Heterozygous germline pathogenic variants (GPVs) in SMARCA4, the gene encoding the ATP-dependent chromatin remodelling protein SMARCA4 (previously known as BRG1), predispose to several rare tumour types, including small cell carcinoma of the ovary, hypercalcaemic type, atypical teratoid and malignant rhabdoid tumour, and uterine sarcoma. The increase in germline testing of SMARCA4 in recent years has revealed putative GPVs affecting SMARCA4 in patients with other cancer types. Here we describe 11 patients with neuroblastoma (NBL), including 4 previously unreported cases, all of whom were found to harbour heterozygous germline variants in SMARCA4. Median age at diagnosis was 5 years (range 2 months–26 years); nine were male; and eight of nine cases had tumour location information in the adrenal gland. Eight of the germline variants were expected to result in loss of function of SMARCA4 (large deletion, truncating and canonical splice variants), while the remaining four were missense variants. Loss of heterozygosity of the wild-type SMARCA4 allele was found in all eight cases where somatic testing was performed, supporting the notion that SMARCA4 functions as a classic tumour suppressor. Altogether, these findings strongly suggest that NBL should be included in the spectrum of SMARCA4-associated tumours.
- Genetic Predisposition to Disease
- Genetic Testing
- Germ-Line Mutation
- Sequence Analysis, DNA
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LW and KEN contributed equally.
Contributors LW and KN contributed equally to this paper. LW, KN, SP and WDF designed the study and contributed to manuscript preparation and editing. MJ, LT, NvE, JH-M, HM, ALD and MJA provided study patients. RRdK, AB, TR, MH performed pathology review on the cases. All authors critically reviewed and approved the final manuscript.
Funding ALD is supported by an Australian Government Research Training Program (RTP) Scholarship and a QIMR Berghofer HDC PhD Top Up Scholarship. Case identified via research was funded by Australian Genomics, NHMRC (grants GNT1113531 and GNT2000001) and the Australian Government’s Medical Research Future Fund. SEP is funded by the National Institutes of Health (grant 5 U01 HG006485). WDF is funded by the Canadian Institutes of Health Research (FDN-148390).
Competing interests MJ is a full-time, salaried employee of Invitae Corporation. JH-M is a full-time, salaried employee of Ambry Genetics. RRdK is a council member European Society of Pathology, unpaid. MJ is a board member of the SIOP Europe host genome working group, unpaid. SP is a member of the board of directors, American Society of Human Genetics, and a member of the scientific advisory panel, Baylor Genetics. LW is a consultant for PierianDx and Precision Rx-Dx Inc.
Provenance and peer review Not commissioned; externally peer reviewed.
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