WRN – Werner syndrome–associated Osteosarcoma

Werner syndrome (WS) is an autosomal recessive segmental progeroid disorder caused by biallelic loss-of-function variants in WRN. WS patients exhibit genomic instability, premature aging, and an elevated cancer risk, including predisposition to Osteosarcoma.

Clinical genetic evidence linking WRN to osteosarcoma comprises ten unrelated Japanese WS probands (ages 35–57 years) who developed osteosarcoma at atypical sites (seven ankle/foot, two radius, one patella) compared with 36 age-matched hospital controls. All ten harbored autosomal recessive founder alleles type 4/4 or 6/6, representing 66% of WS alleles in Japan (PMID:11123436).

Segregation data are limited by the recessive inheritance and absence of additional affected relatives; nevertheless, the markedly increased osteosarcoma incidence in WS versus controls underscores a gene-disease link without reported segregation beyond the probands.

Functional and mechanistic studies demonstrate that WRN encodes a single polypeptide with intrinsic 3′→5′ DNA helicase and exonuclease activities. WRN-deficient cells lack exonuclease function and exhibit defective DNA repair, replication fork recovery, and heightened chromosomal breakage, recapitulating features of genomic instability seen in WS (PMID:9852073).

Concordant cellular and biochemical assays show that loss of WRN function impairs non-homologous end joining and homologous recombination fidelity, compromises replication fork stability, and increases sensitivity to DNA-damaging agents. These data support a loss-of-function mechanism driving osteosarcoma predisposition in WS.

Integration of genetic and experimental findings yields a coherent model whereby biallelic WRN deficiency leads to progressive genomic instability, conferring a moderate predisposition to osteosarcoma in WS patients. Early molecular diagnosis of WRN variants enables targeted surveillance and informed clinical management of osteosarcoma risk.

Key take-home: Germline WRN loss-of-function in Werner syndrome confers a moderate, clinically actionable predisposition to osteosarcoma via genome instability, informing genetic testing and surveillance protocols.

References

• Japanese journal of cancer research : Gann | 2000 | Atypical osteosarcomas in Werner Syndrome (adult progeria) PMID:11123436
• The Journal of biological chemistry | 1998 | Werner syndrome protein. I. DNA helicase and dna exonuclease reside on the same polypeptide. PMID:9852073

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