SMARCA4 – Rhabdoid Tumor Predisposition Syndrome 2

Rhabdoid tumor predisposition syndrome 2 (RTPS2) is a rare autosomal dominant cancer predisposition syndrome characterized by aggressive rhabdoid tumors in early life. Germline truncating variants in SMARCA4 were first described in a mother–daughter pair presenting with ovarian and intracerebral rhabdoid tumors, establishing an autosomal dominant inheritance pattern and loss-of-function mechanism ([PMID:23775540]). Subsequent reports in unrelated individuals, including a prepubertal patient undergoing prophylactic oophorectomy and a pediatric bone sarcoma case, reinforce a consistent association between SMARCA4 haploinsufficiency and RTPS2 ([PMID:37663174];[PMID:39112597]).

Genetic Evidence

RTPS2 is inherited in an autosomal dominant fashion with full penetrance for rhabdoid tumors. Four probands from three independent families have been documented to carry heterozygous SMARCA4 truncating variants, notably c.3533G>A (p.Trp1178Ter) in a familial kindred and c.3980_3981del (p.Glu1327GlyfsTer) in a sporadic pediatric case ([PMID:23775540];[PMID:37663174]). Segregation analysis in the original family confirmed transmission of the nonsense allele to the affected daughter. Tumor sequencing demonstrated somatic second-hit events and loss of heterozygosity in neoplastic tissues, consistent with a two-hit tumor suppressor model ([PMID:39112597]).

Variant Spectrum

All reported germline SMARCA4 alleles in RTPS2 are protein-truncating mutations, including one canonical splice-site variant and two stop-gain or frameshift changes. A survey of 106 sporadic germ cell tumors failed to identify additional deleterious SMARCA4 mutations outside RTPS2 cases, underscoring the specificity of these variants for rhabdoid tumor predisposition ([PMID:23775540]).

Functional Evidence

Functional studies reveal that SMARCA4 truncating mutations undergo nonsense-mediated decay and that affected tumors show absent BRG1 immunostaining with somatic inactivation of the remaining allele, demonstrating haploinsufficiency as the pathogenic mechanism ([PMID:39112597]).

Conflicting Evidence

No studies to date have refuted the link between SMARCA4 loss-of-function variants and RTPS2. The absence of pathogenic SMARCA4 alleles in large cohorts of sporadic germ cell tumors further supports the specificity of these mutations for predisposition to rhabdoid tumors.

Conclusion

Integration of genetic, segregation, and functional data supports a Moderate clinical validity classification for SMARCA4 in RTPS2. Clinical genetic testing for SMARCA4 truncating variants is indicated in families with rhabdoid tumors, and early intervention strategies—including risk-reducing surgery—may improve outcomes. Key take-home: Germline SMARCA4 loss-of-function variants confer autosomal dominant predisposition to rhabdoid tumors through a classic two-hit tumor suppressor mechanism.

References

• The Journal of pathology • 2013 • Familial rhabdoid tumour 'avant la lettre'--from pathology review to exome sequencing and back again. PMID:23775540
• Gynecologic oncology reports • 2023 • Risk reduction for small cell cancer of the ovary, hypercalcemic type in prepubertal patient: A clinical and bioethical perspective. PMID:37663174
• Virchows Archiv : an international journal of pathology • 2024 • SMARCA4-deficient primary bone sarcoma with "teratoid" features in a rhabdoid tumor predisposition syndrome patient. PMID:39112597

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