Work

Assessing the pathogenicity of a variant of uncertain significance in the ALK gene in right-sided colon polyposis

Year: 2025

Type: article

Abstract: • A missense variant in the ALK gene (Gly→Glu) was identified in a patient with right-sided colon polyposis lacking mutations in common polyposis-associated genes. • In silico and molecular dynamics analyses suggested that the substitution alters ALK protein physicochemical properties, increases hydrogen bonding, and impacts structural stability and function. • The findings highlight the potential role of ALK in polyp formation and underscore the need for expanded genomic screening beyond APC and MUTYH . Colorectal cancer (CRC) is the third most common cancer worldwide. Generally, Familial Adenomatous Polyposis (FAP) accounts for about 1% to 2% of all colorectal cancer cases. Mutations in the APC gene, inherited in an autosomal dominant manner, and mutations in the MUTYH gene, inherited in an autosomal recessive manner, are the primary causes of FAP. While, this study focuses on the pathogenicity assessment of a Variant of Uncertain Significance (VUS) in the ALK gene as the only genetic finding predisposing to cancer in a woman with right-sided colon polyposis (exceeding 100 polyps). Initially, the targeted-gene panel associated with CRC was examined. Subsequently, in silico studies, including the protein molecular dynamics (MD) simulations before and after the variant, as well as the interaction networks associated with candidate gene, were conducted. No variants were found in the APC and MUTYH genes, highlighting the importance of identifying other genes. The heterozygous variant in ALK (NM_004304.5): c.3410G>A; p. Gly1137Glu was identified in the proband's gene panel analysis. In silico studies revealed the mutated structure is high stable than the native protein which can originate the disease in humans. The segregation analysis of the parents showed that the proband’s mother is also heterozygous for this variant. Interestingly, the mother also constantly develops numerous paranasal polyps, which may prompt researchers to investigate the role of this gene in the formation of polyps. Finally, the study highlighted the importance of further investigation into the pathogenicity of this variant and emphasized the significance of identifying novel genes.

Source: Cancer Treatment and Research Communications

DOI: 10.1016/j.ctarc.2025.101010