de Groen Florence L M, Krijgsman Oscar, Tijssen Marianne, Vriend Lianne E M, Ylstra Bauke, Hooijberg Erik, Meijer Gerrit A, Steenbergen Renske D M, Carvalho Beatriz
Department of Pathology, VU University Medical Center, PO Box 7057, 1007MB, Amsterdam, The Netherlands.
Genes Chromosomes Cancer. 2014 Apr;53(4):339-48. doi: 10.1002/gcc.22144. Epub 2014 Jan 29.
Colorectal cancer (CRC) development is in most cases marked by the accumulation of genomic alterations including gain of the entire q-arm of chromosome 13. This aberration occurs in 40%-60% of all CRC and is associated with progression from adenoma to carcinoma. To date, little is known about the effect of the 13q amplicon on the expression of the therein located genes and their functional relevance. We therefore aimed to identify candidate genes at the 13q amplicon that contribute to colorectal adenoma to carcinoma progression in a gene dosage-dependent manner. Integrative analysis of whole genome expression and DNA copy number signatures resulted in the identification of 36 genes on 13q of which significant overexpression in carcinomas compared with adenomas was linked to a copy number gain. Five genes showing high levels of overexpression in carcinomas versus adenomas were further tested by quantitative reverse transcription-PCR in two independent sample sets of colorectal tumors (n = 40 and n = 47). DIS3 and LRCH1 revealed significant overexpression in carcinomas compared with adenomas in a 13q gain dependent manner. Silencing of DIS3 affected important tumorigenic characteristics such as viability, migration, and invasion. In conclusion, significant overexpression of DIS3 and LRCH1 associated with adenoma to carcinoma progression is linked to the CRC specific gain of 13q. The functional relevance of this copy number aberration was corroborated for DIS3, thereby identifying this gene as novel candidate oncogene contributing to the 13q-driven adenoma to carcinoma progression.
在大多数情况下，结直肠癌（CRC）的发展以基因组改变的积累为特征，包括13号染色体整个长臂的增加。这种畸变发生在所有CRC的40%-60%中，并与从腺瘤到癌的进展相关。迄今为止，关于13q扩增子对其中所定位基因的表达及其功能相关性的影响知之甚少。因此，我们旨在鉴定13q扩增子上以基因剂量依赖方式促进结直肠腺瘤向癌进展的候选基因。对全基因组表达和DNA拷贝数特征的综合分析导致在13q上鉴定出36个基因，其中与腺瘤相比癌中的显著过表达与拷贝数增加有关。通过定量逆转录PCR在两个独立的结直肠肿瘤样本集（n = 40和n = 47）中进一步测试了五个在癌与腺瘤中显示高过表达水平的基因。与腺瘤相比，DIS3和LRCH1在癌中以13q增加依赖的方式显示出显著过表达。DIS3的沉默影响了重要的致瘤特征，如活力、迁移和侵袭。总之，与腺瘤向癌进展相关的DIS3和LRCH1的显著过表达与CRC特异性的13q增加有关。对于DIS3，这种拷贝数畸变的功能相关性得到了证实，从而将该基因鉴定为促成13q驱动的腺瘤向癌进展的新型候选癌基因。
