Previously reported CCDC26 risk variant and novel germline variants in GALNT13, AR, and MYO10 associated with familial glioma in Finland

Riikka Nurminen; Ebrahim Afyounian; Niina Paunu; Riku Katainen; Mari Isomäki; Anssi Nurminen; Mauro Scaravilli; Jenni Tolppanen; Vidal Fey; Anni Kivinen; Pauli Helén; Niko Välimäki; Juha Kesseli; Lauri A. Aaltonen; Hannu Haapasalo; Matti Nykter; Kirsi J. Rautajoki

doi:10.1038/s41598-024-62296-5

Previously reported CCDC26 risk variant and novel germline variants in GALNT13, AR, and MYO10 associated with familial glioma in Finland

Riikka Nurminen
, Ebrahim Afyounian
, Niina Paunu
, Riku Katainen
, Mari Isomäki
, Anssi Nurminen
, Mauro Scaravilli
, Jenni Tolppanen
, Vidal Fey
, Anni Kivinen
, Pauli Helén
, Niko Välimäki
, Juha Kesseli
, Lauri A. Aaltonen
, Hannu Haapasalo
, Matti Nykter^*
, Kirsi J. Rautajoki^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Scientific › peer-review

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Abstract

Predisposing factors underlying familial aggregation of non-syndromic gliomas are still to be uncovered. Whole-exome sequencing was performed in four Finnish families with brain tumors to identify rare predisposing variants. A total of 417 detected exome variants and 102 previously reported glioma-related variants were further genotyped in 19 Finnish families with brain tumors using targeted sequencing. Rare damaging variants in GALNT13, MYO10 and AR were identified. Two families carried either c.553C>T (R185C) or c.1214T>A (L405Q) on GALNT13. Variant c.553C>T is located on the substrate-binding site of GALNT13. AR c.2180G>T (R727L), which is located on a ligand-binding domain of AR, was detected in two families, one of which also carried a GALNT13 variant. MYO10 c.4448A>G (N1483S) was detected in two families and c.1511C>T (A504V) variant was detected in one family. Both variants are located on functional domains related to MYO10 activity in filopodia formation. In addition, affected cases in six families carried a known glioma risk variant rs55705857 in CCDC26 and low-risk glioma variants. These novel findings indicate polygenic inheritance of familial glioma in Finland and increase our understanding of the genetic contribution to familial glioma susceptibility.

Original language	English
Article number	11562
Journal	Scientific Reports
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41598-024-62296-5
Publication status	Published - 2024
Publication type	A1 Journal article-refereed

Funding

We thank the glioma patients and their families for participation in this study. We also thank Paula Kosonen, P\u00E4ivi Martikainen, and Lila Nikkola for their contributions to sample handling, Sini Eerola for TaqMan genotyping and Hanna Selin for handling samples and data from the Finnish Cancer Registry. Personnel at Tampere University Hospital and Fimlab laboratories Ltd. are acknowledged for their contribution to sample collection. We are grateful for them and the patients for permitting the analysis of patient material. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by the NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal in April 2020 (GTEx Analysis V8, dbGaP Accession phs000424.v8.p2). The authors wish to acknowledge CSC\u2014IT Center for Science, Finland, for computational resources, the Biocenter Finland (BF), and Tampere Genomics Facility for their service. The study was financially supported by the Academy of Finland (#312043 (MN), #333545 (KR)), Cancer Foundation Finland (MN, KR), Sigrid Jus\u00E9lius Foundation (MN, KR), Emil Aaltonen Foundation (KR), Finnish Cancer Institute (MN), and Competitive State Research Financing of the Expert Responsibility area of Tampere University Hospital (MN, KR), and Tampere University Doctoral School (EA).

Funders	Funder number
National Institute of Mental Health
National Human Genome Research Institute
National Institute of Neurological Disorders and Stroke
National Institutes of Health
Emil Aaltosen Säätiö
Finnish Cancer Institute
National Cancer Institute
National Institute on Drug Abuse
National Heart, Lung, and Blood Institute
China Scholarship Council
GTEx Portal in April 2020
Syöpäsäätiö
Fimlab Laboratories Ltd
Tampere Genomics Facility
Suomen syöpärekisteri
Sigrid Juséliuksen Säätiö
Strategic Research Council at the Research Council of Finland	312043, 333545
Biocenter Finland	BF

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Nurminen, R., Afyounian, E., Paunu, N., Katainen, R., Isomäki, M., Nurminen, A., Scaravilli, M., Tolppanen, J., Fey, V., Kivinen, A., Helén, P., Välimäki, N., Kesseli, J., Aaltonen, L. A., Haapasalo, H., Nykter, M., & Rautajoki, K. J. (2024). Previously reported CCDC26 risk variant and novel germline variants in GALNT13, AR, and MYO10 associated with familial glioma in Finland. Scientific Reports, 14(1), Article 11562. https://doi.org/10.1038/s41598-024-62296-5

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title = "Previously reported CCDC26 risk variant and novel germline variants in GALNT13, AR, and MYO10 associated with familial glioma in Finland",

abstract = "Predisposing factors underlying familial aggregation of non-syndromic gliomas are still to be uncovered. Whole-exome sequencing was performed in four Finnish families with brain tumors to identify rare predisposing variants. A total of 417 detected exome variants and 102 previously reported glioma-related variants were further genotyped in 19 Finnish families with brain tumors using targeted sequencing. Rare damaging variants in GALNT13, MYO10 and AR were identified. Two families carried either c.553C>T (R185C) or c.1214T>A (L405Q) on GALNT13. Variant c.553C>T is located on the substrate-binding site of GALNT13. AR c.2180G>T (R727L), which is located on a ligand-binding domain of AR, was detected in two families, one of which also carried a GALNT13 variant. MYO10 c.4448A>G (N1483S) was detected in two families and c.1511C>T (A504V) variant was detected in one family. Both variants are located on functional domains related to MYO10 activity in filopodia formation. In addition, affected cases in six families carried a known glioma risk variant rs55705857 in CCDC26 and low-risk glioma variants. These novel findings indicate polygenic inheritance of familial glioma in Finland and increase our understanding of the genetic contribution to familial glioma susceptibility.",

author = "Riikka Nurminen and Ebrahim Afyounian and Niina Paunu and Riku Katainen and Mari Isom{\"a}ki and Anssi Nurminen and Mauro Scaravilli and Jenni Tolppanen and Vidal Fey and Anni Kivinen and Pauli Hel{\'e}n and Niko V{\"a}lim{\"a}ki and Juha Kesseli and Aaltonen, \{Lauri A.\} and Hannu Haapasalo and Matti Nykter and Rautajoki, \{Kirsi J.\}",

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doi = "10.1038/s41598-024-62296-5",

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Nurminen, R, Afyounian, E, Paunu, N, Katainen, R, Isomäki, M, Nurminen, A, Scaravilli, M, Tolppanen, J, Fey, V, Kivinen, A, Helén, P, Välimäki, N, Kesseli, J, Aaltonen, LA, Haapasalo, H, Nykter, M & Rautajoki, KJ 2024, 'Previously reported CCDC26 risk variant and novel germline variants in GALNT13, AR, and MYO10 associated with familial glioma in Finland', Scientific Reports, vol. 14, no. 1, 11562. https://doi.org/10.1038/s41598-024-62296-5

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T1 - Previously reported CCDC26 risk variant and novel germline variants in GALNT13, AR, and MYO10 associated with familial glioma in Finland

AU - Nurminen, Riikka

AU - Afyounian, Ebrahim

AU - Paunu, Niina

AU - Katainen, Riku

AU - Isomäki, Mari

AU - Nurminen, Anssi

AU - Scaravilli, Mauro

AU - Tolppanen, Jenni

AU - Fey, Vidal

AU - Kivinen, Anni

AU - Helén, Pauli

AU - Välimäki, Niko

AU - Kesseli, Juha

AU - Aaltonen, Lauri A.

AU - Haapasalo, Hannu

AU - Nykter, Matti

AU - Rautajoki, Kirsi J.

PY - 2024

Y1 - 2024

N2 - Predisposing factors underlying familial aggregation of non-syndromic gliomas are still to be uncovered. Whole-exome sequencing was performed in four Finnish families with brain tumors to identify rare predisposing variants. A total of 417 detected exome variants and 102 previously reported glioma-related variants were further genotyped in 19 Finnish families with brain tumors using targeted sequencing. Rare damaging variants in GALNT13, MYO10 and AR were identified. Two families carried either c.553C>T (R185C) or c.1214T>A (L405Q) on GALNT13. Variant c.553C>T is located on the substrate-binding site of GALNT13. AR c.2180G>T (R727L), which is located on a ligand-binding domain of AR, was detected in two families, one of which also carried a GALNT13 variant. MYO10 c.4448A>G (N1483S) was detected in two families and c.1511C>T (A504V) variant was detected in one family. Both variants are located on functional domains related to MYO10 activity in filopodia formation. In addition, affected cases in six families carried a known glioma risk variant rs55705857 in CCDC26 and low-risk glioma variants. These novel findings indicate polygenic inheritance of familial glioma in Finland and increase our understanding of the genetic contribution to familial glioma susceptibility.

AB - Predisposing factors underlying familial aggregation of non-syndromic gliomas are still to be uncovered. Whole-exome sequencing was performed in four Finnish families with brain tumors to identify rare predisposing variants. A total of 417 detected exome variants and 102 previously reported glioma-related variants were further genotyped in 19 Finnish families with brain tumors using targeted sequencing. Rare damaging variants in GALNT13, MYO10 and AR were identified. Two families carried either c.553C>T (R185C) or c.1214T>A (L405Q) on GALNT13. Variant c.553C>T is located on the substrate-binding site of GALNT13. AR c.2180G>T (R727L), which is located on a ligand-binding domain of AR, was detected in two families, one of which also carried a GALNT13 variant. MYO10 c.4448A>G (N1483S) was detected in two families and c.1511C>T (A504V) variant was detected in one family. Both variants are located on functional domains related to MYO10 activity in filopodia formation. In addition, affected cases in six families carried a known glioma risk variant rs55705857 in CCDC26 and low-risk glioma variants. These novel findings indicate polygenic inheritance of familial glioma in Finland and increase our understanding of the genetic contribution to familial glioma susceptibility.

U2 - 10.1038/s41598-024-62296-5

DO - 10.1038/s41598-024-62296-5

M3 - Article

AN - SCOPUS:85194094893

SN - 2045-2322

VL - 14

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 11562

ER -

Previously reported CCDC26 risk variant and novel germline variants in GALNT13, AR, and MYO10 associated with familial glioma in Finland

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