Sibling Osteosarcoma Without Retinoblastoma Associated With a Low Penetrance RB1 Variant: Whole Genome Findings From...

Osteosarcoma is the most common primary malignant bone tumor in children and adolescents, yet its genetic etiology remains poorly understood. In this study, we described a family from the Shanghai General Hospital Osteosarcoma (SGH-OS) cohort in which two siblings developed osteosarcoma as their first primary malignancy, and we investigated the germline and somatic genetic basis underlying this familial presentation.

Whole-genome sequencing (WGS) was performed on tumors and matched germline DNA from the affected siblings, as well as germline DNA from their parents and unaffected sister. Comprehensive somatic and germline analyses were conducted to assess mutational profiles, copy-number alterations, and structural variants.

Both affected siblings carried a paternally inherited RB1 splice-donor variant (NM_000321.3:c.539+1G>A), with biallelic inactivation confirmed by 13q14 loss in both tumors. Tumor WGS revealed additional somatic alterations, suggesting cooperation between germline and acquired mutations in osteosarcoma development. In addition, the carrier father and elder sister remained unaffected, consistent with incomplete penetrance.

This study further supports the expanding spectrum of RB1-associated cancer predisposition, showing that low-penetrance RB1 variants may present with osteosarcoma without preceding retinoblastoma. In addition, our findings underscore the value of integrated WGS for characterizing inherited susceptibility in familial osteosarcoma.