Current recommendations for clinical surveillance and genetic testing in rhabdoid tumor predisposition: a report from the SIOPE Host Genome Working Group

Abstract

The rhabdoid tumor (RT) predisposition syndromes 1 and 2 (RTPS1 and 2) are rare genetic conditions rendering young children vulnerable to an increased risk of RT, malignant neoplasms affecting the kidney, miscellaneous soft-part tissues, the liver and the central nervous system (Atypical Teratoid Rhabdoid Tumors, ATRT). Both, RTPS1&2 are due to pathogenic variants (PV) in genes encoding constituents of the BAF chromatin remodeling complex, i.e. SMARCB1 (RTPS1) and SMARCA4 (RTPS2). In contrast to other genetic disorders related to PVs in SMARCB1 and SMARCA4 such as Coffin-Siris Syndrome, RTPS1&2 are characterized by a predominance of truncating PVs, terminating transcription thus explaining a specific cancer risk. The penetrance of RTPS1 early in life is high and associated with a poor survival. However, few unaffected carriers may be encountered. Beyond RT, the tumor spectrum may be larger than initially suspected, and cancer surveillance offered to unaffected carriers (siblings or parents) and long-term survivors of RT is still a matter of discussion. RTPS2 exposes female carriers to an ill-defined risk of small cell carcinoma of the ovaries, hypercalcemic type (SCCOHT), which may appear in prepubertal females. RT surveillance protocols for these rare families have not been established. To address unresolved issues in the care of individuals with RTPS and to propose appropriate surveillance guidelines in childhood, the SIOPe Host Genome working group invited pediatric oncologists and geneticists to contribute to an expert meeting. The current manuscript summarizes conclusions of the panel discussion, including consented statements as well as non-evidence-based proposals for validation in the future.

Cardiac Rhabdoid Tumor—A Rare Foe—Case Report and Literature Review

“…Given that the age of symptom onset is approximately 2 years old, and the 5-year survival rate is 10%, the surveillance of the proband and familial studies are paramount. The surveillance guidelines suggest physical examination every 2-3 months and imaging studies with a frequency dictated by age (Table 1) [16,17]. According to the WHO Histological Classification of Tumors of the Heart and Pericardium, the majority of malignant primary tumors of the heart can be categorized as various types of sarcomas, with primary cardiac lymphoma and epithelioid hemangioendothelioma accounting for a small fraction of cases.…”

“…Given that the age of symptom onset is approximately 2 years old, and the 5-year survival rate is 10%, the surveillance of the proband and familial studies are paramount. The surveillance guidelines suggest physical examination every 2–3 months and imaging studies with a frequency dictated by age ( Table 1 ) [ 16 , 17 ].…”

Molecular characterization of metachronous atypical teratoid rhabdoid tumors occurring in a young man 15 years apart

“…As more children with RTPS survive childhood, optimizing modalities and frequency of surveillance imaging, including neuraxis and whole‐body MRI, is currently an area of considerable interest. However, a low threshold for thoroughly evaluating new concerning clinical symptoms is warranted 11 …”

Identification of germline cancer predisposition variants in pediatric sarcoma patients from somatic tumor testing

“…According to several studies, approximately 10% of pediatric cancer patients are considered to have a germline mutation 4 , 5 . For some patients, the prevalence of mutations may be higher, as it has been observed in children with choroid plexus carcinoma of which 50% have germline mutations in TP53 6 , 7 or malignant rhabdoid tumors, of which 25–35% have mutations in SMARCB1 8 , 9 . The identification of an inherited genetic variant in a pediatric patient allows physicians to better guide the future management of the patients, as well as to provide genetic counseling to the patients and their families.…”