Abstract
Array-based comparative genomic hybridization (aCGH) emerged as a powerful technology for studying copy number variations at higher resolution in many cancers including colorectal cancer. However, the lack of standardized systematic protocols including bioinformatic algorithms to obtain and analyze genomic data resulted in significant variation in the reported copy number aberration (CNA) data. Here, we present genomic aCGH data obtained using highly stringent and functionally relevant statistical algorithms from 116 well-defined microsatellites instable (MSI) and microsatellite stable (MSS) colorectal cancers. We utilized aCGH to characterize genomic CNAs in 116 well-defined sets of colorectal cancer (CRC) cases. We further applied the significance testing for aberrant copy number (STAC) and Genomic Identification of Significant Targets in Cancer (GISTIC) algorithms to identify functionally relevant (nonrandom) chromosomal aberrations in the analyzed colorectal cancer samples. Our results produced high resolution genomic landscapes of both, MSI and MSS sporadic CRC. We found that CNAs in MSI and MSS CRCs are heterogeneous in nature but may be divided into 3 distinct genomic patterns. Moreover, we show that although CNAs in MSI and MSS CRCs differ with respect to their size, number and chromosomal distribution, the functional copy number aberrations obtained from MSI and MSS CRCs were in fact comparable but not identical. These unifying CNAs were verified by MLPA tumor-loss gene panel, which spans 15 different chromosomal locations and contains 50 probes for at least 20 tumor suppressor genes. Consistently, deletion/amplification in these frequently cancer altered genes were identical in MSS and MSI CRCs. Our results suggest that MSI and MSS copy number aberrations driving CRC may be functionally comparable.
Highlights
Comparative genomics have been extensively used to identify DNA copy number variations in cancer
Chromosomal losses most frequently involved were chromosome arm 1p (71%), 8p (72%), 17p (55%), 22q (60%) and chromosomes 14 (77%), 15 (66%) and 18 (80%) (Fig 1). This data is consistent with previously published data from our and other groups [28,29,30,31,32,33,34]. These data represent a summation of all aberrations involved in colorectal cancer regardless of the type, stage, location and other molecular characteristics that may have a significant impact on the array-based comparative genomic hybridization (aCGH) data obtained
Genomic profiling in microsatellites instable (MSI) and microsatellite stable (MSS) sporadic colorectal cancer to identify copy number differences between MSS and MSI CRCs propagated the notion that these two subtypes of CRC are substantially different at the copy number level
Summary
Comparative genomics have been extensively used to identify DNA copy number variations in cancer. Metaphase-based comparative genomic hybridization (m-CGH), a technique of about 5 million bases resolution, was utilized to decipher chromosomal copy number changes in CRC progression. A plethora of studies used m-CGH to identify chromosomal imbalances in CRC, which included gain of chromosomes 1, 13 and 20 and chromosome arms 7p and 8q, whereas chromosome 4 and chromosome arms 8p and 10q were frequently deleted [2,3,4,5,6,7]. In 2004, array-based comparative genomic hybridization (aCGH) emerged as a more promising technology for studying copy number variations at higher resolutions even from formalin-fixed paraffin-embedded (FFPE) archived material [13,14,15,16,17]. Oligonucleotide-based aCGH is capable of identifying copy number alterations in few thousands of bases or smaller [18,19,20]
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