University of Oulu

Sabatella, M., Mantere, T., Waanders, E., Neveling, K., Mensenkamp, A.R., van Dijk, F., Hehir-Kwa, J.Y., Derks, R., Kwint, M., O'Gorman, L., Tropa Martins, M., Gidding, C.E., Lequin, M.H., Küsters, B., Wesseling, P., Nelen, M., Biegel, J.A., Hoischen, A., Jongmans, M.C. and Kuiper, R.P. (2021), Optical genome mapping identifies a germline retrotransposon insertion in SMARCB1 in two siblings with atypical teratoid rhabdoid tumors. J. Pathol., 255: 202-211. https://doi.org/10.1002/path.5755

Optical genome mapping identifies a germline retrotransposon insertion in SMARCB1 in two siblings with atypical teratoid rhabdoid tumors

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Author: Sabatella, Mariangela1; Mantere, Tuomo2,3,4; Waanders, Esmé5;
Organizations: 1Princess Máxima Centre for Pediatric Oncology, Utrecht, The Netherlands
2Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
3Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
4Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit and Biocenter Oulu, University of Oulu, Oulu, Finland
5Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
6Department of Radiology, University Medical Center Utrecht, Utrecht, The Netherlands
7Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands
8Department of Pathology, Amsterdam University Medical Centers, Location VUmc and Brain Tumor Center Amsterdam, Amsterdam, The Netherlands
9Department of Pathology and Laboratory Medicine, Children's Hospital, Los Angeles, Los Angeles, CA, USA
10Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
11Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, The Netherlands
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 2.5 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2021102151864
Language: English
Published: John Wiley & Sons, 2021
Publish Date: 2021-10-21
Description:

Abstract

In a subset of pediatric cancers, a germline cancer predisposition is highly suspected based on clinical and pathological findings, but genetic evidence is lacking, which hampers genetic counseling and predictive testing in the families involved. We describe a family with two siblings born from healthy parents who were both neonatally diagnosed with atypical teratoid rhabdoid tumor (ATRT). This rare and aggressive pediatric tumor is associated with biallelic inactivation of SMARCB1, and in 30% of the cases, a predisposing germline mutation is involved. Whereas the tumors of both siblings showed loss of expression of SMARCB1 and acquired homozygosity of the locus, whole exome and whole genome sequencing failed to identify germline or somatic SMARCB1 pathogenic mutations. We therefore hypothesized that the insertion of a pathogenic repeat-rich structure might hamper its detection, and we performed optical genome mapping (OGM) as an alternative strategy to identify structural variation in this locus. Using this approach, an insertion of ~2.8 kb within intron 2 of SMARCB1 was detected. Long-range PCR covering this region remained unsuccessful, but PacBio HiFi genome sequencing identified this insertion to be a SINE-VNTR-Alu, subfamily E (SVA-E) retrotransposon element, which was present in a mosaic state in the mother. This SVA-E insertion disrupts correct splicing of the gene, resulting in loss of a functional allele. This case demonstrates the power of OGM and long-read sequencing to identify genomic variations in high-risk cancer-predisposing genes that are refractory to detection with standard techniques, thereby completing the clinical and molecular diagnosis of such complex cases and greatly improving counseling and surveillance of the families involved.

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Series: Journal of pathology
ISSN: 0022-3417
ISSN-E: 1096-9896
ISSN-L: 0022-3417
Volume: 225
Issue: 2
Pages: 202 - 211
DOI: 10.1002/path.5755
OADOI: https://oadoi.org/10.1002/path.5755
Type of Publication: A1 Journal article – refereed
Field of Science: 1184 Genetics, developmental biology, physiology
3111 Biomedicine
Subjects:
Funding: This research was funded by Stichting Kinderen Kankervrij (KiKa) and by NWO (Nederlandse organisatie voor Wetenschappelijk Onderzoek, the Dutch organisation of Scientific Research; project 184.034.019) as part of The Netherlands X-omics Initiative. TM was supported by the Sigrid Jusélius Foundation.
Copyright information: © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
  https://creativecommons.org/licenses/by-nc-nd/4.0/