Computational analyses on genetic alterations in the NSD genes family and the implications for colorectal cancer development

Abstract

Colorectal cancer (CRC) is a prevalent tumour throughout the world. CRC symptoms appear only in advanced stages causing decrease in survival of patients. Therefore, it is necessary to establish new strategies to detect CRC through subclinical screening. Genetic alterations and differential expression of genes that codify histone methyltransferases (HMTs) are linked to tumourigenesis of CRC. One important group of genes that codify HMTs are the NSD family composed of NSD1, NSD2 and NSD3 genes. This family participates in several cancer processes as oncogenes, harbouring several genetic alterations and presenting differential expression in tumour cells. To investigate the implications of NSD genes in CRC cancer, we described the genomic landscape of all NSD family members in a cohort of CRC patients from publicly available cancer datasets. We identified associations among recurrent copy number alterations (CNAs), mutations and differential gene expression concerning clinical outcome. We found in CRC repositories that NSD1 harbours a missense mutation in SET domain-the catalytic region-that probably could decrease its activity. In addition, we found an association between the low expressions of NSD1 and NSD2 and decrease of survival probability in CRC patients. Finally, we reported that NSD3 showed the highest rate of gene amplification, which was highly correlated to its mRNA expression, a common feature of many cancer drivers. Our results highlight the potential use of the NSD1 and NSD2 gene as prognostic markers of poor prognosis in CRC patients. Additionally, we appointed the use of the NSD3 gene as a putative cancer driver gene in CRC given that this gene harbours the highest rate of genetic amplification. All our findings are leading to novel strategies to predict and control CRC, however, some studies need to be conducted to validate these findings.

Histone Methyltransferases Useful in Gastric Cancer Research

“… 33 - 36 Genes that can drive the oncogene process in human cancer have overexpression related to their gene amplification, where they present a correlation between gene expression and change in the number of gene copies. 22 , 37 For example, the high amplification is common for NSD3 gene. This HMT is amplified in breast, lung, head and neck, and osteosarcoma cancers leading cell cycle progression.…”

“…This HMT is amplified in breast, lung, head and neck, and osteosarcoma cancers leading cell cycle progression. 37 …”

“… 39 Furthermore, in previous studies, another gene encoding an HMT, NSD3 , was reported that to be amplified in colorectal and breast cancer. 22 , 37 …”

“…This HMT is amplified in breast, lung, head and neck, and osteosarcoma cancers leading cell cycle progression. 37 Here, except for the SMYD5 gene, all studied HMTs are amplified, being PRDM9, SETDB1, PRDM14, and EHMT2 the most amplified HMTs. In addition, the EHMT2 and NSD3 genes also harbor deep deletion events.…”

“…39 Furthermore, in previous studies, another gene encoding an HMT, NSD3, was reported that to be amplified in colorectal and breast cancer. 22,37 Several studies have proposed that there is a correlation between mRNA expression and SCNA. 22,37 Here, when the HMTs studied undergo a process of deletion or deep deletion, a decrease in gene expression can be observed.…”