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Neuro-Oncology

Research

Dr. Robert Wechsler-Reya talks about his work with RCIGM.

In 2016, the Institute established the Joseph Clayes III Research Center for Neuro-Oncology and Genomics. This was made possible by a generous $10 million endowment from the Joseph Clayes III Charitable Trust. Under the direction of Robert Wechsler-Reya, The Center aims to accelerate the translation of leading-edge genomic research into prevention, diagnosis, treatment and cures.

“The first instinct of parents who have a child diagnosed with cancer is to seek out the best treatments available,” said Stephen Kingsmore, MD, DSc, President and CEO of Rady Children’s Institute for Genomic Medicine.“That’s exactly what our team of scientists, researchers and physicians aim to provide. By sequencing the tumor, we can discover the genomic foundation of the cancer, and develop individualized approaches to treatment.”

The Joseph Clayes III Research Center for Neuro-Oncology and Genomics brings together childhood brain cancer researchers to accelerate the translation of new findings and knowledge into prevention, diagnosis, treatment and cures.

The endowment is divided into three specific programs:

  • The Joseph Clayes III Neuro-Oncology Research Fund that will accelerate research into the understanding of the genomic foundation of childhood brain cancers and help scientists to develop individualized approaches to treatment.
  • The Joseph Clayes III Endowed Chair in Neuro-Oncology Research, allowing Rady Children’s to invest in top leadership talent with the knowledge and skill to lead advanced genomics research.
  • The Joseph Clayes III Neuro-Oncology Research Fellowship and Education Fund, allowing the most promising young scientists to learn the best approaches in pioneering cancer research and preparing them to be future leaders in genomic medicine.

Related Study

Publications​

The genomic landscape of familial glioma

  • Choi DJ, Armstrong G, Lozzi B, Vijayaraghavan P, Plon SE, Wong TC, Boerwinkle E, Muzny DM, Chen HC, Gibbs RA, Ostrom QT, Melin B, Deneen B, Bondy ML; Gliogene Consortium; Genomics England Research Consortium; Bainbridge MN, Amos CI, Barnholtz-Sloan JS, Bernstein JL, Claus EB, Houlston RS, Il'yasova D, Jenkins RB, Johansen C, Lachance D, Lai R, Melin BS, Merrell RT, Olson SH, Sadetzki S, Schildkraut J, Shete S, Ambrose JC, Arumugam P, Bevers R, Bleda M, Boardman-Pretty F, Boustred CR, Brittain H, Brown MA, Caulfield MJ, Chan GC, Giess A, Griffin JN, Hamblin A, Henderson S, Hubbard TJP, Jackson R, Jones LJ, Kasperaviciute D, Kayikci M, Kousathanas A, Lahnstein L, Lakey A, Leigh SEA, Leong IUS, Lopez FJ, Maleady-Crowe F, McEntagart M, Minneci F, Mitchell J, Moutsianas L, Mueller M, Murugaesu N, Need AC, O'Donovan P, Odhams CA, Patch C, Perez-Gil D, Pereira MB, Pullinger J, Rahim T, Rendon A, Rogers T, Savage K, Sawant K, Scott RH, Siddiq A, Sieghart A, Smith SC, Sosinsky A, Stuckey A, Tanguy M, Taylor Tavares AL, Thomas ERA, Thompson SR, Tucci A, Welland MJ, Williams E, Witkowska K, Wood SM, Zarowiecki M.

Sci Adv. 2023 Apr 28;9(17):eade2675. doi: 10.1126/sciadv.ade2675. Epub 2023 Apr 28.

ABSTRACT

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.

PMID:37115922 DOI:10.1126/sciadv.ade2675

3D genome mapping identifies subgroup-specific chromosome conformations and tumor-dependency genes in ependymoma

  • Okonechnikov K, Camgöz A, Chapman O, Wani S, Park DE, Hübner JM, Chakraborty A, Pagadala M, Bump R, Chandran S, Kraft K, Acuna-Hidalgo R, Reid D, Sikkink K, Mauermann M, Juarez EF, Jenseit A, Robinson JT, Pajtler KW, Milde T, Jäger N, Fiesel P, Morgan L, Sridhar S, Coufal NG, Levy M, Malicki D, Hobbs C, Kingsmore S, Nahas S, Snuderl M, Crawford J, Wechsler-Reya RJ, Davidson TB, Cotter J, Michaiel G, Fleischhack G, Mundlos S, Schmitt A, Carter H, Michealraj KA, Kumar SA, Taylor MD, Rich J, Buchholz F, Mesirov JP, Pfister SM, Ay F, Dixon JR, Kool M, Chavez L.

Nat Commun. 2023 Apr 21;14(1):2300. doi: 10.1038/s41467-023-38044-0.

ABSTRACT

Ependymoma is a tumor of the brain or spinal cord. The two most common and aggressive molecular groups of ependymoma are the supratentorial ZFTA-fusion associated and the posterior fossa ependymoma group A. In both groups, tumors occur mainly in young children and frequently recur after treatment. Although molecular mechanisms underlying these diseases have recently been uncovered, they remain difficult to target and innovative therapeutic approaches are urgently needed. Here, we use genome-wide chromosome conformation capture (Hi-C), complemented with CTCF and H3K27ac ChIP-seq, as well as gene expression and DNA methylation analysis in primary and relapsed ependymoma tumors, to identify chromosomal conformations and regulatory mechanisms associated with aberrant gene expression. In particular, we observe the formation of new topologically associating domains (‘neo-TADs’) caused by structural variants, group-specific 3D chromatin loops, and the replacement of CTCF insulators by DNA hyper-methylation. Through inhibition experiments, we validate that genes implicated by these 3D genome conformations are essential for the survival of patient-derived ependymoma models in a group-specific manner. Thus, this study extends our ability to reveal tumor-dependency genes by 3D genome conformations even in tumors that lack targetable genetic alterations.

PMID:37085539 DOI:10.1038/s41467-023-38044-0

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Robert Wechsler-Reya (1)

Robert Wechsler-Reya, PhD

Neuro-Oncology Program Director

Robert Wechsler-Reya, PhD is also a professor and researcher at the Sanford Burnham Prebys Medical Discovery Institute (SBP) where he is focused on investigating the genes and nervous system signaling pathways that contribute to medulloblastoma, the most common malignant brain tumor in children.

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