RPS20 – familial colorectal cancer type X

Familial colorectal cancer type X (FCCX) is an autosomal dominant predisposition to microsatellite-stable colorectal carcinoma without mismatch repair defects. In a four-generation FCCX pedigree, linkage analysis and exome sequencing identified a heterozygous truncating RPS20 variant (c.147dup (p.Val50fs)) that co-segregated with cancer in all affected individuals (PMID:24941021). No additional unrelated probands have been reported to date, and systematic screening in other FCCX families remains limited. The single identified loss-of-function variant in RPS20 reaches a Limited level of genetic evidence under ClinGen criteria, with segregation in one large family but absence of replication in independent cohorts.

Functional studies demonstrate that mutant uS20 protein disrupts pre-ribosomal RNA maturation and fails to incorporate into 40S subunits, leading to transcriptomic changes associated with colorectal tumorigenesis in cellular models (PMID:35682850). These data support a haploinsufficiency mechanism and provide Moderate experimental evidence for RPS20 in FCCX. Further studies are needed to establish prevalence and penetrance, but inclusion of RPS20 in hereditary colorectal cancer panels may improve diagnostic yield.

References

• Gastroenterology • 2014 • Germline mutation of RPS20, encoding a ribosomal protein, causes predisposition to hereditary nonpolyposis colorectal carcinoma without DNA mismatch repair deficiency. PMID:24941021
• International journal of molecular sciences • 2022 • Changes in the Transcriptome Caused by Mutations in the Ribosomal Protein uS10 Associated with a Predisposition to Colorectal Cancer. PMID:35682850

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