Abstract LB206: The progression of chromosomal instability and aberrant DNA methylation during colorectal cancer development
Authors: Saskova Katerina , Landfors Mattias , Horak Josef , Honkova Katerina , Tomasova Kristyna , Drabova Jana , Hackenhaar Fernanda Schäfer , Pavlikova Jitka , Vodickova Ludmila , Nilsson Torbjörn , Farkas Sanja , Vymetalkova Veronika , Vodicka Pavel , Degerman Sofie , Kroupa Michal 
Published: April 2024

Abstract
Chromosomal instability (CIN) and aberrant DNA methylation play a pivotal role in the pathogenesis of colorectal cancer (CRC). Mapping both of these cancer hallmarks during the progression of the disease can help identify potential targets for pharmacological intervention and improve the management of CRC metastasis. In a set of 27 patients diagnosed with either high-grade colorectal adenoma or advanced metastatic CRC disease, high-throughput DNA methylation and/or DNA somatic copy number alterations (SCNAs) analyses were performed. Global genome methylation profiles and the most frequent hot-spot regions harboring SCNAs, identified in the patients' DNA, were verified in a validation set of eight CRC patients through whole-exome sequencing, genome-wide DNA methylation measurement, and gene expression profiling.The study is currently ongoing; however, a panel of 29 cancer-relevant genes, amplified in more than 50% of investigated adenoma tissues (such as PTK6, SRC, MALAT1, BRCA2), was identified. Chromosomal loci amplified in primary tumors were highly concordant with those in liver metastases. An increase in CIN was detected in all metastases, representing mostly gains of Chr7q, 8q, 13q, 20q, and the small arm of ChrX, while the lost chromosomal loci included Chr8p, 17p, and the entire Chr18. A gain unique to metastases was located on Chr6 (p25.1-p22.3), encoding the oncogene DEK. All metastases exhibited an increase in hypomethylated and a decrease in hypermethylated CpGs. The gene enrichment analysis of the differently methylated gene promoters showed the olfactory receptors pathway as the most frequently represented (FDR-adjusted P value=1.06E-8), with all the identified promoters (n=120) less methylated in metastases. Taken together, several genomic hot-spot regions with SCNAs, possibly important during the development of adenoma and also during the metastatic process, were identified. Furthermore, a decrease in methylation within promoters of odorant receptors was the most prominent epigenetic alteration occurring in our set of metastases. The study was funded by the Ministry of Health of the Czech Republic (NU22J-03-00028) and GACR 21-27902S.
Citation Format: Katerina Saskova, Mattias Landfors, Josef Horak, Katerina Honkova, Kristyna Tomasova, Jana Drabova, Fernanda Schäfer Hackenhaar, Jitka Pavlikova, Ludmila Vodickova, Torbjörn Nilsson, Sanja Farkas, Veronika Vymetalkova, Pavel Vodicka, Sofie Degerman, Michal Kroupa. The progression of chromosomal instability and aberrant DNA methylation during colorectal cancer development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB206.