Germline TP53 Mutations Research Articles

EPCO-32. PROSPECTIVE GERMLINE SEQUENCING OF PATIENTS WITH GLIOMAS, GLIONEURONAL OR NEURONAL TUMORS

Abstract BACKGROUND Several genetic syndromes have been linked to the development of central nervous system (CNS) tumors; however, the prevalence and clinical significance of germline pathogenic variants in this population remain unclear. METHODS 2,367 patients with a glioma, glioneuronal, or neuronal tumor (WHO grade 1-4) ages 0.2-93.8 years underwent tumor and matched normal sequencing with MSK-IMPACT. Germline variants and copy-number variants affecting 90 well-established cancer predisposing genes were analyzed; the presence of biallelic inactivation was determined using FACETS. RESULTS Eleven percent harbored germline pathogenic mutations in high-, moderate-, and low-penetrance genes. High- and moderate-penetrance genes included CHEK2 (n=32, 1.3%), BRCA2 (n=10; 0.4%), TP53 (n=9; 0.4%), NF1 (n=6; 0.2%), and mismatch repair (MMR) genes (n=20, 0.9%). Low-penetrance genes included monoallelic MUTYH (n=42; 1.8%) and the APC I1307K variant (n=28, 1.2%). Biallelic inactivation was found in all tumors from patients with germline TP53 and NF1 mutations, with lower rates in tumors from patients with a germline MMR alteration (53%). Biallelic inactivation was rare among patients with a germline mutation in homologous recombination pathway (HRD) genes (27%), and in the aforementioned low-penetrance APC (15.3%) and MUTYH (10.2%) variants. All patients with biallelic inactivation of an MMR gene were hypermutated. Biallelic inactivation of MMR genes and TP53 were observed in IDH-mutant astrocytoma and IDH-WT gliomas, while biallelic inactivation of NF1 and somatic IDH1/2 mutation were mutually exclusive. When examining the age at diagnosis among patients with germline alterations, tumors with biallelic inactivation were diagnosed at a younger age compared to tumors with monoallelic alterations (37.7 vs 51.6 years, p=0.002). CONCLUSION Clinical germline sequencing identifies a germline mutation in a high proportion of patients with CNS tumors. Biallelic inactivation was most commonly identified in tumors from patients with germline TP53 or NF1 mutations and were less common in patients with a germline MMR alteration.

Germline mutations of TP53 gene can be a key factor in prostate cancer genesis

Aim: The aim of this study is to investigate whether germline alterations of exon 5 of TP53 gene could be detected in the blood of known men with prostate cancer and to assess the potential association between the genomic alteration affecting this gene and clinicopathological characteristics of the patients. Methods: Forty-eight blood samples from men diagnosed with prostate cancer were analyzed for TP53 germline mutations and confirmed by Sanger sequencing. The frequency and distribution of high-frequency mutations were analyzed according to the pathological criteria of the patients and a computational study was performed to assess the effect of new mutations. Results: The Sanger sequencing revealed that 79% of the population studied carry mutations in TP53 gene. In summary, a total of 137 mutations have been identified in this gene, out of which 115 are new mutations. Frameshift mutations were the most frequent; the mutation c.392delA was recorded in fifteen cases (31%); the mutations c.383delC and c.432delG were observed at a frequency of 12.5% and 10% respectively. The most frequent missense mutation was the variant c.502C>A (p.His168Asn) identified in eleven patients (23%). One nonsense mutation was identified in one patient and resulted in a stop codon in position 126 (tyrosine). All codons affected by these alterations are part of the DNA binding domain of the protein TP53. Conclusions: The germline mutation frequency observed in prostate cancer patients, and the new mutations recorded in TP53 gene, could be in favor of a potential association of genomic alterations in this gene and prostate cancer genesis, thereby constituting a tool, similar to other genes in the DNA repair pathway such as BRCA1 and BRCA2. This could contribute to the advancement of diagnosis and therapeutic strategies for prostate cancer.

Li-Fraumeni-associated osteosarcomas: The French experience.

Describe clinical characteristics and outcome of Li-Fraumeni syndrome (LFS)-associated osteosarcomas. TP53 germline pathogenic/likely pathogenic variant carriers diagnosed with osteosarcoma in France between 1980 and 2019 were identified via the French Li-Fraumeni database at Rouen University Hospital. Sixty-five osteosarcomas in 52 patients with available clinical and histological data were included. The main clinical characteristics were compared with data from National Cancer Institute's SEER (Surveillance, Epidemiology, and End Results) for patients of the same age group. Median age at first osteosarcoma diagnosis was 13.7years (range: 5.9-36.7). Compared to unselected osteosarcomas, LFS-associated osteosarcomas occurred more frequently in patients less than 10years of age (23% vs. 9%), and when compared with osteosarcomas in patients less than 25years were characterized by an excess of axial (16% vs. 10%) and jaw sites (15% vs. 3%) and histology with predominant chondroblastic component and periosteal subtypes (17% vs. 1%). Metastases incidence (25%) was as expected in osteosarcomas. After the first osteosarcoma treatment, the rate of good histologic response (62%) and the 5-year progression-free survival (55%, 95% confidence interval [CI]: 42.6-71.1) were as expected in unselected series of osteosarcomas, whereas the 5-year event-free survival was 36.5% [95% CI: 25.3-52.7] due to the high incidence of second malignancies reaching a 10-year cumulative risk of 43.4% [95% CI: 28.5-57.5]. In osteosarcoma, young age at diagnosis, axial and jaw sites, histology with periosteal or chondroblastic subtype, and synchronous multifocal tumors should prompt suspicion of a germline TP53 mutation. Standard treatments are effective, but multiple malignancies impair prognosis. Early recognition of these patients is crucial for tailored therapy and follow-up.

Acyl-coenzyme a binding protein (ACBP) - a risk factor for cancer diagnosis and an inhibitor of immunosurveillance

BackgroundThe plasma concentrations of acyl coenzyme A binding protein (ACBP, also known as diazepam-binding inhibitor, DBI, or ‘endozepine’) increase with age and obesity, two parameters that are also amongst the most important risk factors for cancer.MethodsWe measured ACBP/DBI in the plasma from cancer-free individuals, high-risk patients like the carriers of TP53 or BRCA1/2 mutations, and non-syndromic healthy subjects who later developed cancer. In mice, the neutralization of ACBP/DBI was used in models of non-small cell lung cancer (NSCLC) and breast cancer development and as a combination treatment with chemoimmunotherapy (chemotherapy + PD-1 blockade) in the context of NSCLC and sarcomas. The anticancer T cell response upon ACBP/DBI neutralization was characterized by flow cytometry and single-cell RNA sequencing.ResultsCirculating levels of ACBP/DBI were higher in patients with genetic cancer predisposition (BRCA1/2 or TP53 germline mutations) than in matched controls. In non-syndromic cases, high ACBP/DBI levels were predictive of future cancer development, and especially elevated in patients who later developed lung cancer. In preclinical models, ACBP/DBI neutralization slowed down breast cancer and NSCLC development and enhanced the efficacy of chemoimmunotherapy in NSCLC and sarcoma models. When combined with chemoimmunotherapy, the neutralizing monoclonal antibody against ACBP/DBI reduced the frequency of regulatory T cells in the tumor bed, modulated the immune checkpoint profile, and increased activation markers.ConclusionThese findings suggest that ACBP/DBI acts as an endogenous immune suppressor. We conclude that elevation of ACBP/DBI constitutes a risk factor for the development of cancer and that ACBP/DBI is an actionable target for improving cancer immunosurveillance.

Genomic Landscape of Osteosarcoma of Bone in an Older-Aged Patient Population and Analysis of Possible Etiologies Based on Molecular Signature.

Background: Osteosarcoma (OS), the most common primary malignant bone tumor, occurs mostly in the pediatric and adolescent (P/A) population where it has been subject to intense study whereas OS arising in the older-aged adult population has undergone less scrutiny. Materials and Methods: In this study, we assess the molecular aberrations detected in eight older adult patients (>59 years of age) with OS of bone by whole-exome sequencing (WES) on formalin-fixed, paraffin-embedded tissue and quantified the contributions of endogenous and exogenous mutational processes to tumor mutational burden and to tumorigenesis through computational analysis. Results: We identified 86 clinically significant somatic mutations. TP53 mutations occurred in OSs of three patients and one patient harbored a pathogenic germline mutation of TP53. Loss-of-heterozygosity of DNA-damage repair genes occurred in all six tumors evaluated. Computational analysis of single nucleotide variants within each tumor detected eight distinct mutagenic processes of which age-associated mutational processes, thiopurine chemotherapy, and defective homologous DNA recombination repair contributed the most to both tumor mutation burden and tumor pathogenesis. Conclusion: The genomic landscape of our older OS patients deciphered by WES is extremely diverse with only 15% of mutated somatic genes uncovered in our study previously described in P/A-enriched OS studies. Endogenous age-related mutagenic processes, defective DNA homologous recombination repair, and exogenous effects of chemotherapy are mainly responsible for pathogenic mutations in OS occurring in our cohort.

Baseline surveillance in Li Fraumeni syndrome using whole-body MRI: a systematic review and updated meta-analysis.

Li-Fraumeni syndrome (LFS) is a cancer syndrome associated with early-onset neoplasias. The use of whole-body magnetic resonance imaging (WBMRI) is recommended for regular cancer screening, however, evidence supporting the benefits in asymptomatic LFS patients is limited. This study aims to assess the clinical utility of WBMRI in germline TP53 mutation carriers at baseline and follow-up. We systematically searched PubMed, Cochrane, and Embase databases for studies evaluating WBMRI as an early detection method for tumor screening in patients with LFS. We pooled the prevalence of the included variables along with their corresponding 95% confidence intervals (CIs). Statistical analyses were performed using R software, version 4.3.1. From 1687 results, 11 comprising 703 patients (359 females (51%); with a median age of 32 years (IQR 1-74)) were included. An estimated detection rate of 31% (95% CI: 0.28, 0.34) for any suspicious lesions was found in asymptomatic TP53 carriers who underwent baseline WBMRI. A total of 277 lesions requiring clinical follow-up were identified in 215 patients. Cancer was confirmed in 46 lesions across 39 individuals. The estimated cancer diagnosis rate among suspicious lesions was 18% (95% CI: 0.13, 0.25). WBMRI detected 41 of the 46 cancers at an early-disease stage, with an overall detection rate of 6% (95% CI: 0.05, 0.08). The incidence rate was 2% per patient round of WBMRI (95% CI: 0.01, 0.04), including baseline and follow-up. This meta-analysis provides evidence that surveillance with WBMRI is effective in detecting cancers in asymptomatic patients with LFS. Our study demonstrates that whole-body MRI is an effective tool for early cancer detection in asymptomatic Li-Fraumeni Syndrome patients, highlighting its importance in surveillance protocols to improve diagnosis and treatment outcomes. Current evidence for whole-body MRI screening of asymptomatic Li-Fraumeni Syndrome (LFS) patients remains scarce. Whole-body MRI identified 41 out of 46 cancers at an early stage, achieving an overall detection rate of 6%. Whole-body MRI surveillance is a valuable method for detecting cancers in asymptomatic LFS patients.

Selective pressures of platinum compounds shape the evolution of therapy-related myeloid neoplasms

Therapy-related myeloid neoplasms (t-MN) arise as a complication of chemo- and/or radiotherapy. Although t-MN can occur both in adult and childhood cancer survivors, the mechanisms driving therapy-related leukemogenesis likely vary across different ages. Chemotherapy is thought to induce driver mutations in children, whereas in adults pre-existing mutant clones are selected by the exposure. However, selective pressures induced by chemotherapy early in life are less well studied. Here, we use single-cell whole genome sequencing and phylogenetic inference to show that the founding cell of t-MN in children starts expanding after cessation of platinum exposure. In patients with Li-Fraumeni syndrome, characterized by a germline TP53 mutation, we find that the t-MN already expands during treatment, suggesting that platinum-induced growth inhibition is TP53-dependent. Our results demonstrate that germline aberrations can interact with treatment exposures in inducing t-MN, which is important for the development of more targeted, patient-specific treatment regimens and follow-up.

ETMR-13. MARROW-ABLATIVE CONSOLIDATION CHEMOTHERAPY WITH AUTOLOGOUS HEMATOPOIETIC PROGENITOR CELL RESCUE (HDCT) DECREASES THE DEVELOPMENT OF CHOROID PLEXUS CARCINOMA (CPC)-SPECIFIC RELAPSE IN HIGH-RISK TP53-MUTATED (GERMLINE OR SOMATIC) YOUNG CHILDREN WITH NEWLY DIAGNOSED CPC

Abstract BACKGROUND CPC are childhood cancers in which the loss of TP53 function defines unfavorable disease. CPC-free survival rates have remained poor in patients with TP53 mutations and recent data revealed CPC-free survival of 29% with a non-marrow-ablative chemotherapy strategy. Previously reported results of the “Head Start” (HS) HDCT approach were limited by small patient numbers and incomplete TP53 mutation data. Consequently, the role of HDCT in TP53-mutated CPC remains unclear. METHODS We have analyzed data on TP53 status, CPC-free survival and second cancers from the largest cohort of patients who received initial therapy with the intent of undergoing HDCT. RESULTS Twenty-seven children with CPC received HS-like induction chemotherapy and 23 completed HDCT consolidation. Somatic or germline TP53 mutations were identified in 17 patients, 4 exhibited TP53 wild type (TP53wt); TP53 status remained untested in 6. Five-year CPC-free survival was 66% for patients with TP53 germline mutations (n=12), 40% for those with somatic tumor TP53 mutations (n=5) and 50% with confirmed TP53wt (n=4). Among patients with germline TP53 mutations, only 4/12 experienced CPC recurrences, 4 died from secondary cancers and 4 are currently alive. The 5-year CPC-free survival for 23 patients who underwent HDCT was 52%. All six survivors with TP53 mutations had undergone HDCT, and 5/6 avoided irradiation. Eight/12 patients with TP53 germline mutations and Li-Fraumeni Syndrome (LFS) developed second malignancies, including 6 patients in HDCT group and the remaining 2 patients who did not undergo consolidative HDCT. CONCLUSIONS Our data indicate that HDCT consolidation is associated with improved CPC-free survival compared with historical reports in children with TP53 mutated CPC. The ultimate development of second cancers affects outcomes for those with LFS, irrespective of HDCT treatment. These data justify the inclusion of HDCT in the prospective international trial under development for young children with newly diagnosed TP53 mutated CPC.

HGG-46. PEDIATRIC RADIATION-INDUCED GLIOMA PATIENT SAMPLES AND NOVEL PATIENT-DERIVED MODELS REVEAL TRANSLATIONALLY RELEVANT TREATMENT SUSCEPTIBILITIES AND POTENTIAL GERMLINE RISK FACTORS

Abstract BACKGROUND Pediatric radiation-induced glioma (RIG) is an incurable secondary high-grade glioma (HGG) afflicting up to 4% of children who previously received cranial radiotherapy (RT) for other malignancies. RIG accounts for up to 10% of pediatric brain tumor deaths. It has no known genetic risk factors nor effective treatment and is uniformly fatal, partly due to extremely limited available models. Our recent molecular characterization of patient samples showed that while RIG and primary pediatric HGG share histological similarities, their genetic alterations and gene expression profiles differ. METHODS We obtained germline DNA sequencing from 28 RIG patients and 112 matched controls who received RT but did not develop RIG. In addition, we developed cell culture and murine orthotopic patient-derived xenograft (PDX) models from four RIGs. We conducted single-cell RNA-seq (scRNA-seq), drug screening/validation, and CRISPR functional screening on our novel models. RESULTS Germline mutations in TP53, PARP10, POLI, DCLRE1A, and MLH3 were more common in RIG patients than controls (p<0.002). Our matched cell culture and PDX models of RIG represent the genetic diversity of the disease. The PDX models form tumors in 30-120 days and closely recapitulate human RIG by histology and scRNA-seq. They show susceptibility across models to DNA-damaging treatments (etoposide, irinotecan, radiation), as well as MEK, PARP, and proteasome inhibition, with orthogonal supporting findings via CRISPR screening. Several two-treatment combinations also show efficacy and synergy across models, including radiation and trametinib in vivo (logrank p=0.029). Discussion: RIG is an understudied but major cause of pediatric CNS tumor mortality that differs genetically from primary pediatric HGG. Our findings suggest specific germline alterations in DNA repair pathways may put some patients at higher risk of developing RIG after cranial RT. We also introduce the first set of patient-derived RIG models in order to advance translational RIG research, with characterization of translationally relevant treatment susceptibilities.

HGG-19. H3- AND IDH-WILDTYPE DIFFUSE PAEDIATRIC-TYPE HIGH-GRADE GLIOMA WITHMYCN-AMPLIFICATION: AN INDICATION CRITERION FOR LI-FRAUMENI SYNDROME TESTING

Abstract BACKGROUND: In the current World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS) (5th edition), the introduction of a molecular layer to the integrated diagnosis not only helps to characterize and prognosticate paediatric CNS tumors but the molecular alteration may predict a potential therapeutic option with a targeted agent. Furthermore, certain gene alterations may be a presage of germline alterations or cancer predisposition syndromes, portending significant implications to the index patients and their families. We report a 5-year-old boy diagnosed with non-metastatic left hemispheric H3-wildtype and IDH-wildtype diffuse paediatric-type high-grade glioma with MYCN-amplification, who was subsequently found to have Li-Fraumeni syndrome. He presented with a 3-day history of facial asymmetry, unsteady gait and right sided weakness. There was no family history of malignancy. Initial MRI revealed a restricting and enhancing solid cystic lesion (5.9 x 4.3 x 5.8cm) in the left frontal-temporal-parietal region. Tumor debulking was performed. Histopathological examination by the local pathologist revealed features of high-grade glioma. Second pathology review with next generation sequencing confirmed H3-wildtype and IDH-wildtype diffuse paediatric-type high-grade glioma with MYCN-amplification and TP53 p.Y103* mutation. He was started on focal radiotherapy and oral temozolomide but succumbed to local and metastatic progressive disease. After genetic counselling, his DNA extracted from blood was sent for targeted exome sequencing and germline mutation of TP53 was demonstrated. Cascade screening of the family members were negative of TP53 mutation. Guerrini-Rousseau et al reported that 57% (n=7) of H3-wildtype and IDH-wildtype diffuse paediatric-type high-grade glioma with MYCN-amplification harboured germline TP53 pathogenic variants. This case further highlights the importance of screening of Li-Fraumeni syndrome in patient with H3-wildtype and IDH-wildtype diffuse paediatric-type high-grade glioma with MYCN-amplification even in the absence of a family history.

Pedigree analysis exploring the inconsistency between diverse phenotypes and testing criteria for germline TP53 mutations in Chinese women with breast cancer

PurposeIn the present study, we addressed the inconsistency between the testing criteria and diverse phenotypes for germline TP53 mutation in patients with breast cancer in the Chinese population.MethodWe proposed a new added item (synchronous or metachronous bilateral breast cancer) as one of the testing criteria (aimed at high-penetrance breast cancer susceptibility genes) and applied it for determining TP53 germline mutation status in 420 female patients with breast cancer using multigene panel-based next-generation sequencing, Sanger sequencing, and mass spectrometry.ResultsWe found that 1.4% of patients carried a pathogenic or likely pathogenic germline TP53 mutation. Compared with BRCA mutation carriers (8.0%) and non-carriers (7.1%), TP53 mutation carriers (33.3%) developed breast cancer earlier. The majority of TP53 mutation carriers (66.7%) developed breast cancer after age 30 and had bilateral breast cancer (33.3%). Pedigree investigation of four TP53 carriers and a patient with a TP53 variant of unknown significance revealed that neither of their parents harbored the same mutations as the probands, indicating that the mutations might occur de novo.ConclusionOur study revealed distinguishing features of TP53 carriers among Chinese women with breast cancer, which is inconsistent with the currently used testing criteria; therefore, the newly proposed testing criteria may be more appropriate.

Marrow-ablative consolidation chemotherapy (HDCT) to decrease the development of choroid plexus carcinoma (CPC) specific relapse in high-risk TP53-mutated (germline or somatic) young children with newly diagnosed CPC.

2088 Background: Choroid plexus carcinomas (CPC) are highly malignant, early childhood cancers in which the loss of TP53 function is a central element of their development and defines unfavorable disease. To date, CPC-free survival rates have remained poor; recent data from St. Jude including complete TP53 mutation status, yielded CPC-free survival of only 29% with a non-marrow-ablative chemotherapy strategy. The rarity of CPC has constrained the ability to explore the role of HDCT with autologous hematopoietic progenitor cell rescue (AuHPCR). Previously reported results of the "Head Start" (HS) HDCT approach showed some promise of cure, but were limited by small patient numbers, short follow-up and incomplete TP53 mutation data. Consequently, the role of HDCT and AuHPCR in TP53-mutated CPC remains unclear. Methods: We have analyzed data on TP53 status, therapy, treatment responses, CPC-free and overall survivals (OS) and second cancers from the largest cohort of such patients, all who received initial therapy with the intent/consideration of undergoing consolidative HDCT. Results: Twenty-seven children with CPC (median age, 16 months) received HS-like induction chemotherapy regimens or ICE with the intent of utilizing consolidative HDCT. Twenty-three of 27 completed HDCT consolidation; the remaining 4 patients did not proceed with HDCT due to parental choice. Somatic or germline TP53 mutations were identified in 17 patients, while 4 patients exhibited TP53 wild type (TP53wt); TP53 status remains untested or unavailable in 6 patients. Five-year CPC-free survival and OS for the entire cohort were 47.8% and 44.4%. CPC-free survival for those with TP53 germline mutations (n=12) was 66%, for those with somatic tumor TP53 mutations (n=5) was 40% and for those with confirmed TP53wt (n=4) was 50%. The 5-year CPC-free survival for all 23 patients who underwent HDCT and AuHPCR was 52%, comprising 3/4 TP53wt patients, 10/12 TP53 germline mutated patients and all 5 TP53 somatic tumor mutated patients. Notably, all six survivors with TP53 mutations had undergone HDCT with AuHPCR, and all but one avoided irradiation. Eight out of 12 patients with documented genotypic (TP53 germline mutated) Li-Fraumeni Cancer Predisposition Syndrome (LFS) developed second malignancies. Conclusions: Our data indicate that HDCT with AuHPCR consolidation is associated with improved CPC-free survival compared with historical reports in young children with high-risk TP53 mutated CPC. However, the ultimate development of second cancers substantially affects outcomes for those with LFS, irrespective of HDCT treatment. These data justify the inclusion of HDCT and AuHPCR in the prospective international trial under development for young children with newly diagnosed TP53 mutated CPC.

Profile of breast cancer in patients with Li-Fraumeni syndrome: An institutional experience.

e13042 Background: Li Fraumeni syndrome (LFS) is a rare autosomal dominant syndrome, associated with multisystem cancer predisposition. Considering the rarity of this syndrome, studies are very sparse on survival outcomes of breast cancer with germline TP53 mutation and there exists discrepancy amongst the results. Methods: This retrospective observational study included 17 patients with germline TP53 mutated breast cancer registered at All India Institute of Medical Sciences (AIIMS), New Delhi, India between the period of 1st April 2016 to 31st Dec 2023. Among the 577 high-risk breast cancer patients, who underwent germline mutation testing, 231 (40.03%) cases had pathogenic mutation [145(25.12%) were BRCA mutated,15 (2.59%) were TP53 mutated, and the rest were others pathogenic variant]. All the TP53 mutations were crosschecked via the ClinVar mutation database to be classified as pathogenic. Results: The median age of 15 patients was 31 years (23-55) and 12 (80%) cases were premenopausal. All the patients had breast cancer as the index malignancy. The Stage distribution (AJCC-7th edition) Stage I, 1(6.6%); Stage II, 7 (46.6 %); Stage III, 4 (26.6 %); and Stage IV, 3 (20 %). Eight cases (53.3%) were HER2 positive, 4 (26.6%) were hormone receptor-positive, and 3 (20%) were Triple-negative breast carcinoma (TNBC). Ten (10) patients received neoadjuvant chemotherapy and 6 (60%) had a complete pathological response. Eight cases (53.3%) cases had a significant family history with 9 (60%) of them having at least one first-degree relative with cancer and two had more than one first-degree relative with cancer. One patient had a family history of LFS. The most common familial cancer was breast, followed by lung, GI malignancies, brain tumor, and sarcoma. Synchronous breast cancer was seen in 2 patients, synchronous malignancies were seen in 4 cases (one patient: each with lung adenocarcinoma, periampullary carcinoma, carcinoma colon, and synovial sarcoma, along with breast cancer), Four patients (26.6%) had metachronous cancers: lung cancer, ovarian carcinoma, contralateral breast cancer, and high-grade sarcoma respectively. The most common mutations were point mutations ( n = 11, 73.3%) followed by frameshift mutations ( n = 4, 26.6%). The subtypes of point mutations included missense mutations ( n = 9) and nonsense mutations ( n = 2) with the most common aberration being a replacement of arginine with glycine (c.743G>A, p. Arg248Gln) and locus being exon 7. The median disease-free survival was 41 months and progression-free survival was 15 months. Conclusions: The prevalence of TP53 mutation in our breast cancer patients is 2.5%. With standard treatment protocols, the overall survival of LFS-associated breast cancer is similar to the historic cohort of patients without any germline mutation. Active surveillance of the patient and family screening is imperative, for all positive cases.

Baseline surveillance in Li Fraumeni syndrome using whole-body MRI: A systematic review and meta-analysis.

e22555 Background: Li-Fraumeni syndrome (LFS) is a cancer syndrome associated with early-onset neoplasias. Risk management through a routine cancer surveillance strategy is critical. Since patients with LFS are susceptible to radiation-induced cancers, the use of whole-body MRI (WBMRI) is recommended for regular cancer screening. However, the guidelines for clinical management and the evidence supporting the benefits of WBMRI surveillance in asymptomatic LFS patients are limited. Therefore, this systematic review and meta-analysis assessed the clinical utility of WBMRI in germline TP53 mutation carriers at baseline and at follow up. Methods: We systematically searched Pubmed, Cochrane, and Embase libraries for studies evaluating WBMRI as an early detection method for tumor screening in patients with LFS. We pooled the prevalence and presented the overall rate with 95% confidence intervals (CI) of the individuals found to have one or more investigable lesions, the lesions found to be new cancers among suspicious lesions, and the individuals with one or more new cancers among the total population. Statistical analysis was performed using R software version 4.3.1 and heterogeneity was evaluated with I2 statistics. Results: From 1,547 initial studies, 11 (10 observational cohort and 1 case control) comprising 703 patients (359 females [51%]; mean [SD] age, 29.5 [+/-25] years) were included from 7 different countries. Median follow-up of lesions ranged from 2 to 11 years. We found an estimated detection rate of 31% (95% CI 28-34, I2 55%) of any suspicious lesions in asymptomatic TP53 carriers who underwent baseline WBMRI was found. In total, 277 lesions that required clinical follow-up in 215 patients were identified. Cancer was confirmed in 46 lesions in 39 individuals. Most of the cancers found were Central Nervous System (CNS) tumors (n = 16), followed by sarcomas (n = 12) and breast cancer (n = 11). The estimated cancer diagnosis rate among suspicious lesions was 18% (95%CI 13-25, I2 5%). WBMRI detected 41 of 46 cancers in the early disease stage, with an overall detection rate of 6% (95% CI 5-8, I2 47%). Incidence rate was 2% per patient-round of WBMRI (95% CI 1-4, I2 0%), including baseline plus follow up. Conclusions: Our systematic review and meta-analysis supports that surveillance with WBMRI is effective in detecting cancers in patients with LFS. Additionally, WBMRI surveillance was successful in diagnosing almost 90% of cancers in early-disease stage, which increases the chances os cure in this young population.

Hematologic malignancies in Li-Fraumeni syndrome.

10613 Background: Li-Fraumeni Syndrome (LFS) is a hereditary cancer predisposition syndrome caused by mutations in the tumor suppressor gene TP53. Since its discovery, a growing list of cancers have been described in association with LFS, predominantly solid tumors. However, hematologic malignancies (HMs) cumulatively account for 4-10% of cancer diagnoses in LFS. In this study, we present the largest series of HMs in families with LFS with detailed clinical courses. Methods: This was a two-center retrospective observational cohort study conducted at the University of Utah and the University of Wisconsin-Madison with IRB approval. Cancer genetics clinic registries were reviewed to identify all families with LFS who also had a confirmed diagnosis of a HM. To meet criteria for LFS, the patient had to have a confirmed germline pathologic or likely pathologic TP53 variant. Patients with a TP53 variant of unknown significance (VUS) were also included if they met classical LFS testing criteria. Data was gathered by manual chart review of both the families’ histories and electronic health records. Results: Among the 121 families identified with LFS, 35 (29%) families had one or more HM. Of these, 17 individuals from 16 families (13%) had confirmed germline TP53 mutations. The most frequent HMs found were acute lymphoblastic leukemia (ALL) (n=6), non-Hodgkin lymphoma (NHL) (n=5), myelodysplastic syndromes (MDS) (n=3), and chronic lymphocytic leukemia (CLL) (n=2). Acute myeloid leukemia (AML), Langerhans cell histiocytosis (LCH), and chronic myeloid leukemia (CML) were each diagnosed once. Most cases were identified in adulthood (n=12, 71%). Of the 19 total HMs, the minority (n=5, 26%) were diagnosed post-cytotoxic therapy and only six (35%) individuals had received a diagnosis of LFS prior to HM diagnosis. The MDS/AML cohort (n=4) all exhibited bi-allelic inactivation of TP53. Two of these four patients achieved long term survival after matched-unrelated donor (MUD) hematopoietic stem cell transplant (HSCT). All three patients who underwent MUD donor HSCT had immune-mediated adverse events. Conclusions: In this study we found a significantly higher incidence of HMs in LFS than previously described, with a predominance of lymphoid over myeloid malignancies. The majority of patients had excellent outcomes after standard of care therapy pointing towards more favorable outcomes for patients with LFS and HMs than previously reported. We also report several unusual immune-mediated adverse events in our patients indicating possible immunogenicity of some TP53 variants. Most patients did not have prior exposure to cytotoxic treatments and were diagnosed with the HM prior to their LFS diagnosis. We also show that 38% of individuals with an HM have multiple family members with an HM, consistent with a familial HM pattern. This underscores the importance of detailed family and personal histories in HM patients found to carry a somatic TP53 variant.

Sarcoma incidence worldwide: regional differences in histology and molecular subtypes.

There are numerous sarcoma subtypes and vary widely in terms of epidemiology, clinical characteristics, genetic profiles, and pathophysiology. They also differ widely between ethnic groups. This review focuses on the different incidence rates of sarcomas in different regions and the potential explanations for these disparities. In an intercontinental study using national cancer registry databases from France and Taiwan, the French population had a higher risk of liposarcomas, leiomyosarcomas, and synovial sarcomas, whereas the Taiwanese population had a higher incidence of angiosarcomas and malignant peripheral nerve sheath tumors. The anatomical distribution of these sarcomas also varied between these two regions. In France, most angiosarcoma cases occurred in the extremities and trunk, whereas in Taiwan, angiosarcoma cases in the abdomen and pelvis were more common. Another international study showed that in addition to the common known TP53 and NF1 germline mutations, genes involved in centromere and telomere maintenance were also involved in sarcomagenesis. We reviewed factors related to genetics, environmental effects, chemical exposure, and radiation exposure that could explain the differences in sarcoma incidence among different geographical or ethnic regions. Our understanding of the potential cause of sarcomas with different subtypes is limited. Establishing a comprehensive global database for patients with sarcomas from all ethnic groups is essential to deepen our understanding of the potential risk factors and the pathophysiology of all sarcoma subtypes.

Abstract NG02: Distinct genomic and immunologic tumor evolution in germline TP53-driven breast cancers

Abstract NG02: Distinct genomic and immunologic tumor evolution in germline TP53-driven breast cancers

High-Grade Metastatic Pleomorphic Rhabdomyosarcoma in a TP53 Germline Mutation Patient: A Rare Presentation in Adults

Pleomorphic Rhabdomyosarcomas (PRMS) in adults are an exceptionally rare and aggressive soft-tissue tumor arising from undifferentiated mesenchymal cells. While more common in children, rhabdomyosarcomas in adults are associated with poorer outcomes and require immediate, aggressive intervention. Here we present a case of high-grade pleomorphic rhabdomyosarcoma of the left thigh in a 58-year-old male with metastases to the lungs and pelvis. Due to the limited diagnostic and treatment protocols of this rare disease and subtype, the goal of this case study is to highlight a comprehensive clinical approach to this disease.

Abstract 1533: Characterizing tumor-immune surveillance in Li-Fraumeni syndrome

Abstract Li-Fraumeni Syndrome (LFS) is a cancer predisposition syndrome associated with germline TP53 mutations and increased lifetime risk of developing multiple cancers. p53, the protein encoded by TP53, plays a role in regulating various aspects of immune cell biology. Accordingly, inactivation of p53 in tumor cells shapes interactions with the immune system and influences the anti-tumor immune response. Mutation or deletion of p53 in immune cells also favors tumor development and progression. However, to date, a comprehensive study of immune cell populations and the anti-tumor immune response has not been undertaken in the context of LFS. We hypothesized that germline TP53 mutation carriers possess dysfunctional immune cells and/or immune responses, supporting LFS-associated tumor progression. Our preliminary data indicate a profound defect in tumor-immune surveillance in an LFS murine model. We observed that MC38 cancer cells develop significantly faster into tumors when injected into LFS mice (harboring a gain-of-function mutation Trp53R172H/WT) compared to wildtype (WT) control mice. Importantly, we identified significant alterations in immune cell compositions and phenotypes within the tumor microenvironment as well as immune organs using flow cytometry. We are currently using ex vivo proliferation assays and cytotoxicity assays to investigate the impact of mutant p53 on the tumor-killing ability of immune effector cells. Altogether, an improved understanding of anti-tumor immune dysfunction in the context of germline TP53 mutation may reveal the potential for innovative therapies to target different facets of the immune system to intercept cancer progression in LFS patients. Citation Format: Camilla Giovino, Nicholas Fischer, Noel Ong, Ashby Kissoondoyal, Ran Kafri, David Malkin. Characterizing tumor-immune surveillance in Li-Fraumeni syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1533.

Abstract 3564: Survival-based grouping of genetic variants: A novel statistical framework with an application to TP53 mutations

Abstract Advancements in genotyping and sequencing techniques, coupled with the growing magnitude of genome databases, have led to comprehensive investigations into the impact of genetic variants on human diseases, including cancers. It is commonly acknowledged that genetic variants have homogeneous effects on clinical outcomes, i.e., variants exhibit similar effects within a certain group but are distinct from those in other groups. However, such grouping information is typically unknown, and identification of the underlying genetic variation groups is crucial for understanding their functional consequences, facilitating patient management, and improving risk prediction. To resolve this challenge, we introduce a novel statistical framework called Survival-based Clustering of Predictors (SCP) in Cox regression to group genetic variants based on patient survival outcomes. Built upon a penalized Cox regression model, SCP considers different genetic variants, as well as additional patient-specific features if needed, as survival predictors and then searches for homogeneity among the coefficients for individual variants to recover the underlying grouping structure. Focusing on TP53, the most frequently mutated gene in cancer that has resulted in a wide range of functions and clinical outcomes, we apply SCP to group TP53 germline mutations with the age of cancer diagnosis as the time-to-event. Using datasets from four Li-Fraumeni syndrome (LFS) cohorts at MD Anderson, NCI, and DFCI, we obtained 75 recurring TP53 germline mutations from 513 patients and clustered these mutations into high-, medium-, and low-risk groups. Hotspot mutations such as R175H, R248Q, G245S, and R273C are in the high-risk group as supported in many TP53 studies, while several non-hotspot mutations such as R290H, V218G, and G244D also exhibit strong positive effects and are grouped together with hotspot mutations. Overall, mutations in all three risk groups, obtained through applying SCP, are highly consistent with a yeast functional assay-based approach for grouping TP53 mutations, supporting the utility of SCP for survival-based grouping of genetic variants. The contribution of our study is three-fold. Statistically, our method fills a critical gap in the survival analysis literature, offering a novel statistical framework for clustering predictors in Cox regression based on survival outcomes. Clinically, we provide a timely solution to the patient outcome-based grouping of TP53 mutations, facilitating clinical management of TP53 mutation carriers. Biologically, we bring fresh insights into knowledge for the most frequently observed genetic variants in cancer, providing new hypotheses to TP53-related biological research. Citation Format: Xiaoqian Liu, Haoming Shi, Emilie Montellier, Pierre Hainaut, Wenyi Wang. Survival-based grouping of genetic variants: A novel statistical framework with an application to TP53 mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3564.