Li-Fraumeni Research Articles

Li-Fraumeni syndrome presenting with de novo TP53 mutation, severe phenotype and advanced paternal age: a case report

BackgroundLi-Fraumeni syndrome (LFS) is an autosomal dominant hereditary cancer syndrome caused by pathogenic variants in the gene TP53. This gene codes for the P53 protein, a crucial player in genomic stability, which functions as a tumor suppressor gene. Individuals with LFS frequently develop multiple primary tumors at a young age, such as soft tissue sarcomas, breast cancer, and brain tumors.Case presentationA 38 years-old female with a history of femur osteosarcoma, ductal carcinoma of the breast, high-grade breast sarcoma, pleomorphic sarcoma of the left upper limb, infiltrating lobular carcinoma of the breast, gastric adenocarcinoma, leiomyosarcoma of the right upper limb, and high-grade pleomorphic renal sarcoma. Complete molecular sequencing of the TP53 gene showed c.586 C > T (p.R196X) in exon 6, which is a nonsense mutation that produces a shorter and malfunctioning P53. Family history includes advanced father’s age at the time of conception (75 years), which has been associated with an increased risk of de novo germline mutations. The patient had seven paternal half-siblings with no cancer history. The patient received multiple treatments including surgery, systemic therapy, and radiotherapy, but died at the age of 38.ConclusionsAdvanced paternal age is a risk factor to consider when hereditary cancer syndrome is suspected. Early detection of hereditary cancer syndromes and their multi-disciplinary surveillance and treatment is important to improve clinical outcomes for these patients. Further investigation of the relationship between the pathogenic variant of TP53 and its phenotype may guide the stratification of surveillance and treatment.

Phenotype analysis of families with TP53 germline variants at the Center for Familial Breast and Ovarian Cancer, Cologne.

Tumor protein p53 (TP53) pathogenic variant (PV) carriers are identified during genetic testing for hereditary causes of cancer. PVs in TP53 are associated with the Li-Fraumeni syndrome (LFS), and thus, surveillance and preventive measures are important for TP53 PV carriers. However, the penetrance of TP53 PVs can be low if the Chompret criteria are not fulfilled. In this study, we compared the phenotypic characteristics of families that did and did not fulfill the LFS criteria according to Chompret. The German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) database was used to identify index patients with a likely pathogenic/pathogenic TP53 variant and their family members. The study investigated the type of variant, pedigree, age of onset, number of primary tumors, and histological type of BC. TP53 PV were present in the index cases of 35 families, 57% (20/35) of which fulfilled the Chompret criteria. The median age of onset at first BC diagnosis was lower in families that fulfilled the Chompret criteria compared to those who did not. Four of all diseased individuals were minors (4%; 4/105) when malignancy was first diagnosed. Sarcomas and brain tumors occurred in 10% (10/105) and in 7% (7/105) of all diseased persons, respectively. BC was the most frequently occurring first tumor (60%; 62/105) and additional malignancy (45%; 20/44) in this cohort. Subsequent malignancies developed in 31% (20/65) of the individuals who fulfilled the Chompret criteria compared with 15% (6/40) of those who did not. The tumor spectrum and age of onset found in this study showed that tumors other than BC had low disease penetrance in TP53 PV carriers identified using the GC-HBOC criteria for genetic testing.

O-11 A rare cause of thyroid cancer - Li Fraumeni 2 syndrome

Abstract Introduction Thyroid cancer often originates from follicular cells, and papillary thyroid cancer (PTC) is the most common type. There is a familial predisposition in some cases of thyroid cancer. However, a minority of cases have thyroid cancer syndrome (e.g., familial polyposis, MEN 2, or Cowden syndrome). Many known genetic susceptibility genes are RET/PTC, BRAF, RAS, TERT, and TP53. We want to present a case of Li Fraumeni type 2 syndrome as a rare cause of thyroid cancer. Clinical Case A 69-year-old female patient with a history of PTC is admitted to the endocrinology department for follow-up. In 1976, this patient had a thyroid lobectomy, but the pathology result is unknown, and she takes 75 mcg of levothyroxine daily. In 1999, she was diagnosed with rectal cancer. The patient had a completion thyroidectomy in 2002, and the pathology was compatible with PTC. In 2014, she was diagnosed with right breast noninvasive ductal cancer. Cases of cancer were also quite common in her family history. The results of laboratory tests revealed normal TSH levels with negative thyroglobulin and anti-thyroglobulin levels. Neck ultrasonography showed no rest gland and pathological LAP. We requested genetic analysis (55 genes) for familial cancer syndromes. As a result of the analysis, 2 genes were found to be heterozygous. The c.599T>c heterozygous variant in the CHEK 2 gene was found (Figure 1). It was evaluated as pathogenic in the database review. Another heterozygous mutation in the BRIP1 gene, which was evaluated as a VUS also detected. Conclusion The CHEK 2 gene is a DNA-repairing protein kinase at position 22.q12.1. It is responsible for TP53 stabilization, genome maintenance, and apoptosis. CHEK2 phosphorylates p53 in response to DNA damage, leading to cell cycle arrest and stabilization (Figure 2). The mutation(CHEK 2 c.599T>c) we detected in this case has been considered possibly pathogenic in the academic databases. There are reported CHEK 2 c.599T>c cases on the CLINVAR site; the first report is from 2013. Classic Li-Fraumeni syndrome is a rare autosomal dominant syndrome caused by TP53 gene mutation. The chromosome location on classical Li fraumeni is 17p13.1. Li-Fraumeni type 2 develops due to the CHEK 2 gene mutation on chromosome 22q12.1. The results of a mutation of the CHEK2 gene are breast cancer, prostate cancer, PTC, colon cancer, kidney cancer, adrenocortical cancer, lung cancer, and rare cases of myelodysplastic syndromes. There are no data on thyroid-specific mortality in carriers of the CHEK2 mutations, and it is not yet known whether thyroid cancer in this population is more aggressive or has a better outcome.The familial syndromes should also be considered if PTC is detected in breast, colon, and prostate cancer patients. Studies on Li-Fraumeni type 2 syndrome are scarce, and considering the prevalence in European countries, further investigations of this syndrome and screening in patients with multiple cancers in the family should be warranted.Figure 1.Genetic sequencing image of the case

Li Fraumeni Syndrome predisposes to gastro-esophageal junction tumours

Li-Fraumeni Syndrome (LFS), caused by germline pathogenic variants in TP53, predisposes to a wide range of young-onset malignancies, particularly sarcoma, breast and brain cancer. More recently, an increased risk of gastric adenocarcinoma has been recognised, although uptake of surveillance upper endoscopy is unclear. Our retrospective review of 65 patients with LFS, of whom 53.8% had undergone endoscopy, identified four patients (6.2%) with gastro-esophageal junction (GEJ) adenocarcinomas. Two cases were found on asymptomatic screening and were early stage. No cases had family history of gastrointestinal malignancy. Reviewing genomic data from The Cancer Genome Atlas Program, 76.4% of sporadic esophageal adenocarcinomas harboured somatic TP53 pathogenic variants, compared with 39.9% of non-cardia gastric cancers. This similar pattern observed in germline and sporadic cases warrants further investigation. We propose that upper endoscopy be recommended to all patients with LFS, with a focus on appropriate surveillance of the GEJ.

Adrenal cortical carcinoma in children: a clinicopathological analysis of 25 cases

Objective: To investigate the clinicopathological features, diagnosis and differential diagnosis of adrenal cortical carcinoma (ACC) in children. Methods: Twenty-five children with ACC diagnosed in the Department of Pathology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China from March 2014 to August 2022 were retrospectively analyzed. The related literature was reviewed. Results: A total of 25 children with ACC were collected, including 11 males and 14 females, with a male to female ratio of 1.0∶1.3. The patient ages ranged from 8 months to 14 years (median, 4 years). Eighteen cases with clinical data had functional tumors (18/22, 81.8%) presenting with virilization or precocious puberty (15/18), symptoms related to hypercortisolism (8/18) or endocrine symptoms mixed with both (5/18), while 3 cases (3/22, 13.6%) had unknown clinical data. The clinical manifestations of four patients with nonfunctional tumors were an abdominal mass and/or abdominal pain, walking instability and others. Grossly, the average maximum diameter of the tumor was 9.4 cm. Most of the tumors were nodular and partially encapsuled. The cut surfaces were gray or gray brown, soft with hemorrhage. Histologically, the tumor cells were diffusely distributed, separated by a vascular-rich network. The tumor cells were large, with distinct nucleoli, abundant eosinophilic or clear cytoplasm, and round or oval nuclei. The mitotic index was high, and atypical mitoses were common. Necrosis, calcification, capsule invasion or/and venous invasion were present. In some cases, the tumor invaded the surrounding soft tissues or kidneys. Immunohistochemically, the tumor cells were diffusely positive for syn and SF1 and focally positive for α-inhibin, Melan A and Calretinin, but negative for CgA. Ki-67 proliferation index ranged from 2%-90%. TP53 gene status was examined in 7 cases, in which mutations were detected in 4 cases. Follow-up data was obtained in 21 patients, among whom 18 received chemotherapy and 3 received radiotherapy. Distant metastasis occurred in 13 patients. Median progression-free survival (PFS) was 11.2 months and median overall survival (OS) was 54.7 months. Patients aged less than 5 years had a better prognosis for OS (P<0.05) than the older ones (≥5 years), but a similar PFS (P>0.05). Male patients and Ki-67 proliferation index <15% had a better prognosis tendency for OS, but there was no statistically significant difference (P>0.05). Conclusions: ACC in children is a rare, often functional tumor associated with Li-Fraumeni genetic syndrome and has a poor prognosis. Diagnosis and differential diagnosis require a combination of morphological, phenotypic and clinical analysis.

Epidemiology of childhood acute leukemias

Abstract Acute leukemias are the largest group of childhood cancers. According to the latest WHO data 80,491 leukemias were diagnosed in 2020 alone. In the coming years the incidence worldwide will continue at a similar level. The morbidity correlates with biological determinants such age, gender and race. The etiology of leukemia formation is complex and depends on genetic, physiological, environmental and even prior treatment-related factors. Both the incidence and curability are also influenced by age, gender, and race. The peak of incidence of leukemia occurs between the ages of 1–4 years and 9–19. The etiology of leukemia formation is complex and depends on genetic, physiological, environmental and even prior treatment-related factors. Boys suffer from leukemia more often than girls. In 2020 58.2% of diagnoses were for boys. Numerous factors contribute to the development of acute leukemia. In the case of young children, a notable association exists between acute leukemia and infections caused by viruses such as EBV or HHV-6. Furthermore, the risk of leukemia can be elevated by allergies, which involve Th1/Th2 lymphocyte-dependent mechanisms. A familial predisposition to tumorigenesis in children is observed in Li-Fraumeni Syndrome. Also, genetic diseases such as Down syndrome and Fanconi anemia are associated with an increased risk of acute leukemia. Previous exposure to radiation therapy or the use of anti-cancer drugs can also lead to the development of secondary cancers, including leukemia. The analysis of risk factors can be used to support efforts aimed to reduce potentially harmful exposure and to decrease the risk of disease.

Risk factors for glioblastoma are shared by other brain tumor types.

The reported risk factors for glioblastoma (GBM), i.e., ionizing radiation, Li-Fraumeni syndrome, Neurofibromatosis I, and Turcot syndrome, also increase the risk of other brain tumor types. Risk factors for human GBM are associated with different oncogenic mutation profiles. Pedigreed domestic dogs with a shorter nose and flatter face (brachycephalic dogs) display relatively high rates of glioma formation. The genetic profiles of canine gliomas are also idiosyncratic. The association of putatively different mutational patterns in humans and canines with GBM suggests that different oncogenic pathways can result in GBM formation. Strong epidemiological evidence for an association between exposure to chemical carcinogens and an increased risk for development of GBM is currently lacking. Ionizing radiation induces point mutations, frameshift mutations, double-strand breaks, and chromosomal insertions or deletions. Mutational profiles associated with chemical exposures overlap with the broad mutational patterns seen with ionizing radiation. Weak statistical associations between chemical exposures and GBM reported in epidemiology studies are biologically plausible. Molecular approaches comparing reproducible patterns seen in spontaneous GBM with analogous patterns found in GBMs resected from patients with known significant exposures to potentially carcinogenic chemicals can address difficulties presented by traditional exposure assessment.

Primary Axillary Vein Leiomyosarcoma in Li-Fraumeni Syndrome.

Primary Axillary Vein Leiomyosarcoma in Li-Fraumeni Syndrome.

Fuzzy Set Theory Applied on Li-Fraumeni Syndrome Homeopathic Selection of Remedies

In this study, by using the basic concepts and results of the Fuzzy Set Theory, the ambiguous circumstances of homeopathy, regarding the selection, dilution, and potencies are analyzed by parameterization concepts. A comprehensive study of Li-Fraumeni syndrome (LFS) as a genetic autosomal dominant disease is described as related to mutations in the P53 genes. The analysis of the effects and different potencies of some homeopathic medicines like Calcarea Fluorica, Thuja, Carcinosin, Phytolacca, and Calcarea Phos as complementary and alternative medicines are represented through the graphical representation of the different age groups of people. In the context of the Langmuir equation, the dilutions using the Hahnemann and Korsakovian methods with implementing the Fuzzy Set Theory are analyzed.

Secondary refractory lymphoblastic leukaemia in a patient with Li-Fraumeni syndrome

Secondary refractory lymphoblastic leukaemia in a patient with Li-Fraumeni syndrome

Functional pri-miR-34b/c rs4938723 and KRAS 3′UTR rs61764370 SNPs: Novel phenotype modifiers in Li-Fraumeni Syndrome?

PurposeLi-Fraumeni Syndrome (LFS) is a rare cancer predisposing condition caused by germline pathogenic TP53 variants, in which core tumors comprise sarcomas, breast, brain and adrenocortical neoplasms. Clinical manifestations are highly variable in carriers of the Brazilian germline founder variant TP53 p.R337H, possibly due to the influence of modifier genes such as miRNA genes involved in the regulation of the p53 pathway. Herein, we investigated the potential phenotypic effects of two miRNA-related functional SNPs, pri-miR-34b/c rs4938723 and 3′UTR KRAS rs61764370, in a cohort of 273 LFS patients from Southern and Southeastern Brazil. MethodsThe genotyping of selected SNPs was performed by TaqMan® allelic discrimination and subsequently custom TaqMan® genotyping results were confirmed by Sanger sequencing in all SNP-positive LFS patients. ResultsAlthough the KRAS SNP showed no effect as a phenotype modulator, the rs4938723 CC genotype was significantly associated with development of LFS non-core tumors (first tumor diagnosis) in p.R337H carriers (p = 0.039). Non-core tumors were also more frequently diagnosed in carriers of germline TP53 DNA binding domain variants harboring the rs4938723 C variant allele. Previous studies described pri-miR-34b/c rs4938723 C as a risk allele for sporadic occurrence of thyroid and prostate cancers (non-core tumors of the LFS spectrum). ConclusionWith this study, we presented additional evidence about the importance of analyzing miRNA genes that could indirectly regulate p53 expression, and, therefore, may modulate the LFS phenotype, such as those of the miR-34 family.

Scylla and Charybdis: Unpalatable choices in managing hypodiploid acute lymphoblastic leukemia

Acquired TP53 alterations are present in > 90% of cases of paediatric low-hypodiploid acute lymphoblastic leukaemia (ALL), and ≈ 50% of patients with this subtype harbor germline pathogenic / likely pathogenic (P/LP) TP53 alterations. Despite dose intensified, conventional chemotherapy, survival in low-hypodiploid ALL remains dismal compared to other paediatric ALL. Individuals with underlying Li-Fraumeni Syndrome (LFS) are known to have increased sensitivity to genotoxic effect of chemotherapy and radiotherapy. Recent evidence shows a 25.1% 5-year cumulative incidence of SMNs post ALL therapy in an LFS population as compared to 0.7% in patients with either a wild type or VUS TP53. The parallel high risks of both relapse and SMN present unpalatable choices facing clinicians.

Li-Fraumeni Syndrome Cancer Surveillance Strategy Considerations for Glioblastoma Multiforme

Sporadic or inherited deficiencies in the production or activity of the tumor suppressor P53 lead to Li-Fraumeni Syndrome (LFS), a multi-organ tumorigenic condition. Glioblastoma multiforme (GBM), a tumor that commonly presents with a median age of 64, has a higher chance of appearing in much younger patients who have LFS [9]. Since the implementation of the 2016 Toronto Protocol to increase cancer surveillance in LFS patients, three cases of LFS-GBM have been discussed [11-13]. Here, we report a case of LFS in an 18-year-old male who had a seizure due to a GBM that had evaded a full-body MRI six months prior. Furthermore, we discuss the potential quality of life (QOL) benefits of providing patients with a shorter brain MRI screening interval: better survival outcomes and peace of mind. Though there may be a rise in the financial cost with an increase in the number of MRI scans, the prevalence of aggressive tumors that must be treated early for a better prognosis warrants more frequent screening. Furthermore, we address the importance of expanding clinical knowledge on GBM in the LFS setting as well as addressing the benefits of the protocol through statistical studies.

Arsenic trioxide extends survival of Li–Fraumeni syndrome mimicking mouse

Li-Fraumeni syndrome (LFS) is characterized by germline mutations occurring on one allele of genome guardian TP53. It is a severe cancer predisposition syndrome with a poor prognosis, partly due to the frequent development of subsequent primary tumors following DNA-damaging therapies. Here we explored, for the first time, the effectiveness of mutant p53 rescue compound in treating LFS-mimicking mice harboring a deleterious p53 mutation. Among the ten p53 hotspot mutations in IARC LFS cohorts, R282W is one of the mutations predicting the poorest survival prognosis and the earliest tumor onset. Among the six clinical-stage mutant p53 rescue compounds, arsenic trioxide (ATO) effectively restored transactivation activity to p53-R282W. We thus constructed a heterozygous Trp53 R279W (corresponding to human R282W) mouse model for the ATO treatment study. The p53R279W/+ (W/+) mice exhibited tumor onset and overall survival well mimicking the ones of human LFS. Further, 35 mg/L ATO addition in drink water significantly extended the median survival of W/+ mice (from 460 to 596 days, hazard ratio = 0.4003, P = 0.0008). In the isolated tumors from ATO-treated W/+ mice, the representative p53 targets including Cdkn1a, Mdm2, and Tigar were significantly upregulated, accompanying with a decreased level of the proliferation marker Ki67 and increased level of apoptosis marker TUNEL. Together, the non-genotoxic treatment of p53 rescue compound ATO holds promise as an alternative for LFS therapeutic.

Therapy-Related Acute Myeloid Leukemia After Chemotherapy For Osteosarcoma: Report of 2 Cases and Review of The Literature

Abstract Introduction/Objective Therapy-related acute myeloid leukemia (t-AML) and myelodysplastic syndrome (t-MDS) are rare but well-established late complications of chemotherapeutic agents or radiation therapy used to treat various malignancies. Many cases of t-AML/t-MDS have been described secondary to Hodgkin, non-Hodgkin lymphoma, and other solid tumors. However, only a few cases of t-AML and t-MDS have been reported following osteosarcoma treatment. We describe two patients diagnosed with osteosarcoma who developed t-AML after receiving multiple chemotherapeutic agents. Methods/Case Report A 12-year-old male with Li-Fraumeni syndrome was diagnosed with osteosarcoma of the left ilium and sacrum with pulmonary metastases. Despite multiple lines of chemoradiation therapy including doxorubicin and ifosfamide, tumor progressed at the primary tumor site. The patient subsequently presented with altered mental status and pancytopenia. Bone marrow biopsy demonstrated AML. He died despite supportive care. A 14-year-old female was diagnosed with left tibial osteosarcoma with bony and pulmonary metastases. She was treated on standard osteosarcoma chemotherapy including doxorubicin, cisplatin, methotrexate, ifosfamide and etoposide, surgery, and radiation. 1 year following therapy, she had local recurrence of osteosarcoma without progression despite not starting chemotherapy. However, 3 years later, she developed pancytopenia, and immature white blood cells were identified on peripheral smear. Bone marrow biopsy revealed AML-M7. Despite supportive care and zoledronic acid, she ultimately died from sepsis and disseminated intravascular coagulation. Results (if a Case Study enter NA) NA Conclusion With improved therapy and survival for osteosarcoma patients, these patients should be monitored for secondary malignancies. T-AML is rare following osteosarcoma treatment, but outcome remains poor, despite treatment. Underlying Li-Fraumeni syndrome may influence the risk of development of secondary malignant neoplasms. Literature review of types and prognosis of t-AML following osteosarcoma will be reviewed and compared to our cases, including related genetic predisposing factors and chemotherapeutic agents. Our second patient is the first reported case of AML-M7 secondary to osteosarcoma treatment.

The Human Leukemia Immunopeptidome Is Driven By Pathogenic Molecular Variant Biotypes

Background Historically, acute myelogenous leukemia (AML) has been characterized as having a low somatic mutational burden and is predicted to have low neoantigen levels compared to solid tumors. However, recent data has shown that AML is an immunogenic malignancy and oncogenic driver mutations promote immune escape through immunoediting. Downregulation of human leukocyte antigen (HLA) class II HLA-DRB1, HLA-DQB1, HLA-DPA1 and HLA-DPB1 gene expression on leukemia cells has previously been associated with immune escape in AML following allogeneic hematopoietic stem cell transplantation (allo-HCT). While allo-HCT and cellular therapies are well-known potentially curative treatment options in AML, the human leukemia immunopeptidome has still not been well characterized. Here, we sought to uncover the human leukemia immunopeptidome by detecting differential major histocompatibility complex (MHC) class I neopeptide expression using molecular biotype subgroups. Methods We conducted retrospective analysis on 31 patients with hematopoietic malignancies including AML, chronic myelomonocytic leukemia (CMML), myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN), MDS, chronic myelogenous leukemia (CML) and other hematopoietic malignancies (i.e. NK cell leukemia) at MedStar Georgetown University Hospital. Mutations were identified using next generation sequencing and separated into the following annotated molecular biotypes based on the mechanism of pathogenesis: Group 0 (G0) DNA repair, G1 splicing, G2 transcription factor, G3 kinase activation, G4 epigenetic modification, G5 chromatin remodeling, G6 cohesin, G7 tumor suppressor (i.e. p53), G8 telomere maintenance, G9 histone modification, G10 nucleotransport (i.e. NPM1) and G11 cell cycle regulation. FASTA nucleotide sequences were obtained by subjecting mutations to transcript expression and cDNA alignment in the National Center for Biotechnology Information (NCBI) gene database. MHC class I binding neopeptides were identified by mapping patient FASTA nucleotide sequences and HLA class I alleles in the Net MHC pan 4.1 database. Neopeptides were grouped by % Rank and categorized as weak binding (WB) if &amp;gt; 0.5 and strong binding (SB) if ≤0.5. Descriptive and inferential statistics were performed using SAS. Results Thirty-one patients were evaluated including 17 AML (54.8%), 5 MDS (16.1%), 3 CMML (9.7%), 2 MDS/MPN (6.5%), 1 CML (3.2%) and 3 hematopoietic malignancies (9.7%). The median age was 65 years (range 28 -89); 43.8% were female and 43.3% were African American (AA). 144mutations were identified; thus far, 82 mutations have been subjected to FASTA NP_ protein extraction. The G3 biotype had the highest frequency of neopeptide bindings (n=59) followed by G2 (n=50) and G4 biotypes (n=42) ( Fig.1). Among patients with MDS, smokers were more likely to exhibit neopeptide binding compared to non-smokers (p=0.032). Patients with neopeptide binding had a longer median overall survival (mOS) compared to patients without neopeptide binding (mOS = 566 vs 114 days, p=0.0174) (Fig 2). Data exploration allowed isolation of a 54-year-old Asian male with Li-Fraumeni syndrome and p53 mutated AML who demonstrated high affinity neopeptide binding to HLA-B*39:01 with %Rank 0.08. Additionally, a 34 -year-old AA female with FLT3 mutated AML showed very high affinity neopeptide binding to HLA-A*29:02 with %Rank 0.007 as well as evidence of somatic HLA-A*03:01 deletion. Conclusions Pathogenic molecular variant biotypes constitute a novel immune signature, the human leukemia immunopeptidome. Smoking increased the likelihood of MHC class I neopeptide binding among patients with MDS. The presence of neopeptide binding predicted improved mOS in patients with myeloid malignancies. Further investigation of the human leukemia immunopeptidome may provide additional prognostic significance above that of standard molecular and cytogenetic risk stratification.

Hereditary cancer syndromes with increased risk of renal cancer

Renal cancer (RC) is one of the three most common diseases in oncologic urology. Its accurate diagnosis and prognosis remain difficult and important problems. Some cases of RC are associated with hereditary cancer syndromes and are caused by germline mutations. This review describes monogenic forms of hereditary RC (von Hippel–Lindau syndrome, Birt–Hogg– Dubé syndrome, hereditary leiomyomatosis and renal cell cancer, hereditary papillary renal carcinoma, BAP1 tumor predisposition syndrome) and diseases with several candidate genes (SDH-mutated tumors, tuberous sclerosis complex). Additionally, the review discusses the increased risk of RC in patients with frequent hereditary cancer syndromes predisposing to the development of a wide range of tumor types: Lynch and Li-Fraumeni syndromes. RC in combination with other carcinomas can develop in patients carrying pathogenic mutations in the candidate genes of different hereditary cancer syndromes – multi-locus inherited neoplasia allele syndrome (MINAS) – which is especially important due to the growing role of high-throughput sequencing in practical oncologic genetics. Additionally, guidelines on modern laboratory genetic diagnostics and active surveillance are presented for each syndrome.

PATH-15. GLIOBLASTOMA, IDH-WILDTYPE WITHOUT KEY MOLECULAR FEATURES.

Abstract Molecular alterations that predict aggressive behavior of astrocytic tumors include EGFR amplification, TERT promoter (pTERT) mutations, gain of chromosome 7 and loss of chromosome 10. During January 2020 and February 2023, we encountered 21 cases of pathologically diagnosed glioblastoma, IDH-wildtype without the above-mentioned molecular characteristics. In this study, we tried to characterize these tumors. For all cases, genomic DNA was extracted from fresh frozen tissue. Using extracted DNA, to analyze the status of IDH mutation, 1p/19q codeletion, pTERT mutation, EGFR gene amplification, combined gain of entire chromosome 7, and loss of entire chromosome 10 (+7/− 10), whole exome sequencing, Sanger sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA) was performed. In addition, gene panel testing was performed for suspected familial cases. Among 21 cases, 2 harbored histone G34 mutation and was diagnosed as diffuse hemispheric gliomas, H3 G34-mutant. Among the rest 19 patients, CDKN2A/B homozygous deletions were detected in 7. Three of the rest 12 patients were diagnosed as patients with Li Fraumeni syndrome. Glioblastoma IDH-wildtype CNS WHO grade 4 typically presents necrosis and/or microvascular proliferation. Molecular alterations including EGFR amplification, pTERT mutations, gain of chromosome 7 and loss of chromosome 10 are key features that characterize GBM IDH-wildtype. However, some of the pathologically diagnosed GBM, do not carry these gene alterations. Among those, there existed cases harboring CDKN2A/B homozygous deletions or H3 G34 mutations, and cases suffering Li Fraumeni syndrome.

PATH-53. ANAPLASTIC PLEOMORPHIC XANTHROASTROCYTOMA WITH BEND5-NTRK2 FUSION IN A YOUNG ADULT WITH A HISTORY OF CRANIAL RADIATION FOR CHILDHOOD RHABDOMYOSARCOMA

Abstract INTRODUCTION: Pleomorphic xanthoastrocytoma (PXA) is a rare subset of circumscribed astrocytic glioma. While PXA typically has a favorable prognosis, anaplastic (WHO Grade III) PXA (aPXA) has a poorer prognosis. Molecular analysis of PXA often reveals BRAF mutations or CDKN2A/B homozygous deletions. NTRK fusions have been identified in a few cases of pediatric gliomas including PXA. BEND-5 gene alterations have been rarely reported in CNS tumors such as glioblastoma but have not been previously reported in PXA. Case Presentation The patient is a 24-year-old female with history of nasopharyngeal embryonal rhabdomyosarcoma treated with chemotherapy and radiation at age 3. She was tested for Li-Fraumeni Syndrome and was reportedly negative. One year ago, she presented with visual changes and was found to have an occipital aPXA. She underwent a gross total resection but declined further treatment with radiation. Next-generation sequencing (NGS) identified a BEND5-NTRK2 fusion, and she began treatment with Larotrectinib. Serial MRI scans have shown no evidence of disease recurrence. Discussion Pediatric patients are at increased risk for glioma after radiation which is age- and dose/volume-dependent. Radiation-induced gliomas are typically higher grade, present in atypical sites, and have a poor prognosis. Development of PXA following radiation is rare but has been reported. Our patient was diagnosed with aPXA almost 20 years after initial treatment for rhabdomyosarcoma. Her aPXA exhibited a BEND5-NTRK2 fusion and lacked classical BRAF alterations and CDKN2A/B deletions that are present in de novo cases. A Neuro-Onc Panel did not identify her fusion or include testing for BEND5 alterations. However, an expanded RNA Exome Fusion Panel NGS identified a unique fusion, which opened her up to targeted treatment with an NTRK inhibitor. Our patient is now 1 year from resection without disease progression on larotrectinib. This case highlights the importance of expanded NGS testing, particularly in rare tumors.

Abstract 14125: Tricuspid Mass- Solving a Curious Case of Li-Fraumeni Syndrome

Background: Primary cardiac tumors are extremely rare (0.001-0.03%), but can have significant embolic, obstructive, and arrhythmic consequences. Li-Fraumeni syndrome (LFS) is an autosomal dominant genetic syndrome characterized by multiple malignancies, including osteosarcomas, CNS tumors, and adrenocortical, breast, and soft tissue sarcomas. We report diagnostic challenges of a patient with Li-Fraumeni syndrome found to have tricuspid valve mass and atrial septal defects. Case: 30-year-old female with Li-Fraumeni syndrome (ovarian cancer at 6 years,osteosarcoma and soft tissue sarcoma at 16 years, bilateral breast cancer at 26 years) found to have a tricuspid valve leaflet mass, as well as two atrial septal defects on surveillance echocardiography. There was concern for a primary cardiac tumor such as sarcoma or rhabdomyoma. She underwent surgical resection with biopsy showing organized mural thrombus. Decision making: Li-Fraumeni syndrome is a rare autosomal dominant cancer-predisposing syndrome, which can present with various tumor types. Cardiac tumors are extremely rare and have been limited to case reports. Although multimodality imaging is now more readily available, some cases remain diagnostic challenges if imaging is non-conclusive, histopathological studies remain the gold standard. In our case, the mass demonstrated mild enhancement in the post-gadolinium images suggestive for primary cardiac tumor versus a secondary metastatic cancer (Figure). A histopathological analysis by surgical resection demonstrated an organized thrombus. Conclusion: Diagnosis of cardiac masses in the setting of hereditary cancer syndromes such as LFS are rare and remain a challenge given the increased likelihood of primary or metastatic lesions. When imaging is inconclusive, further invasive investigations are warranted since it can alter the clinical management.