TY - JOUR
T1 - The genomic landscape of familial glioma
AU - The Gliogene Consortium
AU - Genomics England Research Consortium
AU - Choi, Dong Joo
AU - Armstrong, Georgina
AU - Lozzi, Brittney
AU - Vijayaraghavan, Prashanth
AU - Plon, Sharon E.
AU - Wong, Terence C.
AU - Boerwinkle, Eric
AU - Muzny, Donna M.
AU - Chen, Hsiao Chi
AU - Gibbs, Richard A.
AU - Ostrom, Quinn T.
AU - Melin, Beatrice
AU - Deneen, Benjamin
AU - Bondy, Melissa L.
AU - Bainbridge, Matthew N.
AU - Amos, Christopher I.
AU - Barnholtz-Sloan, Jill S.
AU - Bernstein, Jonine L.
AU - Claus, Elizabeth B.
AU - Houlston, Richard S.
AU - Il'yasova, Dora
AU - Jenkins, Robert B.
AU - Johansen, Christoffer
AU - Lachance, Daniel
AU - Lai, Rose
AU - Melin, Beatrice S.
AU - Merrell, Ryan T.
AU - Olson, Sara H.
AU - Sadetzki, Siegal
AU - Schildkraut, Joellen
AU - Shete, Sanjay
AU - Ambrose, J. C.
AU - Arumugam, P.
AU - Bevers, R.
AU - Bleda, M.
AU - Boardman-Pretty, F.
AU - Boustred, C. R.
AU - Brittain, H.
AU - Brown, M. A.
AU - Caulfield, M. J.
AU - Chan, G. C.
AU - Giess, A.
AU - Griffin, J. N.
AU - Hamblin, A.
AU - Henderson, S.
AU - Hubbard, T. J.P.
AU - Jackson, R.
AU - Jones, L. J.
AU - Kasperaviciute, D.
AU - Kayikci, M.
N1 - Publisher Copyright:
Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC)
PY - 2023/4/28
Y1 - 2023/4/28
N2 - Glioma is a rare brain tumor with a poor prognosis. Familial glioma is a subset of glioma with a strong genetic predisposition that accounts for approximately 5% of glioma cases. We performed whole-genome sequencing on an exploratory cohort of 203 individuals from 189 families with a history of familial glioma and an additional validation cohort of 122 individuals from 115 families. We found significant enrichment of rare deleterious variants of seven genes in both cohorts, and the most significantly enriched gene was HERC2 (P = 0.0006). Furthermore, we identified rare noncoding variants in both cohorts that were predicted to affect transcription factor binding sites or cause cryptic splicing. Last, we selected a subset of discovered genes for validation by CRISPR knockdown screening and found that DMBT1, HP1BP3, and ZCH7B3 have profound impacts on proliferation. This study performs comprehensive surveillance of the genomic landscape of familial glioma.
AB - Glioma is a rare brain tumor with a poor prognosis. Familial glioma is a subset of glioma with a strong genetic predisposition that accounts for approximately 5% of glioma cases. We performed whole-genome sequencing on an exploratory cohort of 203 individuals from 189 families with a history of familial glioma and an additional validation cohort of 122 individuals from 115 families. We found significant enrichment of rare deleterious variants of seven genes in both cohorts, and the most significantly enriched gene was HERC2 (P = 0.0006). Furthermore, we identified rare noncoding variants in both cohorts that were predicted to affect transcription factor binding sites or cause cryptic splicing. Last, we selected a subset of discovered genes for validation by CRISPR knockdown screening and found that DMBT1, HP1BP3, and ZCH7B3 have profound impacts on proliferation. This study performs comprehensive surveillance of the genomic landscape of familial glioma.
UR - http://www.scopus.com/inward/record.url?scp=85161074771&partnerID=8YFLogxK
U2 - 10.1126/SCIADV.ADE2675
DO - 10.1126/SCIADV.ADE2675
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AN - SCOPUS:85161074771
SN - 2375-2548
VL - 9
JO - Science advances
JF - Science advances
IS - 17
M1 - eade2675
ER -