Abstract
Background: Sporadic colorectal tumors probably carry genetic alterations that may be related to familiar clusters according to risk loci visualized by SNP arrays on normal tissues. The aim of the present study was therefore to search for DNA regions (copy number variations, CNVs) as biomarkers associated to genetic susceptibility for early risk predictions of colorectal cancer. Such sequence alterations could provide additional information on phenotypic grouping of patients. Material and Methods: High resolution 105K oligonucleotide microarrays were used in search for CNV loci in DNA from tumor-free colon mucosa at primary operations for colon cancer in 60 unselected patients in comparison to DNA in buffy coat cells from 44 confirmed tumor-free and healthy blood donors. Array-detected CNVs were confirmed by Multiplex ligation-dependent probe amplification (MLPA). Results: A total number of 205 potential CNVs were present in DNA from colon mucosa. 184 (90%) of the 205 potential CNVs had been identified earlier in mucosa DNA from healthy individuals as reported to the Database of Genomic Variants. Remaining 21 (10%) CNVs were potentially novel sites. Two CNVs (3q23 and 10q21.1) were significantly related to colon cancer, but not confirmed in buffy coat DNA from the cancer patients. Conclusion: Our study reveals two CNVs that indicate increased risk for colon cancer; these DNA alterations may have been acquired by colon stem cells with subsequent appearance among epithelial mucosa cells. Impact: Certain mucosa CNV alterations may indicate individual susceptibility for malignant transformation in relationship to intestinal toxins and bacterial growth.
Highlights
Confirmed large-scale copy number DNA variations were observed in our previous analyses on colon mucosa tissue from colorectal cancer (CRC) patients with different clinical outcome [1]
Large-scale copy number variations (CNVs) in mucosa tissues have been emphasized by others [2] [3], and multiple genome-wide association studies (GWAS) have identified several susceptibility single-nucleotide polymorphism (SNP) loci proposed to predispose for colorectal cancer [4]-[7]
Genome-wide analyses of sequence variations in all patient groups defined by Dukes tumor stages, revealed a total number of 774 potential CNV loci calls identified in DNA from colon mucosa in 60 patients when compared to a reference DNA (NA10851). 205 calls were identified in at least two specimens, where 90% (185)
Summary
Confirmed large-scale copy number DNA variations were observed in our previous analyses on colon mucosa tissue from colorectal cancer (CRC) patients with different clinical outcome [1]. It has appeared that CNVs are common and involve a great proportion of the human genome and may be involved in cancer development [2] [3] [9]-[15] Such findings may be utilized to improve public health care activities [5]. The aim of the present study was to search for DNA regions (copy number variations, CNVs) as biomarkers associated to genetic susceptibility for early risk predictions of colorectal cancer. Such sequence alterations could provide additional information on phenotypic grouping of patients
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