Determination of distinctive hypomethylated genes in African American colorectal neoplastic lesions

Abstract

Background: Few studies have analyzed progressive demethylation in the path to cancer. This is of utmost importance, especially in populations such as African Americans, who display aggressive tumors at diagnosis, and for whom markers of early neoplastic transformation are needed. Here, we determined hypomethylated targets in the path to colorectal cancer (CRC) using Reduced Representation Bisulfite Sequencing (RRBS). Methods: DNA was extracted from fresh frozen tissues of patients with different colon lesions (normal, tubular adenoma, tubulovillous adenoma, and five cancers). RRBS was performed on these DNA extracts to identify hypomethylated gene targets. Alignment, mapping, and methylation analyses were performed. Pathways affected by the hypomethylated gene targets were determined using Ingenuity Pathway Analysis (IPA). Results: Pairwise analyses of samples led to the identification of the following novel hypomethylated genes: ELMO3 (Engulfment and cell motility 3), SLC6A2 (Solute carrier family 6 member 2), SYNM (Synemin), and HMX2 (Homeobox 2). The ELMO3 promoter was significantly hypomethylated at five CpG sites, SYNM at two CpG sites, SLC6A2 at one CpG site, and the HMX2 gene at one CpG site. IPA placed these genes within important carcinogenic pathways. Conclusions: This work provides insight into the role of hypomethylation in colon carcinogenesis in African Americans. The identified targets affected many important pathways, as demonstrated through IPA. These targets might serve as biomarkers for early diagnosis and potential targets for therapy.

Integrated Multi-Omics Data Analysis Identifies a Novel Genetics-Risk Gene of IRF4 Associated with Prognosis of Oral Cavity Cancer

“…The druggable gene of SLC6A2, which encodes a member of the sodium neurotransmitter symporter family that is responsible for the reuptake of norepinephrine into presynaptic nerve terminals, was identified to be targeted by ten drugs, including reboxetine, dexmethylphenidate, and guanethidine. Previous studies have demonstrated that SLC6A2 is associated with neuroblastoma [80], colorectal cancer [81], and head and neck cancer [18]. Multiple lines of evidence have shown that a number of neurotransmitters have roles in the development and maintenance of fatigue and energy levels in breast cancer [82].…”

Drug repurposing for cancer treatment through global propagation with a greedy algorithm in a multilayer network

“…We found that the targets of nifedipine, such as voltage-dependent L-type calcium channel subunit alpha-1C (CACNA1C), subunit alpha-1D (CACNA1D) and beta-2 (CACNB2), have important links to cancer development and progression 45 – 49 . Furthermore, one target of nortriptyline, sodium-dependent noradrenaline transporter (SLC6A2), also affects important pathways in cancer 50 . These clues at the proteomics level and the reported drug targets might contribute to nifedipine/nortriptyline-induced antitumor effects but must be further validated in additional independent experiments.…”

Integrated multi-omics data analysis identifies a novel genetics-risk gene ofIRF4associated with prognosis of oral cavity cancer

“…The druggable gene of SLC6A2, which encodes a member of the sodium neurotransmitter symporter family that is responsible for the reuptake of norepinephrine into presynaptic nerve terminals, was identified to be targeted by ten drugs, including reboxetine, dexmethylphenidate, and guanethidine. Previous studies have demonstrated that SLC6A2 is associated with neuroblastoma [80], colorectal cancer [81], and head and neck cancer [18]. Multiple lines of evidence have shown that a number of neurotransmitters have roles in the development and maintenance of fatigue and energy levels in breast cancer [82].…”