Multiple primary malignancies associated with a germline SMARCB1 pathogenic variant

Eelloo, Judith; Smith, Miriam J.; Bowers, Naomi L.; Ealing, John; Hulse, Paul; Wylie, James; Shenjere, Patrick; Clarke, Noel W.; Soh, Calvin; Whitehouse, Richard W.; Jones, Mark T.; Duff, C.G.; Freemont, Anthony J.; Evans, D. Gareth

doi:10.1007/s10689-019-00138-4

Cited by 3 publications

(3 citation statements)

References 14 publications

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“…Recently several cases have been described mainly in patients harbouring germline mutations in SMARCB1 gene. A clear increased risk of a malignant-peripheral nerve-sheath tumour has been established [ 26 ] although it is possible that a more extended malignancy phenotype associated with a SMARCB1 pathogenic variant does exist [ 27 ]. Due to this increased risk, we have recommended that a changing tumour, in someone with SMARCB1 germline pathogenic variant, especially one causing functional impairment, should prompt exclusion of malignant transformation.…”

Section: Discussionmentioning

confidence: 99%

“…Life expectancy is not usually reduced, unlike in NF2 [ 2 ], but quality of life is strongly affected. Whilst there exists some concern over malignant potential in SMARCB1-related schwannomatosis [ 26 , 27 ], this does not appear to be a feature of other types of schwannomatosis. Other common features of NF2 such as ependymomas and ocular features such as retinal hamartoma, epiretinal folds and juvenile cataracts have not been reported in schwannomatosis [ 1 , 2 ].…”

Section: Introductionmentioning

confidence: 99%

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ERN GENTURIS clinical practice guidelines for the diagnosis, treatment, management and surveillance of people with schwannomatosis

et al. 2022

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A Guideline Group (GG) was convened from multiple specialties and patients to develop the first comprehensive schwannomatosis guideline. The GG undertook thorough literature review and wrote recommendations for treatment and surveillance. A modified Delphi process was used to gain approval for recommendations which were further altered for maximal consensus. Schwannomatosis is a tumour predisposition syndrome leading to development of multiple benign nerve-sheath non-intra-cutaneous schwannomas that infrequently affect the vestibulocochlear nerves. Two definitive genes (SMARCB1/LZTR1) have been identified on chromosome 22q centromeric to NF2 that cause schwannoma development by a 3-event, 4-hit mechanism leading to complete inactivation of each gene plus NF2. These genes together account for 70–85% of familial schwannomatosis and 30–40% of isolated cases in which there is considerable overlap with mosaic NF2. Craniospinal MRI is generally recommended from symptomatic diagnosis or from age 12–14 if molecularly confirmed in asymptomatic individuals whose relative has schwannomas. Whole-body MRI may also be deployed and can alternate with craniospinal MRI. Ultrasound scans are useful in limbs where typical pain is not associated with palpable lumps. Malignant-Peripheral-Nerve-Sheath-Tumour-MPNST should be suspected in anyone with rapidly growing tumours and/or functional loss especially with SMARCB1-related schwannomatosis. Pain (often intractable to medication) is the most frequent symptom. Surgical removal, the most effective treatment, must be balanced against potential loss of function of adjacent nerves. Assessment of patients’ psychosocial needs should be assessed annually as well as review of pain/pain medication. Genetic diagnosis and counselling should be guided ideally by both blood and tumour molecular testing.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

ERN GENTURIS clinical practice guidelines for the diagnosis, treatment, management and surveillance of people with schwannomatosis

et al. 2022

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“…MPNST was remarkably absent from other common CPS like hereditary breast and ovarian cancer (HBOC) syndrome and Lynch syndrome [34] . While MPNST has been rarely reported in association with rhabdoid tumor predisposition syndrome [35,36] , investigation of rhabdoid tumor predisposition syndrome amongst unselected cohorts of MPNST has not been reported. MPNST risk in individuals with NF2 remains controversial.…”

Section: Malignant Peripheral Nerve Sheath Tumormentioning

confidence: 99%

Germline predisposition to soft tissue sarcoma

Vagher¹,

Dietz²,

Schiffman³

et al. 2022

J Cancer Metastasis Treat

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Soft tissue sarcoma (STS) most often occurs sporadically, but can also arise in the setting of a germline cancer predisposition syndrome (CPS). There is significant diversity amongst STS diagnoses as these tumors exhibit a variety of histologies, occur in all age groups, and can occur in any location in the body. This diversity is also reflected in the many known associated germline cancer predisposition associations. Some STS diagnoses, such as anaplastic rhabdomyosarcoma, are associated with high heritability and other STS, such as Ewing sarcoma, are notably absent from known CPS. Recognizing when a STS is more likely to be hereditary can influence clinical management. Individuals diagnosed with STS due to CPS may be at risk for other malignancies and should undergo additional surveillance for early detection. Additionally, family members should undergo genetic testing as they also may be at risk to develop STS and other CPS-associated malignancies. Some underlying cancer predisposition diagnoses may have implications for the treatment of a concurrent malignancy as in the case of PARP inhibitor therapy in the setting of homologous recombination deficiency. This review summarizes current knowledge of selected STS and their associations with CPS.

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