Alonso M Henar, Aussó Susanna, Lopez-Doriga Adriana, Cordero David, Guinó Elisabet, Solé Xavier, Barenys Mercè, de Oca Javier, Capella Gabriel, Salazar Ramón, Sanz-Pamplona Rebeca, Moreno Victor
Unit of Biomarkers and Susceptibility, Cancer Prevention and Control Program, Catalan Institute of Oncology (ICO), CIBERESP, Gran Via 199, Hospitalet Llobregat, 08908 Barcelona, Spain.
Molecular Mechanisms and Experimental Therapy Cancer Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
Br J Cancer. 2017 Jul 25;117(3):421-431. doi: 10.1038/bjc.2017.208. Epub 2017 Jul 6.
Somatic copy number aberrations (CNAs) are common acquired changes in cancer cells having an important role in the progression of colon cancer (colorectal cancer, CRC). This study aimed to perform a characterisation of CNA and their impact in gene expression.
Copy number aberrations were inferred from SNP array data in a series of 99 CRC. Copy number aberration events were calculated and used to assess the association between copy number dosage, clinical and molecular characteristics of the tumours, and gene expression changes. All analyses were adjusted for the quantity of stroma in each sample, which was inferred from gene expression data.
High heterogeneity among samples was observed; the proportion of altered genome ranged between 0.04 and 26.6%. Recurrent CNA regions with gains were frequent in chromosomes 7p, 8q, 13q, and 20, whereas 8p, 17p, and 18 cumulated losses. A significant positive correlation was observed between the number of somatic mutations and total CNA (Spearman's r=0.42, P=0.006). Approximately 37% of genes located in CNA regions changed their level of expression and the average partial correlation (adjusted for stromal content) with copy number was 0.54 (interquartile range 0.20 to 0.81). Altered genes showed enrichment in pathways relevant for CRC. Tumours classified as CMS2 and CMS4 by the consensus molecular subtyping showed higher frequency of CNA. Losses of one small region in 1p36.33, with gene CDK11B, were associated with poor prognosis. More than 66% of the recurrent CNA were validated in the The Cancer Genome Atlas (TCGA) data when analysed with the same procedure. Furthermore, 79% of the genes with altered expression in our data were validated in the TCGA.
Although CNA are frequent events in microsatellite stable CRC, few focal recurrent regions were found. These aberrations have strong effects on gene expression and contribute to deregulate relevant cancer pathways. Owing to the diploid nature of stromal cells, it is important to consider the purity of tumour samples to accurately calculate CNA events in CRC.
体细胞拷贝数变异（CNA）是癌细胞中常见的获得性改变，在结肠癌（结直肠癌，CRC）进展中起重要作用。本研究旨在对CNA进行特征描述及其对基因表达的影响。
从99例CRC的SNP阵列数据推断拷贝数变异。计算拷贝数变异事件，并用于评估拷贝数剂量、肿瘤的临床和分子特征以及基因表达变化之间的关联。所有分析均针对每个样本中的基质数量进行校正，该数量从基因表达数据推断得出。
观察到样本间高度异质性；基因组改变比例在0.04%至26.6%之间。染色体7p、8q、13q和20中频繁出现有增益的复发性CNA区域，而8p、17p和18累积有缺失。体细胞突变数量与总CNA之间观察到显著正相关（Spearman相关系数r=0.42，P=0.006）。位于CNA区域的约37%的基因改变了其表达水平，与拷贝数的平均偏相关（校正基质含量后）为0.54（四分位距0.20至0.81）。改变的基因在与CRC相关的通路中显示出富集。通过共识分子亚型分类为CMS2和CMS4的肿瘤显示出更高频率的CNA。1p36.33中一个小区域的缺失，伴有基因CDK11B，与预后不良相关。当采用相同程序分析时，超过66%的复发性CNA在癌症基因组图谱（TCGA）数据中得到验证。此外，我们数据中表达改变的基因有79%在TCGA中得到验证。
尽管CNA在微卫星稳定的CRC中是常见事件，但发现的局灶性复发性区域很少。这些畸变对基因表达有强烈影响，并导致相关癌症通路失调。由于基质细胞的二倍体性质，考虑肿瘤样本的纯度对于准确计算CRC中的CNA事件很重要。
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