Response to drug therapy in individual colorectal cancer (CRC) patients is associated with tumour biology. Here we describe the genomic landscape of tumour samples of a homogeneous well-annotated series of patients with metastatic CRC (mCRC) of two phase III clinical trials, CAIRO and CAIRO2. DNA copy number aberrations of 349 patients are determined. Within three treatment arms, 194 chromosomal subregions are associated with progression-free survival (PFS; uncorrected single-test P-values <0.005). These subregions are filtered for effect on messenger RNA expression, using an independent data set from The Cancer Genome Atlas which returned 171 genes. Three chromosomal regions are associated with a significant difference in PFS between treatment arms with or without irinotecan. One of these regions, 6q16.1–q21, correlates in vitro with sensitivity to SN-38, the active metabolite of irinotecan. This genomic landscape of mCRC reveals a number of DNA copy number aberrations associated with response to drug therapy.
Array comparative genomic hybridization (array CGH) is widely used for studying chromosomal copy number aberrations (CNAs) on a genome-wide and high-resolution scale in heritable disorders and cancers. The aim of this study was to test if the separate channels of dual channel arrays can be interchanged (across array) to either make array CGH more sensitive and cost effective and/or to generate profiles of CNAs and copy number variations (CNVs). Therefore the BT474 breast cancer cell line was compared with a mix of normal reference DNAs hybridized on different arrays and days and DNA copy number profiles were evaluated. Quality was assessed, using regular dual channel array CGH as a standard, using four quality measures, i.e., the median absolute deviation value of chromosome 2, the amplitude of the ERBB2 gene amplification, a deletion on chromosome 9, and the deflection on chromosome 8. The quality of the across array CGH profiles matched or even surpassed the quality of regular dual channel array CGH. In addition, this across array approach was tested for genomic DNA derived from formalin-fixed paraffin-embedded tumors tissue samples, resulting in high-quality copy number profiles, comparable to regular dual channel arrays. Finally, we demonstrated this approach to obtain both CNA and CNV profiles. In summary, across array CGH avoids redundant hybridizations of the same reference material in every experiment either allowing hybridization of two test samples on one array or producing both CNA and CNV profiles simultaneously.
Formalin-fixed, paraffin-embedded (FFPE) archival tissue is an important source of DNA material. The most commonly used technique to identify copy number aberrations from chromosomal DNA in tumorigenesis is array comparative genomic hybridization (aCGH). Although copy number analysis using DNA from FFPE archival tissue is challenging, several research groups have reported high quality and reproducible DNA copy number results using aCGH. Aim of this study is to compare the commercially available aCGH platforms suitable for high-resolution copy number analysis using FFPE-derived DNA. Two dual channel aCGH platforms (Agilent and NimbleGen) and a single channel SNP-based platform (Affymetrix) were evaluated using seven FFPE colon cancer samples, and median absolute deviation (MAD), deflection, signal-to-noise ratio, and DNA input requirements were used as quality criteria. Large differences were observed between platforms; Agilent and NimbleGen showed better MAD values (0.13 for both) compared with Affymetrix (0.22). On the contrary, Affymetrix showed a better deflection of 0.94, followed by 0.71 for Agilent and 0.51 for NimbleGen. This resulted in signal-to-nose ratios that were comparable between the three commercially available platforms. Interestingly, DNA input amounts from FFPE material lower than recommended still yielded high quality profiles on all platforms. Copy number analysis using DNA derived from FFPE archival material is feasible using all three high-resolution copy number platforms and shows reproducible results, also with DNA input amounts lower than recommended.
The metastatic process is complex and remains a major obstacle in the management of colorectal cancer. To gain a better insight into the pathology of metastasis, we investigated genomic aberrations in a large cohort of matched colorectal cancer primaries and distant metastases from various sites by high resolution array comparative genomic hybridization. In total, 62 primary colorectal cancers, and 68 matched metastases (22 liver, 11 lung, 12 ovary, 12 omentum, and 11 distant lymph nodes) were analyzed. Public datasets were used for validation purposes. Metastases resemble their matched primary tumors in the majority of the patients. This validates the significant overlap in chromosomal aberrations between primary tumors and corresponding metastases observed previously. We observed 15 statistically significant different regions between the primary tumors and their matched metastases, of which only one recurrent event in metastases was observed. We conclude, based on detailed analysis and large independent datasets, that chromosomal copy number aberrations in colorectal metastases resemble their primary counterparts, and differences are typically non-recurrent.
DNA copy number alterations can be detected in cell populations containing 10 % abnormal cells. Detection of sub-megabase alterations requires a higher percentage of abnormal cells or microarrays with a higher probe density.
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