Skip to main content
SpringerLink
Log in

Germline BRCA2 pathogenic variants in pediatric ganglioglioma: Case report and review of the literature

  • Case Report
  • Published:
Child's Nervous System Aims and scope Submit manuscript

Abstract

Background

BRCA1 and BRCA2 are tumor suppressor genes associated with increased risk of breast and ovarian cancer in adulthood. Patients with germline pathogenic variants in these genes have also been reported to develop brain tumors, although it is unclear whether these syndromes are associated with significant increased risk of brain tumor formation.

Results

Here, we report a case of a child with germline BRCA2 pathogenic variant presenting with a symptomatic ganglioglioma. To our knowledge, this is the first such patient to be reported. We discuss prior cases of brain tumors in BRCA1/2 patients and evidence for a potential role for BRCA1/2 pathogenic variants in brain tumor formation.

Conclusion

BRCA2 germline variants may increase the risk of developing some types of pediatric brain tumors, but further study is needed to determine its effect on low-grade glioma formation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

GG:

Ganglioglioma

LGG:

Low-grade glioma

BRCA1 :

BReast CAncer gene 1

BRCA2 :

BReast CAncer gene 2

References

  1. Lipson D, Capelletti M, Yelensky R, Otto G, Parker A, Jarosz M, Curran JA, Balasubramanian S, Bloom T, Brennan KW, Donahue A, Downing SR, Frampton GM, Garcia L, Juhn F, Mitchell KC, White E, White J, Zwirko Z, Peretz T, Nechushtan H, Soussan-Gutman L, Kim J, Sasaki H, Kim HR, Park SI, Ercan D, Sheehan CE, Ross JS, Cronin MT, Jänne PA, Stephens PJ (2012) Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies. Nat Med 18:382–384

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. He J, Abdel-Wahab O, Nahas MK, Wang K, Rampal RK, Intlekofer AM, Patel J, Krivstov A, Frampton GM, Young LE, Zhong S, Bailey M, White JR, Roels S, Deffenbaugh J, Fichtenholtz A, Brennan T, Rosenzweig M, Pelak K, Knapp KM, Brennan KW, Donahue AL, Young G, Garcia L, Beckstrom ST, Zhao M, White E, Banning V, Buell J, Iwanik K, Ross JS, Morosini D, Younes A, Hanash AM, Paietta E, Roberts K, Mullighan C, Dogan A, Armstrong SA, Mughal T, Vergilio JA, Labrecque E, Erlich R, Vietz C, Yelensky R, Stephens PJ, Miller VA, van den Brink MR, Otto GA, Lipson D, Levine RL (2016) Integrated genomic DNA/RNA profiling of hematologic malignancies in the clinical setting. Blood 127:3004–3014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Frampton GM, Fichtenholtz A, Otto GA, Wang K, Downing SR, He J, Schnall-Levin M, White J, Sanford EM, An P, Sun J, Juhn F, Brennan K, Iwanik K, Maillet A, Buell J, White E, Zhao M, Balasubramanian S, Terzic S, Richards T, Banning V, Garcia L, Mahoney K, Zwirko Z, Donahue A, Beltran H, Mosquera JM, Rubin MA, Dogan S, Hedvat CV, Berger MF, Pusztai L, Lechner M, Boshoff C, Jarosz M, Vietz C, Parker A, Miller VA, Ross JS, Curran J, Cronin MT, Stephens PJ, Lipson D, Yelensky R (2013) Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol 31:1023–1031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Tavtigian SV, Simard J, Rommens J, Couch F, Shattuck-Eidens D, Neuhausen S, Merajver S, Thorlacius S, Offit K, Stoppa-Lyonnet D, Belanger C, Bell R, Berry S, Bogden R, Chen Q, Davis T, Dumont M, Frye C, Hattier T, Jammulapati S, Janecki T, Jiang P, Kehrer R, Leblanc JF, Mitchell JT, McArthur-Morrison J, Nguyen K, Peng Y, Samson C, Schroeder M, Snyder SC, Steele L, Stringfellow M, Stroup C, Swedlund B, Swense J, Teng D, Thomas A, Tran T, Tranchant M, Weaver-Feldhaus J, Wong AKC, Shizuya H, Eyfjord JE, Cannon-Albright L, Tranchant M, Labrie F, Skolnick MH, Weber B, Kamb A, Goldgar DE (1996) The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds. Nat Genet 12:333–337

    Article  CAS  PubMed  Google Scholar 

  5. Landrum MJ, Lee JM, Benson M, Brown GR, Chao C, Chitipiralla S, Gu B, Hart J, Hoffman D, Jang W, Karapetyan K, Katz K, Liu C, Maddipatla Z, Malheiro A, McDaniel K, Ovetsky M, Riley G, Zhou G, Holmes JB, Kattman BL, Maglott DR (2018) ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res 46:D1062–D1067

  6. Compton JJ, Laack NN, Eckel LJ, Schomas DA, Giannini C, Meyer FB (2012) Long-term outcomes for low-grade intracranial ganglioglioma: 30-year experience from the Mayo Clinic. J Neurosurg 117:825–830

    Article  PubMed  Google Scholar 

  7. Song JY, Kim JH, Cho YH, Kim CJ, Lee EJ (2014) Treatment and outcomes for gangliogliomas: a single-center review of 16 patients. Brain Tumor Res Treat 2:49–55

    Article  PubMed  PubMed Central  Google Scholar 

  8. Blumcke I, Spreafico R, Haaker G, Coras R, Kobow K, Bien CG, Pfäfflin M, Elger C, Widman G, Schramm J, Becker A, Braun KP, Leijten F, Baayen JC, Aronica E, Chassoux F, Hamer H, Stefan H, Rössler K, Thom M, Walker MC, Sisodiya SM, Duncan JS, McEvoy AW, Pieper T, Holthausen H, Kudernatsch M, Meencke HJ, Kahane P, Schulze-Bonhage A, Zentner J, Heiland DH, Urbach H, Steinhoff BJ, Bast T, Tassi L, Lo Russo G, Özkara C, Oz B, Krsek P, Vogelgesang S, Runge U, Lerche H, Weber Y, Honavar M, Pimentel J, Arzimanoglou A, Ulate-Campos A, Noachtar S, Hartl E, Schijns O, Guerrini R, Barba C, Jacques TS, Cross JH, Feucht M, Mühlebner A, Grunwald T, Trinka E, Winkler PA, Gil-Nagel A, Toledano Delgado R, Mayer T, Lutz M, Zountsas B, Garganis K, Rosenow F, Hermsen A, von Oertzen TJ, Diepgen TL, Avanzini G (2017) Histopathological findings in brain tissue obtained during epilepsy surgery. N Engl J Med 377:1648–1656

    Article  PubMed  Google Scholar 

  9. Blümcke I, Aronica E, Becker A, Capper D, Coras R, Honavar M, Jacques TS, Kobow K, Miyata H, Mühlebner A, Pimentel J, Söylemezoğlu F, Thom M (2016) Low-grade epilepsy-associated neuroepithelial tumours — the 2016 WHO classification. Nat Rev Neurol 12:732–740

    Article  PubMed  Google Scholar 

  10. Koh HY, Kim SH, Jang J, Kim H, Han S, Lim JS, Son G, Choi J, Park BO, Heo WD, Han J, Lee HJ, Lee D, Kang H-C, Shong M, Paik S-B, Kim DS, Lee JH (2018) BRAF somatic mutation contributes to intrinsic epileptogenicity in pediatric brain tumors. Nat Med 24:1662–1668

    Article  CAS  PubMed  Google Scholar 

  11. Pekmezci M, Villanueva-Meyer JE, Goode B, Van Ziffle J, Onodera C, Grenert JP, Bastian BC, Chamyan G, Maher OM, Khatib Z, Kleinschmidt-DeMasters BK, Samuel D, Mueller S, Banerjee A, Clarke JL, Cooney T, Torkildson J, Gupta N, Theodosopoulos P, Chang EF, Berger M, Bollen AW, Perry A, Tihan T, Solomon DA (2018) The genetic landscape of ganglioglioma. Acta Neuropathol Commun 6:47

    Article  PubMed  PubMed Central  Google Scholar 

  12. Lee LJ, Alexander B, Schnitt SJ, Comander A, Gallagher B, Garber JE, Tung N (2011) Clinical outcome of triple negative breast cancer in BRCA1 mutation carriers and noncarriers. Cancer 117:3093–3100

    Article  CAS  PubMed  Google Scholar 

  13. Garber HR, Raghavendra AS, Lehner M, Qiao W, Gutierrez-Barrera AM, Tripathy D, Arun B, Ibrahim NK (2022) Incidence and impact of brain metastasis in patients with hereditary BRCA1 or BRCA2 mutated invasive breast cancer. Breast Cancer 8:46

  14. Ratner E, Bala M, Louie-Gao M, Aydin E, Hazard S, Brastianos PK (2019) Increased risk of brain metastases in ovarian cancer patients with BRCA mutations. Gynecol Oncol 153:568–573

    Article  PubMed  Google Scholar 

  15. Korhonen L, Brännvall K, Skoglösa Y, Lindholm D (2003) Tumor suppressor gene BRCA-1 is expressed by embryonic and adult neural stem cells and involved in cell proliferation. J Neurosci Res 71:769–776

    Article  CAS  PubMed  Google Scholar 

  16. Lee JH, Lee JE, Kahng JY, Kim SH, Park JS, Yoon SJ, Um JY, Kim WK, Lee JK, Park J, Kim EH, Lee JH, Lee JH, Chung WS, Ju YS, Park SH, Chang JH, Kang SG, Lee JH (2018) Human glioblastoma arises from subventricular zone cells with low-level driver mutations. Nature 560:243–247

    Article  CAS  PubMed  Google Scholar 

  17. Alcantara Llaguno S, Chen J, Kwon C-H, Jackson EL, Li Y, Burns DK, Alvarez-Buylla A, Parada LF (2009) Malignant astrocytomas originate from neural stem/progenitor cells in a somatic tumor suppressor mouse model. Cancer Cell 15:45–56

  18. Brossier NM, Thondapu S, Cobb OM, Dahiya S, Gutmann DH (2020) Temporal, spatial, and genetic constraints contribute to the patterning and penetrance of murine Neurofibromatosis-1 optic glioma. Neuro Oncol

  19. Anastasaki C, Chatterjee J, Cobb O, Sanapala S, Scheaffer SM, De Andrade CA, Wilson AF, Kernan CM, Zafar AH, Ge X, Garbow JR, Rodriguez FJ, Gutmann DH (2022) Human induced pluripotent stem cell engineering establishes a humanized mouse platform for pediatric low-grade glioma modeling. Acta Neuropathol Commun 10:120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Pao GM, Zhu Q, Perez-Garcia CG, Chou SJ, Suh H, Gage FH, O’Leary DD, Verma IM (2014) Role of BRCA1 in brain development. Proc Natl Acad Sci USA 111:E1240–E1248

  21. Frappart P-O, Lee Y, Lamont J, McKinnon PJ (2007) BRCA2 is required for neurogenesis and suppression of medulloblastoma. EMBO J 26:2732–2742

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Offit K, Levran O, Mullaney B, Mah K, Nafa K, Batish SD, Diotti R, Schneider H, Deffenbaugh A, Scholl T, Proud VK, Robson M, Norton L, Ellis N, Hanenberg H, Auerbach AD (2003) Shared genetic susceptibility to breast cancer, brain tumors, and Fanconi anemia. J Natl Cancer Inst 95:1548–1551

    Article  CAS  PubMed  Google Scholar 

  23. Blanche PA, Philip SR, Lawrence CB (2007) Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2. J Med Genet 44:1

    Google Scholar 

  24. Reid S, Renwick A, Seal S, Baskcomb L, Barfoot R, Jayatilake H, Pritchard-Jones K, Stratton MR, Ridolfi-Lüthy A, Rahman N (2005) Biallelic BRCA2 mutations are associated with multiple malignancies in childhood including familial Wilms tumour. J Med Genet 42:147–151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Waszak SM, Northcott PA, Buchhalter I, Robinson GW, Sutter C, Groebner S, Grund KB, Brugières L, Jones DTW, Pajtler KW, Morrissy AS, Kool M, Sturm D, Chavez L, Ernst A, Brabetz S, Hain M, Zichner T, Segura-Wang M, Weischenfeldt J, Rausch T, Mardin BR, Zhou X, Baciu C, Lawerenz C, Chan JA, Varlet P, Guerrini-Rousseau L, Fults DW, Grajkowska W, Hauser P, Jabado N, Ra Y-S, Zitterbart K, Shringarpure SS, De La Vega FM, Bustamante CD, Ng H-K, Perry A, MacDonald TJ, Hernáiz Driever P, Bendel AE, Bowers DC, McCowage G, Chintagumpala MM, Cohn R, Hassall T, Fleischhack G, Eggen T, Wesenberg F, Feychting M, Lannering B, Schüz J, Johansen C, Andersen TV, Röösli M, Kuehni CE, Grotzer M, Kjaerheim K, Monoranu CM, Archer TC, Duke E, Pomeroy SL, Shelagh R, Frank S, Sumerauer D, Scheurlen W, Ryzhova MV, Milde T, Kratz CP, Samuel D, Zhang J, Solomon DA, Marra M, Eils R, Bartram CR, von Hoff K, Rutkowski S, Ramaswamy V, Gilbertson RJ, Korshunov A, Taylor MD, Lichter P, Malkin D, Gajjar A, Korbel JO, Pfister SM (2018) Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort. Lancet Oncol 19:785–798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Dodgshun AJ, Sexton-Oates A, Saffery R, Sullivan MJ (2016) Biallelic FANCD1/BRCA2 mutations predisposing to glioblastoma multiforme with multiple oncogenic amplifications. Cancer Genet 209:53–56

    Article  CAS  PubMed  Google Scholar 

  27. Meimand SE, Pour-Rashidi A, Shahrbabak MM, Mohammadi E, Meimand FE, Rezaei N (2022) The prognostication potential of BRCA genes expression in gliomas: a genetic survival analysis study. World Neurosurg 157:e123–e128

    Article  PubMed  Google Scholar 

  28. Kratz CP, Smirnov D, Autry R, Jäger N, Waszak SM, Großhennig A, Berutti R, Wendorff M, Hainaut P, Pfister SM, Prokisch H, Ripperger T, Malkin D (2022) Heterozygous BRCA1 and BRCA2 and mismatch repair gene pathogenic variants in children and adolescents with cancer. J Natl Cancer Inst 114:1523–1532

  29. Qin N, Wang Z, Liu Q, Song N, Wilson CL, Ehrhardt MJ, Shelton K, Easton J, Mulder H, Kennetz D, Edmonson MN, Rusch MC, Downing JR, Hudson MM, Nichols KE, Zhang J, Robison LL, Yasui Y (2020) Pathogenic germline mutations in DNA repair genes in combination with cancer treatment exposures and risk of subsequent neoplasms among long-term survivors of childhood cancer. J Clin Oncol 38:2728–2740

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Li H, Sisoudiya SD, Martin-Giacalone BA, Khayat MM, Dugan-Perez S, Marquez-Do DA, Scheurer ME, Muzny D, Boerwinkle E, Gibbs RA, Chi YY, Barkauskas DA, Lo T, Hall D, Stewart DR, Schiffman JD, Skapek SX, Hawkins DS, Plon SE, Sabo A, Lupo PJ (2021) Germline cancer predisposition variants in pediatric rhabdomyosarcoma: a report from the children’s oncology group. J Natl Cancer Inst 113:875–883

    Article  PubMed  Google Scholar 

Download references

Funding

This work is funded by grants from the St. Louis Children’s Hospital Foundation (FDN20231203 to NMB).

Author information

Authors and Affiliations

  1. Departments of Pediatrics, Washington University School of Medicine, Box 8208, 660 South Euclid Avenue, St. Louis, MO, 63110, USA

    Anya Gupta & Nicole M. Brossier

  2. Foundation One Medicine, Cambridge, USA

    Mirna Lechpammer

Authors
  1. Anya Gupta
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mirna Lechpammer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nicole M. Brossier
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Writing, original draft, A.G., M.L., and N.M.B.; writing—review and editing, N.M.B.; supervision, N.M.B.; funding acquisition, N.M.B. All authors have reviewed and agree to the content of the manuscript.

Corresponding author

Correspondence to Nicole M. Brossier.

Ethics declarations

Conflict of interest

Mirna Lechpammer is the Associate Medical Director of Pathology at Foundation One Medicine. Samples were tested via Foundation One CDx per standardized clinical workflow at Washington University in St. Louis. Dr. Lechpammer’s contribution to the manuscript was limited to the technical description of the assay. All other authors have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gupta, A., Lechpammer, M. & Brossier, N.M. Germline BRCA2 pathogenic variants in pediatric ganglioglioma: Case report and review of the literature. Childs Nerv Syst 40, 1609–1612 (2024). https://doi.org/10.1007/s00381-023-06267-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00381-023-06267-7

Keywords

Search

Navigation