TY - JOUR
T1 - Germline pathogenic SMARCA4 variants in neuroblastoma
AU - Witkowski, Leora
AU - Nichols, Kim E.
AU - Jongmans, Marjolijn
AU - Van Engelen, Nienke
AU - De Krijger, Ronald R.
AU - Herrera-Mullar, Jennifer
AU - Tytgat, Lieve
AU - Bahrami, Armita
AU - Mar Fan, Helen
AU - Davidson, Aimee L.
AU - Robertson, Thomas
AU - Anderson, Michael
AU - Hasselblatt, Martin
AU - Plon, Sharon E.
AU - Foulkes, William D.
N1 - Publisher Copyright:
© 2023 Authors. All rights reserved.
PY - 2023/10/1
Y1 - 2023/10/1
N2 - 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.
AB - 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.
KW - Genetic Predisposition to Disease
KW - Genetic Testing
KW - Germ-Line Mutation
KW - Pediatrics
KW - Sequence Analysis, DNA
UR - http://www.scopus.com/inward/record.url?scp=85152650055&partnerID=8YFLogxK
U2 - 10.1136/jmg-2022-108854
DO - 10.1136/jmg-2022-108854
M3 - Article
C2 - 36813544
AN - SCOPUS:85152650055
SN - 0022-2593
VL - 60
SP - 987
EP - 992
JO - Journal of Medical Genetics
JF - Journal of Medical Genetics
IS - 10
ER -