Department of Molecular Medicine (MOMA), Aarhus University Hospital, Skejby, Aarhus N, Denmark.
Int J Cancer. 2011 Oct 15;129(8):1848-58. doi: 10.1002/ijc.25841. Epub 2011 Mar 11.
Genomic alterations play important roles in colorectal cancer (CRC) carcinogenesis. Here, we aimed to identify and characterize recurrent copy-number alterations (CNAs) associated with clinical outcome of CRC by the use of single nucleotide polymorphism arrays, genomic quantitative PCR (qPCR) and fluorescence in situ hybridization (FISH). Colorectal neoplasia specimens and paired germline samples from 144 patients (40 adenomas and 104 carcinomas) as well as 40 CRC cell lines were investigated. This large dataset revealed frequent loss, including homozygous loss, at chr16p13.2 (from 5.9 to 7.42Mb). The loss was observed in 30% of adenomas and even more frequently in carcinomas, 56%, indicating that the loss define a subset of adenomas with a propensity for invasion. Consistent with this, the loss occurred twice as frequent in villous (40%) as in tubular adenomas (20%). The loss occurred independently of microsatellite stability and could be validated by qPCR in an independent sample cohort (n = 71). In Stage II/III, microsatellite stable (MSS) CRC it was associated with poor recurrence free survival (hazard ratio 2.4; p = 0.02; Multivariate Cox regression analysis). No transcriptional consequences of the losses were observed, and the only gene, A2BP1, located in the region showed no mutations. Correlation with other CNAs was established for chr3p22 in carcinomas and chr20p (inverse) in adenomas. FISH documented the chr16p13.2 region to be involved in complex structural rearrangements that included translocation to chr3p22 in some cases. The findings indicate that structural rearrangements involving chr16p13.2 are very frequent in colorectal neoplasia, often lead to homozygous deletion, and are associated with poor clinical outcome.
基因组改变在结直肠癌 (CRC) 的发生发展中起着重要作用。在这里，我们旨在通过使用单核苷酸多态性微阵列、基因组定量 PCR (qPCR) 和荧光原位杂交 (FISH) 来鉴定和描述与 CRC 临床结果相关的复发性拷贝数改变 (CNA)。研究了来自 144 名患者（40 个腺瘤和 104 个癌）以及 40 个 CRC 细胞系的结直肠肿瘤标本和配对的种系样本。这个大数据集显示了频繁的缺失，包括 chr16p13.2（从 5.9 到 7.42Mb）的纯合缺失。这种缺失在 30%的腺瘤中观察到，在癌中甚至更常见，为 56%，表明缺失定义了具有侵袭倾向的腺瘤亚群。与此一致的是，绒毛状腺瘤（40%）中缺失的频率是管状腺瘤（20%）的两倍。这种缺失与微卫星不稳定性无关，可以在独立的样本队列（n=71）中通过 qPCR 验证。在 II/III 期，微卫星稳定（MSS）CRC 中，它与无复发生存不良相关（危险比 2.4；p=0.02；多变量 Cox 回归分析）。未观察到缺失的转录后果，并且位于该区域的唯一基因 A2BP1 没有突变。在癌中，与 chr3p22 相关，在腺瘤中，与 chr20p（反向）相关。FISH 记录到 chr16p13.2 区域涉及复杂的结构重排，在某些情况下包括易位到 chr3p22。这些发现表明，涉及 chr16p13.2 的结构重排在结直肠肿瘤中非常常见，通常导致纯合缺失，并与不良的临床结果相关。
