SMARCA4-associated rhabdoid tumour predisposition syndrome – risk management

Rhabdoid tumour predisposition syndrome 2 (RTPS2) is an autosomal dominant syndrome predisposing to childhood-onset rhabdoid tumours and small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT) and is due to a heritable pathogenic variant in the SMARCA4 gene.

Individuals with RTPS2 typically present before age 12 months and often with synchronous tumours that exhibit aggressive clinical behaviour.^r SCCOHT may present in teenage years/young adults.

• Unaffected known or obligate SMARCA4 pathogenic variant carriers
• Individuals at 50% risk of inheriting a SMARCA4 pathogenic variant

Exclusion criteria

• Individuals with a SMARCB1 pathogenic variant
• Individuals with a variant of uncertain significance

The penetrance of germline SMARCA4 pathogenic variant is unknown. Somatic mosaicism contributes to this uncertainty.

The choice of risk management strategy should take into account current age, other health issues and age-related cancer risk. Risks and benefits of interventions should be discussed with an experienced medical professional.

There is no evidence for surveillance in individuals with SMARCA4-deficient non-rhabdoid tumours, but testing could be offered in the setting of a research protocol.

* The impact of lifestyle on cancer risk should be discussed e.g. exercise most days for at least 30 minutes at moderate or strenuous intensity, maintain a healthy weight, have a healthy diet, limit alcohol intake, do not smoke and avoid excessive sun exposure.

Rhabdoid tumours can occur in almost any anatomic location, commonly in the central nervous system (atypical teratoid/rhabdoid tumour). Other locations include kidneys (renal rhabdoid tumour), head and neck, paravertebral muscles, liver, bladder, mediastinum, retroperitoneum, pelvis (extracranial extrarenal malignant rhabdoid tumour), and ovary (small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT)).

There are limited data on the effectiveness of surveillance in children at increased risk of RTPS2. RTPS2 is extremely rare, and this limits the ability of clinical researchers to perform large prospective studies to address the utility of surveillance. In addition, there are uncertainties with regard to the natural history of SMARCA4-associated malignancies.

SCCOHT is a rare, highly aggressive cancer that occurs in young women. The average age at diagnosis is around age 24 years and approximately one-third of cases are diagnosed under age 20 years.^r SCCOHT has poor prognosis, even for early stage disease.

Risk reducing bilateral oophorectomy should be discussed with all female carriers of a SMARCA4 pathogenic variant, or with their parent(s)/guardian(s) if a germline pathogenic variant is detected in a minor.^r The impact of oophorectomy on fertility and pubertal development, menopausal hormone therapy and other health factors needs to be weighed against the poor prognosis associated with malignancy. Where surgery is considered, individuals should be referred to an appropriate specialist to discuss fertility preservation. The optimal age for oophorectomy is undetermined because of the lack of penetrance data. The role of salpingectomy at the time of oophorectomy is unknown.

These recommendations represent expert opinion and are informed by a paper published by attendees of the 2017 American Association for Cancer Research (AACR) Childhood Cancer Predisposition Workshop.^r

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