Camps Jordi, Armengol Gemma, del Rey Javier, Lozano Juan José, Vauhkonen Hanna, Prat Esther, Egozcue Josep, Sumoy Lauro, Knuutila Sakari, Miró Rosa
Laboratory of Cytogenetics, Departament de Biologia Cellular, Fisiologia i Immunologia and Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.
Carcinogenesis. 2006 Mar;27(3):419-28. doi: 10.1093/carcin/bgi244. Epub 2005 Nov 4.
Genomic copy number changes are frequently found in cancers and they have been demonstrated to contribute to carcinogenesis; and it is widely accepted that tumors with microsatellite instability (MSI) are genetically stable and mostly diploid. In the present study we compared the copy number alterations and the gene-expression profiles of microsatellite stable (MSS) and MSI colorectal tumors. A total number of 31 fresh-frozen primary tumors (16 MSS and 15 MSI) were used. Twenty-eight samples (15 MSS and 13 MSI) were analyzed with metaphase comparative genomic hybridization (CGH), nine of which plus one additional sample (4 MSS and 6 MSI) were further analyzed by cDNA-based array-CGH. Gene expression analysis was performed with six samples [3 MSS and 3 MSI, four of these used in metaphase CGH (mCGH) analysis] to identify differentially expressed genes possibly located in the lost or amplified regions found by CGH, stressing the biological significance of copy number changes. Metaphase and array-CGH analysis of two colon cancer cell lines (HTC116 and SW480, reported as MSI and MSS archetypes) gave comparable results. Alterations found by mCGH in MSS tumors were +20, +8q, -8p and -18q. Interestingly, 1p22, 4q26 and 15q21 were found deleted preferentially in MSS tumors, while 22q13 was found gained in MSI tumors. The regions of alterations identified by array-CGH were gains at 8q24, 16q24.3 and 20q13, and the loss of 5q21, appearing in the both types of tumors. Gene expression analysis revealed genes with specific associations with the copy number changes of the corresponding genomic regions. As a conclusion, colorectal cancer is a heterogeneous disease, demonstrated by the genomic profiles of individual samples. However, our data shows that copy number changes do not occur exclusively in the MSS phenotypes.
基因组拷贝数变化在癌症中经常被发现，并且已被证明与致癌作用有关；普遍认为，微卫星不稳定（MSI）的肿瘤在基因上是稳定的，且大多为二倍体。在本研究中，我们比较了微卫星稳定（MSS）和MSI结直肠肿瘤的拷贝数改变及基因表达谱。共使用了31例新鲜冷冻的原发性肿瘤（16例MSS和15例MSI）。28个样本（15例MSS和13例MSI）采用中期比较基因组杂交（CGH）进行分析，其中9个样本加1个额外样本（4例MSS和6例MSI）进一步通过基于cDNA的芯片CGH进行分析。对6个样本[3例MSS和3例MSI，其中4个用于中期CGH（mCGH）分析]进行基因表达分析，以鉴定可能位于CGH发现的缺失或扩增区域的差异表达基因，强调拷贝数变化的生物学意义。对两种结肠癌细胞系（HTC116和SW480，分别作为MSI和MSS原型）进行中期和芯片CGH分析，结果具有可比性。mCGH在MSS肿瘤中发现的改变为+20、+8q、-8p和-18q。有趣的是，1p22、4q26和15q21在MSS肿瘤中优先被发现缺失，而22q13在MSI肿瘤中被发现增加。芯片CGH鉴定出的改变区域为8q24、16q24.3和20q13的增益以及5q21的缺失，这两种类型的肿瘤中均出现。基因表达分析揭示了与相应基因组区域拷贝数变化具有特定关联的基因。总之，结直肠癌是一种异质性疾病，这在个体样本的基因组图谱中得到了证明。然而，我们的数据表明，拷贝数变化并非仅发生在MSS表型中。
