ASTE1 and Lynch Syndrome

Multiple independent studies have highlighted a recurrent association between ASTE1 (HGNC:25021) and Lynch syndrome (MONDO:0005835). In Lynch syndrome, defects in the DNA mismatch repair system lead to microsatellite instability and a high prevalence of coding frameshift mutations. Among these, ASTE1 has emerged as a notable target, with studies reporting that approximately 33% of mutations in coding microsatellites affect this gene (PMID:25816162).

Lynch syndrome is inherited in an autosomal dominant manner, and although detailed segregation analyses with extended family members were not provided, the detection of recurrent frameshift mutations in multi‐patient cohorts supports a significant genetic contribution. The collective genetic evidence for ASTE1 comes from case series and studies where patterns of loss‐of‑function mutations are consistent with a pathogenic role in the development of Lynch syndrome (PMID:26060019).

While no specific HGVS‐formatted variant from Lynch syndrome cohorts for ASTE1 is available from the supplied evidence, the overall mutation spectrum, characterized by frameshift events in coding mononucleotide repeats, aligns with a deleterious effect on gene function. The absence of a standardized variant does not preclude the evidence from supporting a strong genetic contribution.

Functional studies further buttress the association by demonstrating that frameshift mutations in target genes contribute to aberrant protein processing. In particular, experiments have shown that such mutant proteins are subjected to rapid degradation via the ubiquitin–proteasome pathway, which may contribute to neoantigen formation and an enhanced immune response within the tumor microenvironment (PMID:23674496).

Although ASTE1 has been implicated in other disease contexts, the consistent identification of frameshift events specifically in Lynch syndrome cohorts underscores its relevance in this tumorigenic pathway. Contrasting evidence in non–Lynch syndrome settings highlights the need for continued research; however, the convergence of multiple lines of genetic and functional evidence lends robust support to its role in Lynch syndrome.

This integrated analysis supports a strong ClinGen gene–disease association for ASTE1 and Lynch syndrome and offers clinical utility for diagnostic decision‑making as well as potential avenues for personalized immunotherapeutic strategies.

References

• PloS One • 2015 • Mismatch repair-deficient crypt foci in Lynch syndrome--molecular alterations and association with clinical parameters PMID:25816162
• Cancer Research • 2015 • Correlation between Density of CD8+ T-cell Infiltrate in Microsatellite Unstable Colorectal Cancers and Frameshift Mutations: A Rationale for Personalized Immunotherapy PMID:26060019
• Clinical Cancer Research • 2013 • Identification and selective degradation of neopeptide-containing truncated mutant proteins in the tumors with high microsatellite instability PMID:23674496

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