APC 和 SMAD4 在内的肿瘤抑制因子的缺失，这些基因的表达与拷贝数畸变高度一致。新的扩增子包括潜在的癌基因，如 WNK1 和 HNF4A，它们在拷贝数和表达之间也有很高的一致性。生存分析将一个特定的患者亚段与染色体 20q 增益相关联，以改善整体生存率，这可能是由于 EEF1B2 和 PTK6 等基因的高表达所致。CNA 聚类还将肿瘤分为具有较差预后的 BRAF 突变样特征的组，该特征源自该队列的 mRNA 数据。我们进一步揭示了非连锁基因座之间 CNA 的非随机相关性，包括 20q 增益与 8q 增益之间的正相关，以及 20q 增益与 18 号染色体缺失之间的正相关，这与这些 CNA 的共同选择一致。这些结果强化了 II/III 期 CRC 中体细胞 CNA 的非随机性质，并突出了可能在推动该疾病的发展和结局中发挥重要作用的基因座和基因。
