Dalmasso Cyril, Carpentier Wassila, Guettier Catherine, Camilleri-Broët Sophie, Borelli Wyllians Vendramini, Campos Dos Santos Cedália Rosane, Castaing Denis, Duclos-Vallée Jean-Charles, Broët Philippe
Laboratoire de Mathématiques et Modélisation d'Evry (LaMME), Université d'Evry Val d'Essonne, UMR CNRS 8071, USC INRA, Evry, France.
Plate-forme Post-Génomique P3S, UPMC, Faculté de Médecine, Paris, France.
BMC Cancer. 2015 Mar 14;15:126. doi: 10.1186/s12885-015-1111-6.
Intrahepatic cholangiocarcinomas (ICC) are relatively rare malignant tumors associated with a poor prognosis. Recent studies using genome-wide sequencing technologies have mainly focused on identifying new driver mutations. There is nevertheless a need to investigate the spectrum of copy number aberrations in order to identify potential target genes in the altered chromosomal regions. The aim of this study was to characterize the patterns of chromosomal copy-number alterations (CNAs) in ICC.
53 patients having ICC with frozen material were selected. In 47 cases, DNA hybridization has been performed on a genomewide SNP array. A procedure with a segmentation step and a calling step classified genomic regions into copy-number aberration states. We identified the exclusively amplified and deleted recurrent genomic areas. These areas are those showing the highest estimated propensity level for copy loss (resp. copy gain) together with the lowest level for copy gain (resp. copy loss). We investigated ICC clustering. We analyzed the relationships between CNAs and clinico-pathological characteristics.
The overall genomic profile of ICC showed many alterations with higher rates for the deletions. Exclusively deleted genomic areas were 1p, 3p and 14q. The main exclusively amplified genomic areas were 1q, 7p, 7q and 8q. Based on the exclusively deleted/amplified genomic areas, a clustering analysis identified three tumors groups: the first group characterized by copy loss of 1p and copy gain of 7p, the second group characterized by 1p and 3p copy losses without 7p copy gain, the last group characterized mainly by very few CNAs. From univariate analyses, the number of tumors, the size of the largest tumor and the stage were significantly associated with shorter time recurrence. We found no relationship between the number of altered cytobands or tumor groups and time to recurrence.
This study describes the spectrum of chromosomal aberrations across the whole genome. Some of the recurrent exclusive CNAs harbor candidate target genes. Despite the absence of correlation between CNAs and clinico-pathological characteristics, the co-occurence of 7p gain and 1p loss in a subgroup of patients may suggest a differential activation of EGFR and its downstream pathways, which may have a potential effect on targeted therapies.
肝内胆管癌（ICC）是相对罕见的恶性肿瘤，预后较差。近期使用全基因组测序技术的研究主要集中于识别新的驱动突变。然而，仍有必要研究拷贝数变异谱，以确定染色体区域改变中的潜在靶基因。本研究的目的是描述ICC中染色体拷贝数改变（CNA）的模式。
选取53例有冷冻组织的ICC患者。47例患者进行了全基因组SNP阵列DNA杂交。通过一个分段步骤和一个识别步骤的程序将基因组区域分类为拷贝数变异状态。我们识别了仅扩增和仅缺失的复发性基因组区域。这些区域是显示出最高估计拷贝数丢失（分别为拷贝数增加）倾向水平以及最低拷贝数增加（分别为拷贝数丢失）水平的区域。我们研究了ICC聚类情况。分析了CNA与临床病理特征之间的关系。
ICC的总体基因组图谱显示出许多改变，缺失发生率更高。仅缺失的基因组区域为1p、3p和14q。主要的仅扩增基因组区域为1q、7p、7q和8q。基于仅缺失/扩增的基因组区域，聚类分析确定了三个肿瘤组：第一组特征为1p拷贝数丢失和7p拷贝数增加；第二组特征为1p和3p拷贝数丢失且无7p拷贝数增加；最后一组主要特征为极少的CNA。单因素分析显示，肿瘤数量、最大肿瘤大小和分期与较短的复发时间显著相关。我们未发现改变的细胞带数量或肿瘤组与复发时间之间存在关联。
本研究描述了全基因组的染色体畸变谱。一些复发性的独特CNA包含候选靶基因。尽管CNA与临床病理特征之间缺乏相关性，但一部分患者中7p增加和1p丢失的同时出现可能提示表皮生长因子受体（EGFR）及其下游通路的差异激活，这可能对靶向治疗有潜在影响。
