Recurrent NOMO1 Gene Deletion Is a Potential Clinical Marker in Early-Onset Colorectal Cancer and Is Involved in the Regulation of Cell Migration

Abstract

The incidence of early-onset colorectal cancer (EOCRC; age younger than 50 years) has been progressively increasing over the last decades globally, with causes unexplained. A distinct molecular feature of EOCRC is that compared with cases of late-onset colorectal cancer, in EOCRC cases, there is a higher incidence of Nodal Modulator 1 (NOMO1) somatic deletions. However, the mechanisms of NOMO1 in early-onset colorectal carcinogenesis are currently unknown. In this study, we show that in 30% of EOCRCs with heterozygous deletion of NOMO1, there were pathogenic mutations in this gene, suggesting that NOMO1 can be inactivated by deletion or mutation in EOCRC. To study the role of NOMO1 in EOCRC, CRISPR/cas9 technology was employed to generate NOMO1 knockout HCT-116 (EOCRC) and HS-5 (bone marrow) cell lines. NOMO1 loss in these cell lines did not perturb Nodal pathway signaling nor cell proliferation. Expression microarrays, RNA sequencing, and protein expression analysis by LC–IMS/MS showed that NOMO1 inactivation deregulates other signaling pathways independent of the Nodal pathway, such as epithelial–mesenchymal transition and cell migration. Significantly, NOMO1 loss increased the migration capacity of CRC cells. Additionally, a gut-specific conditional NOMO1 KO mouse model revealed no subsequent tumor development in mice. Overall, these findings suggest that NOMO1 could play a secondary role in early-onset colorectal carcinogenesis because its loss increases the migration capacity of CRC cells. Therefore, further study is warranted to explore other signalling pathways deregulated by NOMO1 loss that may play a significant role in the pathogenesis of the disease.

Reduced expression of alanyl aminopeptidase is a robust biomarker of non‐familial adenomatous polyposis and non‐hereditary nonpolyposis colorectal cancer syndrome early‐onset colorectal cancer

“…10 In terms of genomic variant, the deletion of the NOMO1 gene has been reported as a clinical marker in EOCRC, and the regulation of cell migration has been suggested for its role in tumorigenesis. 42 In summary, our study showed concordance with those EOCRC studies that have reported EMT-related features of the biomarker in EOCRC, regarding that the EMT pathway was significantly distinct between EOCRC and LOCRC in our research. In another respect, some studies have identified immune-related gene expressions as a biomarker of EOCRC, suggesting that EOCRC was distinct in immunity compared to LOCRC.…”

“…Another recent study has reported that the biomarker of EOCRC, PEG10, that they identified played a role in tumor cell invasion 10 . In terms of genomic variant, the deletion of the NOMO1 gene has been reported as a clinical marker in EOCRC, and the regulation of cell migration has been suggested for its role in tumorigenesis 42 . In summary, our study showed concordance with those EOCRC studies that have reported EMT‐related features of the biomarker in EOCRC, regarding that the EMT pathway was significantly distinct between EOCRC and LOCRC in our research.…”

Risk factors, histopathological landscape, biomarkers, treatment patterns and survival of early‐onset colorectal cancer: A narrative review

“…Other studies have linked EOCRC to mutations in genes resulting in DNA‐repair deficiencies, histone modification, and increased cell turnover (Table 1). 25–28 This higher tumor mutational burden is important as it indicates the potential role and favorable response of EOCRCs to immune checkpoint inhibitors 29 . Knowledge of molecular characterization has not yet translated into therapeutic improvements.…”

“…Other studies have linked EOCRC to mutations in genes resulting in DNA-repair deficiencies, histone modification, and increased cell turnover (Table 1). [25][26][27][28] This is significant as a dysregulated innate immune response has been found to be the main driver behind "inflammaging", a phenomenon characterized by persistent low levels of systemic and tissue microenvironment inflammation. 32 Other studies investigating the relationship between certain environmental exposures and EOCRCrelated gene and metabolomic modifications have established links between inflammation, obesity, and the NOTCH1-GATA4-IRG1 axis, alcohol consumption and overexpression of NOTUM/GDF11, and red meat consumption and choline/tryptophan/bile acid accumulation and upregulation of phosphatidylcholine and tryptophan biosynthesis genes in EOCRC patients.…”

Co-Occurrence of Germline Genomic Variants and Copy Number Variations in Hereditary Breast and Colorectal Cancer Patients

“…Heterozygous loss of NOMO1 (start: 14946287, end: 14959012) was also detected in index case 1. Colorectal cancer frequently exhibits NOMO1 deletion [ 60 , 61 ]. This biomarker is a potential therapeutic target for early-onset colorectal cancer [ 60 ].…”