Characterization of medulloblastoma in Fanconi Anemia: a novel mutation in the BRCA2 gene and SHH molecular subgroup
- Evelina Miele†1, 2,
- Angela Mastronuzzi†3,
- Agnese Po1,
- Andrea Carai4,
- Vincenzo Alfano1, 2,
- Annalisa Serra3,
- Giovanna Stefania Colafati5,
- Luisa Strocchio3,
- Manila Antonelli6,
- Francesca Romana Buttarelli6,
- Massimo Zani1,
- Sergio Ferraro1,
- Amelia Buffone1,
- Alessandra Vacca7,
- Isabella Screpanti1,
- Felice Giangaspero6, 8,
- Giuseppe Giannini1, 9,
- Franco Locatelli3 and
- Elisabetta Ferretti7Email author
© Miele et al. 2015
Received: 26 March 2015
Accepted: 26 May 2015
Published: 6 June 2015
Fanconi Anemia (FA) is an inherited disorder characterized by the variable presence of multiple congenital somatic abnormalities, bone marrow failure and cancer susceptibility. Medulloblastoma (MB) has been described only in few cases of FA with biallelic inactivation in the tumor suppressor gene BRCA2/FANCD1 or its associated gene PALB2/FANCN.
We report the case of a patient affected by Fanconi Anemia with Wilms tumor and unusual presentation of two medulloblastomas (MB1 and MB2). We identified a new pathogenetic germline BRCA2 mutation: c.2944_2944delA. Molecular analysis of MBs allowed us to define new features of MB in FA. MBs were found to belong to the Sonic Hedgehog (SHH) molecular subgroup with some differences between MB1 and MB2. We highlighted that MB in FA could share molecular aspects and hemispheric localization with sporadic adult SHH-MB. Our report provides new findings that shed new light on the genetic and molecular pathogenesis of MB in FA patients with implications in the disease management.
KeywordsFanconi anemia Medulloblastoma BRCA2 FANCD1 SHH molecular subgroup
Fanconi Anemia (FA) is a genetically and phenotypically heterogeneous disorder, inherited with an autosomal (or rarely X-linked) recessive pattern, occurring in approximately 1/100,000 births per year . Main features of FA are the presence of multiple congenital somatic abnormalities, the gradual onset of bone marrow failure, and a strong predisposition to cancer. The most common malignancies include acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), followed by solid tumors, mostly squamous-cell carcinomas at young age [2–4].
Solid tumors may represent the first manifestation of FA in individuals without congenital somatic abnormalities or hematological manifestations . These tumors include squamous cell carcinomas of head and neck, esophagus, vulva and cervix, liver tumors, and rarely embryonic tumors.
The hallmark of FA is chromosome fragility and hypersensitivity to DNA interstrand cross-linking agents [6, 7, 1, 8–10]. To date, 17 genes (FANCA, FANCB, FANCC, FANCD1/BRCA2, FANCD2, FANCE, FANCF, FANCG/XRCC9, FANCI, FANCJ/BRIP1, FANCL, FANCM, FANCN/PALB2/BRIP1, FANCO/RAD51C, FANCP/SLX4, FANCQ/ERCC4, and FANCS/BRCA1) are known to be involved in the pathogenesis of FA [1, 8, 9, 11]. The 17 gene products appear to interact in a common cellular pathway involved in the regulation of DNA repair. Mutations in eight FA genes (FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, and FANCM) result in loss of FANCD2 and FANCI monoubiquitination, the central regulatory event of the FA pathway, while FA proteins downstream to FANCD2 (e.g. FANCJ/BRIP1, FANCN/PALB2, and FANCD1/BRCA2) cooperate in DNA repair .
Although a clear picture of genotype-phenotype correlation in FA is currently not completely elucidated, many data suggest that specific complementation groups play a significant role in both phenotypic expression and survival [12, 13].
In particular, biallelic mutations in FANCD1/BRCA2 (about 2 % of all FA patients)  and FANCN/PALB2 are associated with an extremely high predisposition to leukemia and solid tumors (e.g. medulloblastoma, Wilms tumor) at a very early age [15, 16], with a cumulative incidence probability of malignancy of 97 % by the age of 5.2 years in FANCD1/BRCA2 patients .
Previously reported cases of brain tumors associated with BRCA2 mutations
BRCA2 mutation I
BRCA mutation 2
c.2830A > T
c.7964A > G
9435 T > A
Ashkenazi Jewish congenital anomalies Sibling of the following
9435 T > A
Ashkenazi Jewish Sibling of the previous
Mixed Ashkenazi Jewish
c.7469 T > C
c.3922G > T
c.9196C > T
8447 T > A
Sibling of the following
MB, WT (15 mo)
8447 T > A
Sibling of the previous
GB, WT (3.5 yrs)
c.5645C > A
Sibling of the following
MB, WT (7mo) ALL-B (10 yrs)
c.5645C > A
Sibling of the previous
Consanguinity VACTERL syndrome
c.9196C > T
PNET or HGG
Sibling of the following
Sibling of the previous
c.IVS19 + 3A > G (c. 8487 + 3A > G)
MB, WT (8 mo) AML (24 mo)
c.1114A > C
c.1114A > C
MB WT (4 yrs)
MB WT(15 mo)
MB1: Hemispheric; MB2: vermian
MB1, MB2: SHH subtype
Here, we report a case of a patient affected by FA, who sequentially developed WT and unexpected two distinct MBs, in which we identified a novel pathogenetic germline BRCA2 mutation and MB molecular subgroup.
Clinical and neurophatologic features
A 15-month-old female patient born at term, small for gestational age, the second daughter of non-consanguineous parents was referred to the Bambino Gesù Children Hospital for macroscopic hematuria due to a large renal neoplasm in a solitary pelvic cake kidney.
Laboratory tests showed mild renal failure (creatinine 1.37 mg/dl, BUN 46 mg/dl), normocytic anemia (Hb 7.5 g/dl; MCV 77 fl), hyperuricemia (8.4 mg/dl) and increased LDH (1963 UI/dl). Hypertension (both diastolic and systolic blood pressure exceeding the 90th percentile) required pharmacological treatment.
Physical examination revealed growth retardation (both weight and height lower than 3rd percentile), abnormal skin pigmentation (both café au lait spots and hypopigmentation), elfin facies with epicanthus. Echocardiography showed a mitral valve insufficiency. The patient also had right-convex scoliosis and ribs anomalies. A clinical suspect of FA was formulated and a DEB-test was performed which showed multiple spontaneous and DEB-induced chromosomal breaks per cell. Radiologic tumor assessment confirmed the presence of a renal neoplasm (78.1 × 42.2 × 62.8 mm) (Additional file 1: Figure S1a) with bilateral lung metastases (Additional file 1: Figure S1b).
Neoadjuvant chemotherapy was started, according to SIOP WT 2001 protocol, obtaining a partial response on both primary tumor (44 × 33 × 22 mm) (Additional file 1: Figure S1c) and metastatic lesions. Despite dose-adapted chemotherapy, chosen considering chromosomal fragility and according to renal function, the child experienced a grade-IV hematological toxicity and respiratory failure requiring admission to the intensive care unit. Afterwards, tumorectomy was performed, sparing residual renal functioning tissue. Histologic analysis confirmed a grade-III nephroblastoma, according to SIOP 2001 classification . Post-surgical chemotherapy was resumed until completion of the protocol. At that point, a single residual lung metastasis was present and therefore resected by thoracotomy with no significant complications. Follow up confirmed stable remission with a mild chronic renal failure.
Histology showed a neoplasm with an expanded lobular architecture, due to the reticulin-free zones rich in neuropil-like tissue. Such zones contained a population of small cells with rounded nuclei diagnostic of a desmoplastic/nodular medulloblastoma (Fig. 1g-h) without C/N-myc amplification evaluated by FISH analysis. Due to previous clinical history and to the persistence of a mild chronic renal failure, a tailored chemotherapeutic regimen with Carboplatin and Vincristine was chosen. Despite the low dose of chemotherapy employed, the patient presented a significant toxicity after the first course of treatment including pancytopenia (WHO grade IV), sepsis and deterioration of renal function that slowly recovered in 3 months. Considering this relevant toxicity no further treatment was offered.
Considering the toxicity shown during previous treatments, an evaluation of target molecular expression on the tumor was performed. Based on the evidence of expression of P-mTor, a personalized treatment with rapamycin  associated with intrathecal liposomal cytarabine  was started. Despite therapy, patient died of relapse and disease progression two months after the diagnosis of the second MB at 55 months of age.
Based on published data, the onset of MB after a WT in this FA patient raised the suspicion of a biallelic mutation in FANCD1/BRCA2. To confirm this hypothesis, we performed a genetic analysis of FANC1/BRCA2 on patient’s DNA extracted from both from peripheral blood and MB1 cells, which revealed the presence of compound heterozygosis for BRCA2 frameshift mutations.
MBs molecular features
We performed gene expression analysis of both hemispheric MB1 and vermian MB2 by real-time quantitative PCR (RT-QPCR). We used TaqMan Low Density Array custom designed with TaqMan assays (Life Technologies - Thermo Fisher Scientific, Waltham, MA USA) for genes of interest for medulloblastoma subgrouping, according to Northcott 2012 [36, 37], while we used single TaqMan assay (Life Technologies - Thermo Fisher Scientific, Waltham, MA USA) for all other shown mRNA analyses . Gene expression analysis on samples was performed using a ViiA7 sequence detection system according to the manufacturer’s instructions. RNA of normal human cerebellum (7 adult samples from 25- to 70-year-old subjects were purchased from Biocat (Heidelberg, Germany), Ambion (Life Technologies - Thermo Fisher Scientific, Waltham, MA USA) and BD Biosciences (San Jose, CA) .
Unsupervised clustering and heatmaps were generated using the analyzed transcript levels expressed as Delta Ct values as input. We used Spotfire software (TIBCO Software, Inc. CA, USA) to cluster the samples and to generate the heatmaps, as previously described [39, 40].
Genes associated with chromatin modifications, such as histone methylases/demethylases and polycomb (EZH2, KDM6B, KDM6A, BMI1) and the homeobox transcription factor OTX2 , were also evaluated. Indeed, large cell/anaplastic MB2 showed higher levels of EZH2, OTX2 and KDM6B and lower levels of KDM6A and BMI1 (Fig. 5f).
Finally, hemispheric localization of MB is rare in infancy, while is common in adulthood. Moreover, despite the common activation of Hh signaling, infant, childhood and adult SHH MBs have been demonstrated to be clinically, transcriptionally, genetically and prognostically distinct [42, 43].
This analysis allowed us to better define features of MBs in FA. We identified a new pathogenetic germline BRCA2 mutation in FA; both MBs belonged to SHH molecular subgroup with a more “aggressive” phenotype in MB2, and, finally, we documented that MB1 shared similarities with sporadic adult SHH-MB, such as hemispheric localization and gene expression pattern.
In our patient, the first manifestation that led to the diagnosis of FA was the onset of WT.
WT and MB in FA have been reported in few cases and are associated with mutations of FANCD1/BRCA2 and more rarely with mutations of FANCN/PALB2 [24, 44]. Based on this evidence, we investigated BRCA2 mutational status and confirmed the presence of biallelic truncating mutations in the FA patient. The c.658_659delGT mutation occurring on BRCA2 exon 8 had been previously reported in hereditary breast/ovarian cancer cohorts (see in example ) and is one of the most frequently occurring in FANCD1/BRCA2 mutated FA cases . The second truncating mutation, the previously undescribed c.2944_2944delA (p.Ile982Tyrfs), occurs on BRCA2 exon 11. The segregation analysis among the available relatives allowed us to assign the two mutations as of paternal and maternal origin, respectively. The absence of breast and ovarian cancer cases in the pedigree could appear surprising, at first. However, both paternal and maternal sides of the tree were characterized by a relatively small number of potential female carriers. Indeed, the c.658_659delGT allele was inherited by the patient via two male carriers (father and grandfather) and the only female member on this line (affected by gastric cancer) was not available for segregation analysis. The c.2944_2944delA allele, possibly coming from the mother’s maternal grandfather affected with pancreatic cancer, reached the patients via a 64 years old grandmother and a 36 years old mother, a female carrier of rather young age compared to 43 and 54 years, the mean ages of breast and ovarian cancer diagnosis, respectively, recently reported in a very large cohort analysis . The preponderance of male relatives in this side of the tree further hindered any possible speculation on the role of the c.2944_2944delA on breast and ovarian cancer predisposition.
Complete BRCA1 or BRCA2 loss is lethal in mice . This is likely to be the case also in humans, since no biallelic BRCA2 mutations occurring 5′ to exon 7 have been reported in FA patients so far, while monoallelic truncating mutations from exon 2 to exon 7 have been frequently associated with breast/ovarian cancer susceptibility. In three out of four FA patients, the c.658_659delGT mutation occurred in association with a truncating mutations of exon 11 . This is also the case for the patient described here, in which the c.658_659delGT mutation is associated with a truncating mutation of BRCA2 exon 11, the previously undescribed c.2944_2944delA (p.Ile982Tyrfs) mutation. Overall, these data suggest that BRCA2 truncation downstream of exon 7/8 is probably hypomorphic, but still compatible with life especially in association with exon 11 truncated BRCA2 forms. However, as already noticed by Meyer, homozygous or compound heterozygous exon 11 mutations have not been reported in FA patients despite the relatively high frequency of these alleles. Together with the report of the recurrent miscarriages in Jewish BRCA2 mutation carriers , this suggests that biallelic exon 11 BRCA2 mutation may also be incompatible with life. More definitive answers on this topic may come from directly addressing this issue in specifically modeled mice.
MB in FA patients reported in the literature typically show cerebellar hemispheric localization and desmoplastic histology, as we observed in MB1 (Table 1). Cerebellar hemispheric MBs are frequently desmoplastic and belong to the SHH subgroup, especially in adults . Hemispheric location is consistent with the results from MB mouse models that have shown SHH-MB origin from committed granule neuron precursors (GNPs) of the cerebellum. Teo et al., reported hemispheric involvement in 9 of 17 (53 %) SHH-MBs, regardless of age at diagnosis . In Perreault study , SHH lesions rarely invaded the brain stem, consistent with a prior study that reported brain stem infiltration by WNT, but not by SHH tumors .
Gene expression analysis of our MBs allowed us to clearly define that both MB1 and MB2 belonged to SHH subgroup.
Biological explanation of the association between FA and SHH-MB has been analyzed in different papers. Frappart et al. first showed that BRCA2 loss affects neurogenesis and promotes MB growth, using a mouse model harboring neural tissue-restricted BRCA2 inactivation . They also identified PTCH1 (a gatekeeper gene often inactivated in MB) as a critical target in all DNA repair-deficient MB.
Huang et al. reported that conditional knockdown BCCIP (BRCA2-interacting protein with a role in homologous recombination and chromosome stability) in concomitance with p53 deletion caused rapid development of MB in the external granular layer, triggered by SHH pathway activation  via the inactivation of the Ptch1 gatekeeper tumor suppressor . As reported above, biallelic PALB2/FANCN mutation carriers show a cancer spectrum comparable to those with biallelic BRCA2/FANCD1, characterized by early onset AML and embryonic tumors, including MB and WT . This observation strengthens the role of BRCA2 in medulloblastomagenesis, since FANCN (also known as ‘partner and localizer of BRCA2′, PALB2) is well known to co-localize with BRCA2 in the nucleus . Interestingly, BRIP1/FANCJ maps on 17q chromosome, a region frequently deleted in MBs . Thus, deleterious mutations in one of the members of the homologous recombination machinery could lead to MB onset (Fig. 7). This feature may provide the rationale for new therapeutic approaches for MB, as also suggested by Bayrakli et al. . Platinum compounds or similar drugs, inducing growth arrest by ICL-stalled- DNA replication fork, could be combined with agents which take advantage of the incapacity of HR-deficient neoplastic cells to face up this stall (e.g. enzyme poly-ADP-ribose polymerase I) . Indeed, PARP- inhibition has already been shown to sensitize childhood glioma, medulloblastoma and ependymoma to radiation .
It has been reported that MBs do not change subgroup at the time of recurrence and that SHH tumors more frequently have tumor bed recurrence than metastatic dissemination [58–60]. Even though we cannot completely rule out that the second MB was not a distant relapse from the first one, in our patient, the occurrence of MB2 with a different localization, a more aggressive histology, and distinct gene expression patterns could be suggestive for a second tumor. We hypothesize that Hedgehog signaling activation could have been triggered in two distinct cells of origin. Indeed, MBs have long been known to arise in GNPs in the external granule layer (EGL) and, more recently, GNPs derived from cochlear nuclei of the brainstem . SHH-dependent MBs may also arise from neural stem cells (NSCs) of the subventricular zone (SVZ). The different tumor location and expression levels of stemness/differentiation genes sustain this assumption. MB2 was characterized by higher levels of EZH2, which trimethylates histone 3 lysine 27 (H3K27me3), concurrently with down regulation of the lysine demethylase 6A (KDM6A), which removes the same repressive mark on chromatin (Fig. 5e). Both these events converge on shutting off oncosuppressor/differentiation genes and contribute to the maintenance of a more “cancer stem-like” phenotype [37, 62].
It has been reported that pediatric and adult SHH-MBs are clinically and molecularly distinct [42, 43]. In a data analysis based on Whole Genome Sequencing Kool et al. reported that the molecular differences among infant, childhood and adult SHH-MBs reside not only at the transcriptional level, but also in DNA methylation .
In our report, we found that the hemispheric, desmoplastic, myc-not amplified SHH MB1 was more similar to other adult/childhood SHH-MBs, while the vermian, large cell/anaplastic, N-myc amplified MB2 was more similar to infant SHH-MB. The hypothesis of different cells of origin stands also for such differences between adults and infants SHH-MBs.
Lastly, the suspect of SHH-MB in FA could direct the therapy toward a tailored approach, based on the use of PARP inhibitors or/and SHH inhibitors. However, giving the specific genetic background (BRCA2), it is highly unlikely that these tumors have PTCH1 or SMO mutations making them sensitive to the ‘upstream’ Hedgehog inhibitors targeting SMO. It is more likely that they have activated the SHH pathway more downstream at the level of MYCN and probably also GLI2 amplification (as probably in our MB2). Indeed, as Kool et al. have shown in their recent paper, these tumors are resistant to these ‘upstream’ Hedgehog inhibitors . Inhibitors that target downstream components of the Hh pathway are under pre-clinical evaluation  (e.g. Gant61 , Glabrescione B ).
In conclusion, we report a novel BRCA2 mutation in a FA patient with diagnosis of two distinct MBs. Molecular features of MB in our FANCD1/BRCA2 patient highlight that MB in FA patients belongs to SHH subgroup.
Two points are worthy of discussion, due to potential clinical implications. First, it is important to suspect a diagnosis of FA in patients whose first manifestations are embryonic tumors with a sequence WT-MB.
Second, the identification of SHH subtype MB in FA patients with FANCD1/BRCA2 mutations may play a critical role for targeted therapeutic interventions. Indeed, in patients characterized by a peculiar difficulty in cancer therapeutic management, due to the underlying chromosomal instability, a benefit could be provided by target therapy or new combined therapies.
Written informed consent was obtained from the patient’s parents for publication of this Case report and of any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Acute myeloid leukemia
International Society of Paediatric Oncology
Fluorescent in situ hybridization
Magnetic Resonance Imaging
World Heath Organization
Granule neuron precursors
External granule layer
Neural stem cells
We acknowledge patient’s family for collaboration. This work was supported by Ministry of University and Research (FIRB, PRIN and PON projects), Associazione Italiana Ricerca Cancro (AIRC), Sapienza Ateneo-Awards, Pasteur Institute/Cenci Bolognetti Foundation, Associazione Italiana per la Ricerca sull'Anemia di Fanconi (AIRFA) and Italian Institute of Technology (IIT). EM is supported by a post-doctoral fellowship from IIT.
- Kottemann MC, Smogorzewska A. Fanconi anaemia and the repair of Watson and Crick DNA crosslinks. Nature. 2013;493(7432):356–63. doi:10.1038/nature11863.PubMed CentralPubMedView ArticleGoogle Scholar
- Rosenberg PS, Greene MH, Alter BP. Cancer incidence in persons with Fanconi anemia. Blood. 2003;101(3):822–6. doi:10.1182/blood-2002-05-1498.PubMedView ArticleGoogle Scholar
- Alter BP, Greene MH, Velazquez I, Rosenberg PS. Cancer in Fanconi anemia. Blood. 2003;101(5):2072. doi:10.1182/blood-2002-11-3597.PubMedView ArticleGoogle Scholar
- Joenje H, Patel KJ. The emerging genetic and molecular basis of Fanconi anaemia. Nat Rev Genet. 2001;2(6):446–57. doi:10.1038/35076590.PubMedView ArticleGoogle Scholar
- Wang AT, Smogorzewska A. SnapShot: Fanconi Anemia and Associated Proteins. Cell. 2015;160(1–2):354- e1. doi:10.1016/j.cell.2014.12.031.Google Scholar
- Knies K, Schuster B, Ameziane N, Rooimans M, Bettecken T, de Winter J, et al. Genotyping of fanconi anemia patients by whole exome sequencing: advantages and challenges. PLoS One. 2012;7(12), e52648. doi:10.1371/journal.pone.0052648.PubMed CentralPubMedView ArticleGoogle Scholar
- Mehta P, Locatelli F, Stary J, Smith FO. Bone marrow transplantation for inherited bone marrow failure syndromes. Pediatr Clin N Am. 2010;57(1):147–70. doi:10.1016/j.pcl.2010.01.002.View ArticleGoogle Scholar
- Bogliolo M, Schuster B, Stoepker C, Derkunt B, Su Y, Raams A, et al. Mutations in ERCC4, encoding the DNA-repair endonuclease XPF, cause Fanconi anemia. Am J Hum Genet. 2013;92(5):800–6. doi:10.1016/j.ajhg.2013.04.002.PubMed CentralPubMedView ArticleGoogle Scholar
- Kashiyama K, Nakazawa Y, Pilz DT, Guo C, Shimada M, Sasaki K, et al. Malfunction of nuclease ERCC1-XPF results in diverse clinical manifestations and causes Cockayne syndrome, xeroderma pigmentosum, and Fanconi anemia. Am J Hum Genet. 2013;92(5):807–19. doi:10.1016/j.ajhg.2013.04.007.PubMed CentralPubMedView ArticleGoogle Scholar
- Kee Y, D'Andrea AD. Expanded roles of the Fanconi anemia pathway in preserving genomic stability. Genes Dev. 2010;24(16):1680–94. doi:10.1101/gad.1955310.PubMed CentralPubMedView ArticleGoogle Scholar
- Sawyer SL, Tian L, Kahkonen M, Schwartzentruber J, Kircher M, Majewski J, et al. Biallelic mutations in BRCA1 cause a new Fanconi Anemia subtype. Cancer Discov. 2015;5(2):135–42. doi:10.1158/2159-8290.CD-14-1156.PubMedView ArticleGoogle Scholar
- Kutler DI, Singh B, Satagopan J, Batish SD, Berwick M, Giampietro PF, et al. A 20-year perspective on the International Fanconi Anemia Registry (IFAR). Blood. 2003;101(4):1249–56. doi:10.1182/blood-2002-07-2170.PubMedView ArticleGoogle Scholar
- Neveling K, Endt D, Hoehn H, Schindler D. Genotype-phenotype correlations in Fanconi anemia. Mutat Res. 2009;668(1–2):73–91. doi:10.1016/j.mrfmmm.2009.05.006.PubMedView ArticleGoogle Scholar
- Kee Y, D'Andrea AD. Molecular pathogenesis and clinical management of Fanconi anemia. J Clin Invest. 2012;122(11):3799–806. doi:10.1172/JCI58321.PubMed CentralPubMedView ArticleGoogle Scholar
- Wagner JE, Tolar J, Levran O, Scholl T, Deffenbaugh A, Satagopan J, et al. Germline mutations in BRCA2: shared genetic susceptibility to breast cancer, early onset leukemia, and Fanconi anemia. Blood. 2004;103(8):3226–9. doi:10.1182/blood-2003-09-3138.PubMedView ArticleGoogle Scholar
- Hirsch B, Shimamura A, Moreau L, Baldinger S, Hag-alshiekh M, Bostrom B, et al. Association of biallelic BRCA2/FANCD1 mutations with spontaneous chromosomal instability and solid tumors of childhood. Blood. 2004;103(7):2554–9. doi:10.1182/blood-2003-06-1970.PubMedView ArticleGoogle Scholar
- Alter BP, Rosenberg PS, Brody LC. Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2. J Med Genet. 2007;44(1):1–9. doi:10.1136/jmg.2006.043257.PubMed CentralPubMedView ArticleGoogle Scholar
- Alter BP, Olson SB. Wilms tumor, AML, and medulloblastoma in a child with cancer prone syndrome of total premature chromatid separation and Fanconi anemia. Pediatr Blood Cancer. 2010;54(3):488. author reply 9. doi:10.1002/pbc.22333.PubMedView ArticleGoogle Scholar
- Ruud E, Wesenberg F. Microcephalus, medulloblastoma and excessive toxicity from chemotherapy: an unusual presentation of Fanconi anaemia. Acta Paediatr. 2001;90(5):580–3.PubMedView ArticleGoogle Scholar
- Tischkowitz MD, Chisholm J, Gaze M, Michalski A, Rosser EM. Medulloblastoma as a first presentation of fanconi anemia. J Pediatr Hematol Oncol. 2004;26(1):52–5.PubMedView ArticleGoogle Scholar
- Dewire MD, Ellison DW, Patay Z, McKinnon PJ, Sanders RP, Gajjar A. Fanconi anemia and biallelic BRCA2 mutation diagnosed in a young child with an embryonal CNS tumor. Pediatr Blood Cancer. 2009;53(6):1140–2. doi:10.1002/pbc.22139.PubMed CentralPubMedView ArticleGoogle Scholar
- de Chadarevian JP, Vekemans M, Bernstein M. Fanconi's anemia, medulloblastoma, Wilms' tumor, horseshoe kidney, and gonadal dysgenesis. Arch Pathol Lab Med. 1985;109(4):367–9.PubMedGoogle Scholar
- Alter BP, Tenner MS. Brain tumors in patients with Fanconi's anemia. Arch Pediatr Adolesc Med. 1994;148(6):661–3.PubMedView ArticleGoogle Scholar
- Offit K, Levran O, Mullaney B, Mah K, Nafa K, Batish SD, et al. Shared genetic susceptibility to breast cancer, brain tumors, and Fanconi anemia. J Natl Cancer Inst. 2003;95(20):1548–51.PubMedView ArticleGoogle Scholar
- Faivre L, Portnoi MF, Pals G, Stoppa-Lyonnet D, Le Merrer M, Thauvin-Robinet C, et al. Should chromosome breakage studies be performed in patients with VACTERL association? Am J Med Genet A. 2005;137(1):55–8. doi:10.1002/ajmg.a.30853.PubMedView ArticleGoogle Scholar
- Bayrakli F, Akgun B, Soylemez B, Kaplan M, Gurelik M. Variation in the BRCA2 gene in a child with medulloblastoma and a family history of breast cancer. J Neurosurg Pediatr. 2011;8(5):476–8. doi:10.3171/2011.8.PEDS11210.PubMedView ArticleGoogle Scholar
- Reid S, Renwick A, Seal S, Baskcomb L, Barfoot R, Jayatilake H, et al. Biallelic BRCA2 mutations are associated with multiple malignancies in childhood including familial Wilms tumour. J Med Genet. 2005;42(2):147–51. doi:10.1136/jmg.2004.022673.PubMed CentralPubMedView ArticleGoogle Scholar
- Rizk T, Taslakian B, Torbey PH, Issa G, Hourani R. Sequential development of Wilms tumor and medulloblastoma in a child: an unusual presentation of fanconi anemia. Pediatr Hematol Oncol. 2013;30(5):400–2. doi:10.3109/08880018.2013.788593.PubMedView ArticleGoogle Scholar
- Meyer S, Tischkowitz M, Chandler K, Gillespie A, Birch JM, Evans DG. Fanconi anaemia, BRCA2 mutations and childhood cancer: a developmental perspective from clinical and epidemiological observations with implications for genetic counselling. J Med Genet. 2014;51(2):71–5. doi:10.1136/jmedgenet-2013-101642.PubMedView ArticleGoogle Scholar
- Bodd TL, Van Ghelue M, Eiklid K, Ruud E, Moller P, Maehle L. Fanconi anaemia, BRCA2 and familial considerations - follow up on a previous case report. Acta Paediatr. 2010. doi:10.1111/j.1651-2227.2010.01929.x.
- Sari N, Akyuz C, Aktas D, Gumruk F, Orhan D, Alikasifoglu M, et al. Wilms tumor, AML and medulloblastoma in a child with cancer prone syndrome of total premature chromatid separation and Fanconi anemia. Pediatr Blood Cancer. 2009;53(2):208–10. doi:10.1002/pbc.21966.PubMedView ArticleGoogle Scholar
- Howlett NG, Taniguchi T, Olson S, Cox B, Waisfisz Q, De Die-Smulders C, et al. Biallelic inactivation of BRCA2 in Fanconi anemia. Science. 2002;297(5581):606–9. doi:10.1126/science.1073834.PubMedView ArticleGoogle Scholar
- Vujanic GM, Sandstedt B, Harms D, Kelsey A, Leuschner I, de Kraker J, et al. Revised International Society of Paediatric Oncology (SIOP) working classification of renal tumors of childhood. Med Pediatr Oncol. 2002;38(2):79–82.PubMedView ArticleGoogle Scholar
- Pocza T, Sebestyen A, Turanyi E, Krenacs T, Mark A, Sticz TB, et al. mTOR pathway as a potential target in a subset of human medulloblastoma. Pathol Oncol Res. 2014;20(4):893–900. doi:10.1007/s12253-014-9771-0.PubMedView ArticleGoogle Scholar
- Mastronuzzi A, Del Bufalo F, Iacono A, Secco DE, Serra A, Colafati GS, et al. Intrathecal liposomal cytarabine and leptomeningeal medulloblastoma relapse: a valuable therapeutic option. Anticancer Res. 2013;33(8):3515–8.PubMedGoogle Scholar
- Northcott PA, Shih DJ, Remke M, Cho YJ, Kool M, Hawkins C, et al. Rapid, reliable, and reproducible molecular sub-grouping of clinical medulloblastoma samples. Acta Neuropathol. 2012;123(4):615–26. doi:10.1007/s00401-011-0899-7.PubMed CentralPubMedView ArticleGoogle Scholar
- Mastronuzzi A, Miele E, Po A, Antonelli M, Buttarelli FR, Colafati GS, et al. Large cell anaplastic medulloblastoma metastatic to the scalp: tumor and derived stem-like cells features. BMC Cancer. 2014;14(1):262. doi:10.1186/1471-2407-14-262.PubMed CentralPubMedView ArticleGoogle Scholar
- Ferretti E, De Smaele E, Miele E, Laneve P, Po A, Pelloni M, et al. Concerted microRNA control of Hedgehog signalling in cerebellar neuronal progenitor and tumour cells. EMBO J. 2008;27(19):2616–27. doi:10.1038/emboj.2008.172.PubMed CentralPubMedView ArticleGoogle Scholar
- Ferretti E, De Smaele E, Po A, Di Marcotullio L, Tosi E, Espinola MS, et al. MicroRNA profiling in human medulloblastoma. Int J Cancer. 2009;124(3):568–77. doi:10.1002/ijc.23948.PubMedView ArticleGoogle Scholar
- Miele E, Buttarelli FR, Arcella A, Begalli F, Garg N, Silvano M, et al. High-throughput microRNA profiling of pediatric high-grade gliomas. Neuro Oncol. 2014;16(2):228–40. doi:10.1093/neuonc/not215.PubMed CentralPubMedView ArticleGoogle Scholar
- Bunt J, Hasselt NA, Zwijnenburg DA, Koster J, Versteeg R, Kool M. OTX2 sustains a bivalent-like state of OTX2-bound promoters in medulloblastoma by maintaining their H3K27me3 levels. Acta Neuropathol. 2013;125(3):385–94. doi:10.1007/s00401-012-1069-2.PubMedView ArticleGoogle Scholar
- Northcott PA, Hielscher T, Dubuc A, Mack S, Shih D, Remke M, et al. Pediatric and adult sonic hedgehog medulloblastomas are clinically and molecularly distinct. Acta Neuropathol. 2011;122(2):231–40. doi:10.1007/s00401-011-0846-7.PubMedView ArticleGoogle Scholar
- Kool M, Jones DT, Jager N, Northcott PA, Pugh TJ, Hovestadt V, et al. Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition. Cancer Cell. 2014;25(3):393–405. doi:10.1016/j.ccr.2014.02.004.PubMedView ArticleGoogle Scholar
- Reid S, Schindler D, Hanenberg H, Barker K, Hanks S, Kalb R, et al. Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nat Genet. 2007;39(2):162–4. doi:10.1038/ng1947.PubMedView ArticleGoogle Scholar
- Novakovic S, Milatovic M, Cerkovnik P, Stegel V, Krajc M, Hocevar M, et al. Novel BRCA1 and BRCA2 pathogenic mutations in Slovene hereditary breast and ovarian cancer families. Int J Oncol. 2012;41(5):1619–27. doi:10.3892/ijo.2012.1595.PubMed CentralPubMedGoogle Scholar
- Rebbeck TR, Mitra N, Wan F, Sinilnikova OM, Healey S, McGuffog L, et al. Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer. JAMA. 2015;313(13):1347–61. doi:10.1001/jama.2014.5985.PubMedView ArticleGoogle Scholar
- Sharan SK, Morimatsu M, Albrecht U, Lim DS, Regel E, Dinh C, et al. Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2. Nature. 1997;386(6627):804–10. doi:10.1038/386804a0.PubMedView ArticleGoogle Scholar
- Perreault S, Ramaswamy V, Achrol AS, Chao K, Liu TT, Shih D, et al. MRI surrogates for molecular subgroups of medulloblastoma. AJNR Am J Neuroradiol. 2014;35(7):1263–9. doi:10.3174/ajnr.A3990.PubMedView ArticleGoogle Scholar
- Teo WY, Shen J, Su JM, Yu A, Wang J, Chow WY, et al. Implications of tumor location on subtypes of medulloblastoma. Pediatr Blood Cancer. 2013;60(9):1408–10. doi:10.1002/pbc.24511.PubMedView ArticleGoogle Scholar
- Gibson P, Tong Y, Robinson G, Thompson MC, Currle DS, Eden C, et al. Subtypes of medulloblastoma have distinct developmental origins. Nature. 2010;468(7327):1095–9. doi:10.1038/nature09587.PubMed CentralPubMedView ArticleGoogle Scholar
- Frappart PO, Lee Y, Russell HR, Chalhoub N, Wang YD, Orii KE, et al. Recurrent genomic alterations characterize medulloblastoma arising from DNA double-strand break repair deficiency. Proc Natl Acad Sci U S A. 2009;106(6):1880–5. doi:10.1073/pnas.0806882106.PubMed CentralPubMedView ArticleGoogle Scholar
- Deans AJ, West SC. DNA interstrand crosslink repair and cancer. Nat Rev Cancer. 2011;11(7):467–80. doi:10.1038/nrc3088.PubMed CentralPubMedView ArticleGoogle Scholar
- Kim H, D'Andrea AD. Regulation of DNA cross-link repair by the Fanconi anemia/BRCA pathway. Genes Dev. 2012;26(13):1393–408. doi:10.1101/gad.195248.112.PubMed CentralPubMedView ArticleGoogle Scholar
- Huang YY, Dai L, Gaines D, Droz-Rosario R, Lu H, Liu J, et al. BCCIP suppresses tumor initiation but is required for tumor progression. Cancer Res. 2013;73(23):7122–33. doi:10.1158/0008-5472.CAN-13-1766.PubMed CentralPubMedView ArticleGoogle Scholar
- Xia B, Sheng Q, Nakanishi K, Ohashi A, Wu J, Christ N, et al. Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol Cell. 2006;22(6):719–29. doi:10.1016/j.molcel.2006.05.022.PubMedView ArticleGoogle Scholar
- Ferretti E, De Smaele E, Di Marcotullio L, Screpanti I, Gulino A. Hedgehog checkpoints in medulloblastoma: the chromosome 17p deletion paradigm. Trends Mol Med. 2005;11(12):537–45. doi:10.1016/j.molmed.2005.10.005.PubMedView ArticleGoogle Scholar
- van Vuurden DG, Hulleman E, Meijer OL, Wedekind LE, Kool M, Witt H, et al. PARP inhibition sensitizes childhood high grade glioma, medulloblastoma and ependymoma to radiation. Oncotarget. 2011;2(12):984–96.PubMed CentralPubMedGoogle Scholar
- Ramaswamy V, Remke M, Bouffet E, Faria CC, Perreault S, Cho YJ, et al. Recurrence patterns across medulloblastoma subgroups: an integrated clinical and molecular analysis. Lancet Oncol. 2013;14(12):1200–7. doi:10.1016/S1470-2045(13)70449-2.PubMed CentralPubMedView ArticleGoogle Scholar
- Poschl J, Koch A, Schuller U. Histological subtype of medulloblastoma frequently changes upon recurrence. Acta Neuropathol. 2015;129(3):459–61. doi:10.1007/s00401-015-1397-0.PubMedView ArticleGoogle Scholar
- Wang X, Dubuc AM, Ramaswamy V, Mack S, Gendoo DM, Remke M, et al. Medulloblastoma subgroups remain stable across primary and metastatic compartments. Acta Neuropathol. 2015;129(3):449–57. doi:10.1007/s00401-015-1389-0.PubMedView ArticleGoogle Scholar
- Northcott PA, Jones DT, Kool M, Robinson GW, Gilbertson RJ, Cho YJ, et al. Medulloblastomics: the end of the beginning. Nat Rev Cancer. 2012;12(12):818–34. doi:10.1038/nrc3410.PubMed CentralPubMedView ArticleGoogle Scholar
- Hemming S, Cakouros D, Isenmann S, Cooper L, Menicanin D, Zannettino A, et al. EZH2 and KDM6A act as an epigenetic switch to regulate mesenchymal stem cell lineage specification. Stem Cells. 2014;32(3):802–15. doi:10.1002/stem.1573.PubMedView ArticleGoogle Scholar
- Kieran MW. Targeted treatment for sonic hedgehog-dependent medulloblastoma. Neuro Oncol. 2014;16(8):1037–47. doi:10.1093/neuonc/nou109.PubMedView ArticleGoogle Scholar
- Lauth M, Toftgard R. The Hedgehog pathway as a drug target in cancer therapy. Curr Opin Investig Drugs. 2007;8(6):457–61.PubMedGoogle Scholar
- Infante P, Mori M, Alfonsi R, Ghirga F, Aiello F, Toscano S, et al. Gli1/DNA interaction is a druggable target for Hedgehog-dependent tumors. EMBO J. 2015;34(2):200–17. doi:10.15252/embj.201489213.PubMed CentralPubMedView ArticleGoogle Scholar
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.