# Deciphering Deleterious nsSNPs in MUC16's SEA Domain: Structural and Functional Implications in Cancer Metastasis via Computational Analysis

## TL;DR

This study identifies harmful mutations in the MUC16 gene that may contribute to cancer metastasis by affecting structural and functional properties of the protein.

## Contribution

The study introduces a computational analysis of pathogenic nsSNPs in MUC16's SEA domain, highlighting their impact on cancer metastasis.

## Key findings

- Four pathogenic nsSNPs (L151P, Y144N, C111Y, D108Y) were identified in the MUC16 gene.
- The Y144N variant in the SEA5 domain is particularly deleterious, affecting stability and metastatic potential.
- These findings provide insights into disease susceptibility linked to MUC16 mutations and potential drug development.

## Abstract

MUC16 ranks among the top three genes exhibiting the highest mutation frequencies in various cancer types. It encodes transmembrane mucins present in the epithelial linings of the ocular, respiratory, gastric and female reproductive systems, serving to protect and maintain mucosal surfaces. Overexpression of MUC16 contributes to the differentiation, proliferation, invasion and metastasis of cancer cells in ovarian, endometrial, pancreatic, colon, breast and non‐small‐cell lung cancers. In this study, we analysed the structural and functional effects of pathogenic and potentially harmful non‐synonymous single nucleotide polymorphisms (nsSNPs) of MUC16, employing a blend of computational algorithms. Initially, SNPs data for MUC16 were gathered from the Ensembl database and refined using computational tools (PROVEAN, SIFT, PolyPhen‐2, SNAP‐2, MutPred, I‐Mutant3.0 and MUpro) to isolate four final pathogenic SNP variants (L151P, Y144N, C111Y and D108Y). Through evolutionary conservation analysis, we determined that these mutational variants originate from a highly conserved and stable domain. Our findings particularly emphasise the Y144N variant as a potentially highly deleterious mutation situated in the SEA5 domain. This variant could significantly impact stability, overall flexibility, compactness, expansion, glycosylation ability and metastatic potential when compared to both the wild‐type and other mutant variants. In summary, these findings shed light on missense mutational variants, providing insights into the vast array of disease susceptibilities associated with MUC16's glycosylation process. This understanding could aid in the development of effective drugs for diseases linked with these mutations.