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Fanconi Anemia Pathway. Endogenous and exogenous agent cause interstrand crosslink lesions (ICL). When an ICL occurs, the replication fork is stalled and the FA pathway is activated with the recruitment of the FA core complex (FANCA, B, C, E, F, G, L, and M). FANCL ubiqiuitinates the FANCD2-FANCI (ID2) complex that guides the nucleolytic incisions and translesion synthesis repair events by “unhooking” the ICL. This allows the homologous recombination repair through FANCD1/BRCA2, FANCJ/BRIP1, FANCN/PALB2, FANCO/RAD51C, and FANCS/BRCA1. Yellow stars highlight FA/HR repair molecules that have been found genetically inactivated in FA patients with medulloblastoma. BCCIP is a BRCA2 interacting protein which is able to induce medulloblastoma growth when genetically loss in concomitance with p53 deletion (See text). Readapted from 52
Source publication
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...
Contexts in source publication
Context 1
... FA core complex is recruited (FANCA, B, C, E, F, G, L, and M). Then, FANCL ubiquitinates the FANCD2-FANCI (ID2) complex, essential for nucleolytic incisions and translesion synthesis repair events. The complex then "unhooks" ICL, allowing homologous recombination re- pair by FANCD1/BRCA2, FANCJ/BRIP1, FANCN/ PALB2, FANCO/RAD51C, and FANCS/BRCA1 (Fig. ...
Context 2
... since FANCN (also known as 'partner and localizer of BRCA2′, PALB2) is well known to co- localize with BRCA2 in the nucleus [55]. Interestingly, BRIP1/FANCJ maps on 17q chromosome, a region fre- quently deleted in MBs [56]. Thus, deleterious mutations in one of the members of the homologous recombin- ation 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. [26]. 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 ...
Citations
... FA-D1 patients, in particular, exhibit a high childhood cancer risk (> 300 fold increased risk), with cumulative cancer incidences greater than 70% until age 18 years [2,4]. Embryonal tumors such as medulloblastoma (MB) and nephroblastoma (Wilms tumor) as well as primarily myeloid neoplasms are typical cancer types occurring in these patients [2,[4][5][6][7][8], which might be explained by additional function of BRCA2 in DNA fork protection and homologous recombinational repair. Little is known about the clinical characteristics of FA-D1 patients with specific cancer types. ...
... All six MBs with available data were classified as sonic hedgehog (SHH)-MB. This finding is in agreement with previous reports [8,9] and with data from genetically engineered models of SHH-MB showing that genomic instability promotes transformation of proliferating cerebellar granule neurons [10]. Six patients received chemotherapy with a documented dose reduction in two patients. ...
Constitutional heterozygous pathogenic variants in genes coding for some components of the Fanconi anemia-BRCA signaling pathway, which repairs DNA interstrand crosslinks, represent risk factors for common cancers, including breast, ovarian, pancreatic and prostate cancer. A high cancer risk is also a main clinical feature in patients with Fanconi anemia (FA), a rare condition characterized by bone marrow failure, endocrine and physical abnormalities. The mainly recessive condition is caused by germline pathogenic variants in one of 21 FA-BRCA pathway genes. Among patients with FA, the highest cancer risks are observed in patients with biallelic pathogenic variants in BRCA2 or PALB2 . These patients develop a range of embryonal tumors and leukemia during the first decade of life, however, little is known about specific clinical, genetic and pathologic features or toxicities. Here, we present genetic, clinical, pathological and treatment characteristics observed in an international cohort of eight patients with FA due to biallelic BRCA2 pathogenic variants and medulloblastoma (MB), an embryonal tumor of the cerebellum. Median age at MB diagnosis was 32.5 months (range 7–58 months). All patients with available data had sonic hedgehog-MB. Six patients received chemotherapy and one patient also received proton radiation treatment. No life-threatening toxicities were documented. Prognosis was poor and all patients died shortly after MB diagnosis (median survival time 4.5 months, range 0–21 months) due to MB or other neoplasms. In conclusion, MB in patients with biallelic BRCA2 pathogenic variants is a lethal disease. Future experimental treatments are necessary to help these patients.
... 39 Medulloblastoma is the characteristic CNS tumor in FA secondary to biallelic germline mutations in BRCA2 or PALB2. 1,3,40 A few cases of cerebroretinal vasculopathy and leukoencephalopathy have been reported in literature. These are characterized by recurrent space-occupying brain lesions that can mimic glial neoplasms along with retinal vasculopathy, with patients presenting in their early twenties (Fig 7 and Online Supplemental Data). ...
... These medulloblastomas with germline BRCA2 or PALB2 mutations have a poor prognosis and a significantly higher risk of the patient developing metastases after treatment. 40,42 The poor prognosis is due to the aggressive biology of the tumor and because these patients cannot tolerate high-dose chemotherapy, given the underlying myelodysplastic condition. The essential diagnostic criterion for FA is positive findings on the diepoxybutane test, wherein chromosomal breakage is seen after exposure to diepoxybutane in leukocytes. ...
The nervous system is commonly involved in a wide range of genetic tumor-predisposition syndromes. The classification of genetic tumor syndromes has evolved during the past years; however, it has now become clear that these syndromes can be categorized into a relatively small number of major mechanisms, which form the basis of the new 5th edition of the World Health Organization book (beta online version) on genetic tumor syndromes. For the first time, the World Health Organization has also included a separate chapter on genetic tumor syndromes in the latest edition of all the multisystem tumor series, including the 5th edition of CNS tumors. Our understanding of these syndromes has evolved rapidly since the previous edition (4th edition, 2016) with recognition of 8 new syndromes, including the following: Elongator protein complex-medulloblastoma syndrome, BRCA1-associated protein 1 tumor-predisposition syndrome, DICER1 syndrome, familial paraganglioma syndrome, melanoma-astrocytoma syndrome, Carney complex, Fanconi anemia, and familial retinoblastoma. This review provides a description of these new CNS tumor syndromes with a focus on imaging and genetic characteristics.
... Sci. 2023, 24, 15334 2 of 7 domain encoded by exons 2-7, in the coding region of exons [11][12][13], and the C-terminus/or BRCT domain encoded by exons [16][17][18][19][20][21][22][23][24]. These three domains are important for interaction with different proteins and subcellular localization of the BRCA1 protein. ...
... (Val220Ilefs*4)) is a loss-of-function variant in the BRCA2 gene (BIC designation 886delGT), which has been described in numerous patients with BRCA2-associated cancers in many countries. The mutation has also been detected in compound heterozygous individuals with Fanconi anemia [19][20][21][22]. In ClinVar (ID: 9342), an expert panel and several laboratories classified it as pathogenic. ...
Hereditary breast cancer is most commonly attributed to germline BRCA1 and BRCA2 gene variants. The vast majority of BRCA1 and BRCA2 mutation carriers are single heterozygotes, and double heterozygosity (DH) is a very rare finding. Here, we describe the case of a BRCA1/BRCA2 double heterozygous female proband diagnosed with breast cancer. Genetic testing for hereditary breast and ovarian cancer revealed two pathogenic variants in the BRCA1 (c.5095C>T, p.(Arg1699Trp)) and in BRCA2 genes (c.658_659delGT, p.(Val220Ilefs*4)) in heterozygous form. None of the variants were founder Jewish mutations; to our knowledge, these rare deleterious variants have not been previously described in DH patients in the literature. The patient had triple-negative unilateral breast cancer at the age of 36 and 44 years. Based on family studies, the BRCA1 variant was maternally inherited.
... For SHH-activated MB, the Gorlin (PTCH1 and SUFU) and the Li-Fraumeni syndromes (TP53) are the most common predisposition syndromes [56][57][58][59]. Additional candidates for SHH-activated MB include BRCA2 and PALB2, which can be associated to Fanconi anemia [15,60,61]. About 5% of patients with Gorlin syndrome (GS) develop MB, mainly the desmoplastic form [62]. Between 50% and 85% of patients with GS have germline mutations in PTCH1. ...
The prevalence of hereditary cancer in children was estimated to be very low until recent studies suggested that at least 10% of pediatric cancer patients carry a germline mutation in a cancer predisposition gene. A significant proportion of pathogenic variants associated with an increased risk of hereditary cancer are variants affecting splicing. RNA splicing is an essential process involved in different cellular processes such as proliferation, survival, and differentiation, and alterations in this pathway have been implicated in many human cancers. Hereditary cancer genes are highly susceptible to splicing mutations, and among them there are several genes that may contribute to pediatric solid tumors when mutated in the germline. In this review, we have focused on the analysis of germline splicing-disrupting mutations found in pediatric solid tumors, as the discovery of pathogenic splice variants in pediatric cancer is a growing field for the development of personalized therapies. Therapies developed to correct aberrant splicing in cancer are also discussed as well as the options to improve the diagnostic yield based on the increase in the knowledge in splicing.
... Patients with Gorlin syndrome who have a PTCH1 germline mutation are more likely to develop basal cell carcinoma and medulloblastoma, particularly MBEN [26]. Patients with Fanconi anemia have been observed to have an unusual presentation of SHH subgroup medulloblastomas [27]. ...
Medulloblastoma is the most prevalent malignant brain tumor in children, accounting for roughly 15% to 20% of all malignancies of the Central Nervous System (CNS), for 40% of childhood, tumors are in the posterior fossa. Medulloblastoma is a heterogeneous combination of several subgroups with discrete characteristics, rather than a homogeneous illness. Genomic profiling of medulloblastomas revealed that the medulloblastoma may be further divided into four separate molecular subgroups. In this review, we aim to focus on the current state of understanding of the molecularity of the disease with a focus on genomic events that define the aforementioned subgroups and an overview of the molecular subtype of medulloblastoma upon discussing the following points (i) introduction to medulloblastoma and basic classification of the molecular subtype of medulloblastoma followed by their prevalence, age and gender discrimination, and specific molecular characterization. (ii) specific MRI features of the locality of a molecular subtype of medulloblastoma (iii) finally MRI distinguishable features for the identification of the specific molecular type. This review will enhance your knowledge regarding the subtype of medulloblastoma and the role of MRI in the identification of these subtypes.
... Patients with biallelic BRCA2 or PALB2 variants develop medulloblastomas at an early age, typically following the diagnosis of a Wilms tumor. Unexpectedly, these tumors may adhere to the four known molecular subsets of medulloblastoma [31]. No clinical trials have addressed the treatment of these tumors, but extreme bone marrow sensitivity to chemotherapy with platinum is seen due to induction of interstrand crosslinks. ...
... PARP inhibitors may be considered. It has been proposed that SMO inhibition (see previous text) is unlikely to be effective in this setting because the SHH pathway is activated downstream of SMO [31]. The development of downstream SHH inhibitors will be of interest. ...
Opinion statement
Nervous system tumors arising in the setting of monogenic, hereditary cancer predisposition syndromes are unique in that the initiating genetic event in tumor formation is known. This knowledge provides a powerful treatment approach if the alteration or pathway can be targeted with a therapeutic agent. A reasonable argument can be made for the use of targeted agents in these tumor patients, even though many of them have FDA approval only for other tumor types. It is our practice to use and employ targeted therapy when standard treatments have failed or represent an unattractive option. Over time, however, targeted therapies will likely become first-line options.
... Li-Fraumeni syndrome Brain tumor: annual brain MRI (first MRI with contrast; thereafter without contrast if previous MRI normal and no new abnormality). 22 Complete physical examination every 3-4 months, including blood pressure, anthropometric measurements plotted on a growth curve (with attention to rapid acceleration in weight or height), Cushingoid appearance, signs of virilization (pubic hair, axillary moisture, adult body odor, androgenic hair loss, clitoromegaly, or penile growth), and full neurologic assessment. ACC: US of abdomen and pelvis every 3-4 months. ...
... any earlyonset pediatric brain tumor with cutaneous, skeletal, or neurological abnormalities consistent with a diagnosis of FA or in case of severe unexpected toxicity from chemotherapy, genetic counseling is recommended. 22,61,62 For individuals with mutations in the FANCD1/BRCA2 and FANCN/PALB2 genes, the identity of the patient's mutations is essential for proper cancer surveillance and medical management. 63 If a patient has biallelic FANCD1/ BRCA2 mutations or a family history or clinical manifestations that are highly suggestive of FANCD1/BRCA2 mutations, additional tests such as a brain MRI and kidney ultrasound should be performed immediately to rule out any evidence of tumors. ...
... Individuals with FA undergoing treatment for MB are known to be highly sensitive to both RT and chemotherapy, with increased susceptibility for treatment-associated toxicities, especially from alkylatorbased chemotherapy. 12,22,62,64 Tumors harboring either BRCA1 or BRCA2 mutations have been demonstrated to have increased sensitivity to Poly ADP-ribose polymerase (PARP) inhibitors owing to defects in homologous recombination and reliance on alternative pathways to repair DNA damage that are targeted by these inhibitors. The concept of synthetic lethality is being exploited in the use of PARP inhibitors and may be useful in FA associated CNS tumors, analogous to their use in BRCA1/2 deficient breast, ovarian, and pancreatic cancers. ...
The application of high-throughput sequencing approaches including paired tumor/normal sampling with therapeutic intent has demonstrated that 8–19% of pediatric CNS tumor patients harbor a germline alteration in a classical tumor predisposition gene (NF1, P53). In addition, large scale germline sequencing studies in unselected cohorts of pediatric neuro-oncology patients have demonstrated novel candidate tumor predisposition genes (ELP1 alterations in sonic hedgehog medulloblastoma). Therefore, the possibility of an underlying tumor predisposition syndrome (TPS) should be considered in all pediatric patients diagnosed with a CNS tumor which carries critical implications including accurate prognostication, selection of optimal therapy, screening, risk reduction and family planning. The Pediatric Cancer Working Group of the American Association for Cancer Research (AACR) recently published consensus screening recommendations for children with the most common tumor predisposition syndromes. In this review, we provide an overview of the most relevant as well as recently identified TPS associated with the most frequently encountered pediatric CNS tumors with an emphasis on pathogenesis, genetic testing, clinical features and treatment implications.
... MA, USA) and best-coverage TaqMan gene expression assays specific for each mRNA analyzed. MB subgroup classification was performed by qRT-PCR using Taq-Man probes, as described elsewhere [33,34]. One microgram of RNA was reverse-transcribed using the High-capacity cDNA Reverse Transcription Kit (Thermo Fisher Scientific). ...
Persistent mortality rates of medulloblastoma (MB) and severe side effects of the current therapies require the definition of the molecular mechanisms that contribute to tumor progression. Using cultured MB cancer stem cells and xenograft tumors generated in mice, we show that low expression of miR-326 and its host gene β-arrestin1 (ARRB1) promotes tumor growth enhancing the E2F1 pro-survival function. Our models revealed that miR-326 and ARRB1 are controlled by a bivalent domain, since the H3K27me3 repressive mark is found at their regulatory region together with the activation-associated H3K4me3 mark. High levels of EZH2, a feature of MB, are responsible for the presence of H3K27me3. Ectopic expression of miR-326 and ARRB1 provides hints into how their low levels regulate E2F1 activity. MiR-326 targets E2F1 mRNA, thereby reducing its protein levels; ARRB1, triggering E2F1 acetylation, reverses its function into pro-apoptotic activity. Similar to miR-326 and ARRB1 overexpression, we also show that EZH2 inhibition restores miR-326/ARRB1 expression, limiting E2F1 pro-proliferative activity. Our results reveal a new regulatory molecular axis critical for MB progression.
... More recently, they have been recognized to also play a role in CNS tumors (60). In particular, germline variants of BRCA2 which is also essential for normal neurogenesis (61) have been described in individuals with brain tumors including glial tumors, meningioma and medulloblastoma (62)(63)(64). ...
Pediatric High-Grade Gliomas (pHGG) are among the deadliest childhood brain tumors and can be associated with an underlying cancer predisposing syndrome. The thorough understanding of these syndromes can aid the clinician in their prompt recognition, leading to an informed genetic counseling for families and to a wider understanding of a specific genetic landscape of the tumor for target therapies. In this review, we summarize the main pHGG-associated cancer predisposing conditions, providing a guide for suspecting these syndromes and referring for genetic counseling.
... Molecular analysis showed a MB SHH for both the firstand the second-diagnosed MB. However differences in localization, more aggressive histology, and distinct gene expression pattern led to hypothesize a second distinct tumor rather than a distant relapse from the first one (109). The identification of SHH subgroup in FA patients may play a crucial role for their treatment with the use of targeted therapies, especially in these individuals extremely sensitive to conventional treatments. ...
Medulloblastoma is the most common malignant brain tumor in children. In addition to sporadic cases, medulloblastoma may occur in association with cancer predisposition syndromes. This review aims to provide a complete description of inherited cancer syndromes associated with medulloblastoma. We examine their epidemiological, clinical, genetic, and diagnostic features and therapeutic approaches, including their correlation with medulloblastoma. Furthermore, according to the most recent molecular advances, we describe the association between the various molecular subgroups of medulloblastoma and each cancer predisposition syndrome. Knowledge of the aforementioned conditions can guide pediatric oncologists in performing adequate cancer surveillance. This will allow clinicians to promptly diagnose and treat medulloblastoma in syndromic children, forming a team with all specialists necessary for the correct management of the other various manifestations/symptoms related to the inherited cancer syndromes.
