Detection of structural variants and recurrent breakpoint genes in colorectal adenoma-to-carcinoma progression

Background and Aim: The transition of pre-malignant colorectal adenomas (CRAs) into malignant colorectal carcinomas (CRCs) is accompanied by accumulation of somatic genetic alterations. The contribution of small nucleotide variants (SNVs, such as gene point mutations) and numerical DNA copy number aberrations (CNAs, such as gains and losses of large chromosomal segments) in tumor genomes has been studied extensively. In contrast, studies that systematically detect recurrent structural variants (SVs, such as chromosomal breaks) across large series of clinically well-defined samples are scarce. We recently developed “GeneBreak”, a computational method to identify genes that are recurrently affected by the genomic location of CNA-associated chromosomal breaks, and demonstrated high prevalence and clinical relevance of recurrent breakpoint genes in advanced CRCs (PLoS One 2015;10(9):e0138141). Using a similar approach, the present study aimed to determine what recurrent breakpoint genes contribute to colorectal adenoma-to-carcinoma progression.

Methods: Differences in somatic CNA-associated gene breakpoint frequencies in 466 CRC and 118 CRA samples were examined using high-resolution array-comparative genomic hybridization (aCGH) profiles. Pearson's Chi-square statistic was applied to determine differences in gene breakpoint frequencies between CRC and CRA samples.

Results: In total 21 recurrent breakpoint genes were more frequently affected in CRCs compared to CRAs (p<0.05). MACROD2 was affected by chromosomal breakpoints in 40% of CRCs while not being affected in CRAs. The frequencies of SVs in the other 20 recurrent breakpoint genes ranged from 5% to 29% in CRCs, and from 0% to 2% in CRAs.

Conclusion: We identified 21 recurrent breakpoint genes that are frequently affected by SVs in CRCs but not in CRAs. Additional studies are needed to further elaborate the biological and clinical role of these 21 candidate driver genes for colorectal tumor progression.