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Although tumors of Li-Fraumeni syndrome (LFS) have a premalignant or dormant phase that could be exploited by early imaging detection, this has been underevaluated in the literature. We present a case series of patients with LFS followed by imaging over time to highlight patterns of growth of tumors and hotspots of missed tumors in this population. Clinical and imaging features were available for 29 tumors of 24 carriers of a germline TP53 pathogenic variant, developed between 1999 and 2023 were retrospectively reviewed in a single tertiary pediatric center. Imaging characteristics of tumors were evaluated with MRI, CT, and radiographs. Local invasion, time interval for developing primary cancer, and/or recurrent disease and metastasis, and factors that delayed the tumor diagnosis were assessed. In patients with multiple tumors the median time intervals for development of first, second, and third primary cancers were 45.9, 79.8, and 28.1 months, respectively. Hotspots of missed tumors included superficial soft tissues, areas close to bones, on the scalp, in tissues around the adrenal region and in small hypodense lesions on brain CT. In conclusion, the pattern of growth of tumors is variable and erratic in LFS patients with some tumors presenting with a dormant pattern., Competing Interests: A.S.D. is the Principal Investigator of the following grants unrelated to the current study: Novo Nordisk (Research Grant), Terry Fox Foundation (Research Grant), PSI Foundation (Research Grant), Society of Pediatric Radiology (Research Grant), Radiological Society of North America (Education Grant). The remaining authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Germline pathogenic mutations in TP53 gene are associated with a cancer predisposition syndrome known as Li Fraumeni syndrome. Albeit infrequently, non-small cell lung cancer, especially as oncogene-addicted disease, may be diagnosed in young patients with Li Fraumeni syndrome., Case Description: We report three cases of patients affected by Li Fraumeni syndrome who developed non-small cell lung cancer with EGFR or HER2 exon 20 insertions. The first patient suffered from liposarcoma and, then, brain metastases from HER2 -mutated non-small cell lung cancer: after stereotactic radiotherapy, he benefited from enrollment in a clinical trial with a HER2 -targeted therapy. The second young patient was a female with personal history of rhabdomyosarcoma, diagnosed with brain metastases from EGFR -mutated non-small cell lung cancer: enrollment in a clinical trial led to a temporary clinical benefit. The last case was a female diagnosed with breast carcinoma, ovarian granulosa cell tumor and advanced EGFR -mutated non-small cell lung cancer at a young age., Conclusions: Young patients affected by oncogene-addicted non-small cell lung cancer and with a positive familial cancer history should be referred for an accurate genetic counselling to look for Li Fraumeni syndrome. The underlying molecular connection between TP53 and HER family receptor tyrosine kinases remains unclear, but an extensive molecular characterization of tumors from patients with Li Fraumeni syndrome should always be performed, to offer patients a personalized therapeutic approach., Competing Interests: Declaration of conflicting interestThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: M.T. received speakers’ and consultants’ fee from Astra-Zeneca, Pfizer, Eli-Lilly, BMS, Novartis, Roche, MSD, Boehringer Ingelheim, Otsuka, Takeda, Pierre Fabre, Amgen, Merck, Sanofi. M.T. received institutional research grants from Astra-Zeneca, Boehringer Ingelheim.F. G. received honoraria or personal fees for the advisory role or consulting from Eli Lilly, Novartis, AstraZeneca, and Bristol-Myers Squibb outside the submitted work.The other authors declare that there is no conflict of interest.

Background: A recent large, well-annotated international cohort of patients with Li-Fraumeni syndrome and early-stage breast cancer was examined for shared features., Methods: This multicenter cohort study included women with a germline TP53 pathogenic or likely pathogenic variant and nonmetastatic breast cancer diagnosed between 2002 and 2022. Clinical and genetic data were obtained from institutional registries and clinical charts. Descriptive statistics were used to summarize proportions, and differences were assessed using χ2 or Wilcoxon rank sum tests. Metachronous contralateral breast cancer risk, radiation-induced sarcoma risk, and recurrence-free survival were analyzed using the Kaplan-Meier methodology., Results: Among 227 women who met study criteria, the median age of first breast cancer diagnosis was 37 years (range = 21-71), 11.9% presented with bilateral synchronous breast cancer, and 18.1% had ductal carcinoma in situ only. In total, 166 (73.1%) patients underwent mastectomies, including 67 bilateral mastectomies as first breast cancer surgery. Among those patients with retained breast tissue, the contralateral breast cancer rate was 25.3% at 5 years. Among 186 invasive tumors, 72.1% were stages I to II, 48.9% were node negative, and the most common subtypes were hormone receptor-positive/HER2-negative (40.9%) and hormone receptor positive/HER2 positive (34.4%). At a median follow-up of 69.9 months (interquartile range = 32.6-125.9), invasive hormone receptor-positive/HER2-negative disease had the highest recurrence risk among the subtypes (5-year recurrence-free survival = 61.1%, P = .001). Among those who received radiation therapy (n = 79), the 5-year radiation-induced sarcoma rate was 4.8%., Conclusion: We observed high rates of ductal carcinoma in situ, hormone receptor-positive, and HER2-positive breast cancers, with a worse outcome in the hormone receptor-positive/HER2-negative luminal tumors, despite appropriate treatment. Confirmation of these findings in further studies could have implications for breast cancer care in those with Li-Fraumeni syndrome., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Li-Fraumeni syndrome (LFS) is a rare syndrome characterized by an increased lifetime risk of cancer development in multiple organ systems, typically caused by de novo or inherited germline pathogenic variants in the tumor suppressor TP53 gene. LFS is more classically associated with solid tumors; however, it is also associated with hematologic malignancies such as therapy-related acute myeloid leukemia (AML). We present the case of a female patient with a strong family and personal history of cancer who presented to our institution with therapy-related AML with next-generation sequencing showing a pathogenic TP53 mutation. She received several lines of systemic therapy and underwent stem cell transplant using her adult daughter as a haploidentical donor after achieving minimal residual disease (MRD). Her posttransplant bone marrow evaluations demonstrated persistence of the same pathogenic TP53 mutation despite ongoing clinical remission with full donor engraftment and negative MRD. Genetic testing was performed which confirmed the germline origin of the TP53 pathogenic variant in the patient. The patient's adult donor daughter was also identified to have the same pathogenic variant in TP53 consistent with LFS. The presented case highlights the need for increased awareness of LFS in the adult hematologic community, particularly for patients undergoing evaluation for stem cell transplant., (© 2024 Wiley Periodicals LLC.)

Background: Choroid plexus carcinomas (CPCs) are rare, aggressive grade 3 tumors of the central nervous system associated with Li-Fraumeni syndrome (LFS) in a notable percentage of cases due to TP53 germline mutations. Understanding the correlation between CPCs and LFS is crucial for tailored management strategies. However, distinguishing CPCs from benign choroid plexus papillomas (CPPs) remains challenging, relying largely on histologic features. This study aimed to explore the association between CPCs and LFS, emphasizing the impact of TP53 mutations on diagnosis, treatment, and clinical outcomes., Materials and Methods: Scientific databases such as PubMed, Scopus, and Web of Science were systematically searched up to January 2024 using keywords related to CPCs, LFS, TP53 mutation, and central nervous system tumors. Selection criteria included studies investigating the link between CPCs and LFS, their management approaches, and genetic implications of TP53 mutations. Ten relevant studies were selected for analysis after screening titles, abstracts, and full-text articles. Data extraction focused on clinical, genetic, and management factors related to CPCs associated with LFS., Results: The review highlighted the strong association (36%) between CPCs and LFS, primarily due to TP53 germline mutations. Studies emphasized the need for genetic testing in patients with CPCs, especially in pediatric cases, to identify LFS implications. Furthermore, the impact of TP53 mutations on treatment strategies was emphasized, recommending irradiation-sparing therapies due to inferior survival rates associated with radiotherapy in LFS patients with CPCs. Cases illustrated the challenges in diagnosing CPCs and the importance of immunohistochemistry and genetic testing for TP53 mutations., Conclusion: CPCs pose challenges in diagnosis and management, particularly in distinguishing them from benign tumors. The association with LFS, often due to TP53 germline mutations, underscores the importance of genetic testing for early detection and tailored treatment strategies. Irradiation-sparing therapies are recommended for LFS-associated CPCs to mitigate the risk of secondary malignancies. Comprehensive profiling of CPC patients, especially in pediatric cases, is crucial for early detection and management of potential secondary cancers associated with LFS., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Li-Fraumeni syndrome (LFS), linked to heterozygous germline pathogenic/likely pathogenic variants in TP53, confers exceptionally high cancer risk, including core cancers (sarcoma, breast, adrenocortical, and brain cancer) among many other cancer types. 1 Colorectal cancer (CRC) is most common after the core and hematologic cancers, accounting for ∼2.8% of diagnoses. Stomach and esophageal cancers constitute another 1.3% (TP53 Database; R20, July 2019: https://tp53.isb-cgc.org). 2 ., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Purpose: The purpose of this article was to provide an overview of syndromic gliomas., Design: The authors conducted a nonsystematic literature review., Results: Cancer predisposition syndromes (CPSs) are genetic conditions that increase one's risk for certain types of cancer compared with the general population. Syndromes that can predispose one to developing gliomas include neurofibromatosis, Li-Fraumeni syndrome, Lynch syndrome, and tuberous sclerosis complex. The standard treatment for sporadic glioma may involve resection, radiation therapy, and/or alkylating chemotherapy. However, DNA-damaging approaches, such as radiation and alkylating agents, may increase the risk of secondary malignancies and other complications in patients with CPSs. In some cases, depending on genetic aberrations, targeted therapies or immunotherapeutic approaches may be considered. Data on clinical characteristics, therapeutic strategies, and prognosis of syndromic gliomas remain limited., Conclusion: In this review, we provide an overview of syndromic gliomas with a focus on management for patients with CPSs and the role of novel treatments that can be considered.

Background: Epithelioid angiomyolipoma (EAML) is a rare variant of angiomyolipoma that predominantly consists of epithelioid cells and belongs to the perivascular epithelioid cell neoplasm (PEComa) family. The majority of EAMLs arise in the kidneys, and primary hepatic EAML appears to be much less common than renal EAML. Most PEComas arise sporadically, but may be associated with tuberous sclerosis complex (TSC), an autosomal dominant genetic disorder characterized by germline mutations in the TSC1 or TSC2 genes. However, PEComas have previously been reported in five patients with Li-Fraumeni syndrome (LFS), which is an inherited cancer susceptibility disorder resulting from germline mutations in the TP53 tumor suppressor gene., Case Presentation: We report a 49-year-old female patient with hepatic EAML and pancreatic cancer. Because she had previously been diagnosed with bilateral breast cancer at the age of 30, we performed a comprehensive genetic analysis to identify genetic alterations associated with any cancer predisposition syndrome. Whole-exome sequencing of a blood sample identified a heterozygous germline variant of TP53 (NM_000546.5):c.708C>A, and targeted next-generation sequencing of liver EAML and pancreatic cancer tissue samples demonstrated the same TP53 (NM_000546.5):c.708C>A variant in both. This, plus the patient's history of early-onset breast cancer, met the 2015 version of the Chompret criteria for diagnosis of LFS., Conclusions: There have been very few case reports regarding the presence of PEComa in LFS, and to the best of our knowledge, this is the first report of EAML of the liver in a patient with LFS., (© 2024. The Author(s).)

Background: The prognosis for Li-Fraumeni syndrome (LFS) patients with medulloblastoma (MB) is poor. Comprehensive clinical data for this patient group is lacking, challenging the development of novel therapeutic strategies. Here, we present clinical and molecular data on a retrospective cohort of pediatric LFS MB patients., Methods: In this multinational, multicenter retrospective cohort study, LFS patients under 21 years with MB and class 5 or class 4 constitutional TP53 variants were included. TP53 mutation status, methylation subgroup, treatment, progression free- (PFS) and overall survival (OS), recurrence patterns, and incidence of subsequent neoplasms were evaluated., Results: The study evaluated 47 LFS individuals diagnosed with MB, mainly classified as DNA methylation subgroup "SHH_3" (86%). The majority (74%) of constitutional TP53 variants represented missense variants. The 2- and 5-year (y-) PFS were 36% and 20%, and 2- and 5y-OS were 53% and 23%, respectively. Patients who received postoperative radiotherapy (RT) (2y-PFS: 44%, 2y-OS: 60%) or chemotherapy before RT (2y-PFS: 32%, 2y-OS: 48%) had significantly better clinical outcome then patients who were not treated with RT (2y-PFS: 0%, 2y-OS: 25%). Patients treated according to protocols including high-intensity chemotherapy and patients who received only maintenance-type chemotherapy showed similar outcomes (2y-PFS: 42% and 35%, 2y-OS: 68% and 53%, respectively)., Conclusions: LFS MB patients have a dismal prognosis. In the presented cohort use of RT significantly increased survival rates, whereas chemotherapy intensity did not influence their clinical outcome. Prospective collection of clinical data and development of novel treatments are required to improve the outcome of LFS MB patients., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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 p53 R279W/+ (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., (© 2023. The Author(s).)

Li-Fraumeni syndrome (LFS) is associated with many different cancers, including early onset breast cancer. Due to an increased risk of radiation-induced malignancy, radiation therapy is often avoided in this patient population. This case study evaluates a 38-year-old female with a history of juvenile granulosa cell tumor of the ovary and malignant phyllodes tumor of right breast, who subsequently developed bilateral invasive ductal carcinoma and was treated with bilateral mastectomies. Studies show that in a high-risk patient, post-mastectomy radiation therapy (PMRT) should not be ruled out due to a history of LFS, as the benefit of PMRT may outweigh the risk of a radiation-induced malignancy., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Li-Fraumeni syndrome (LFS) is a rare autosomal dominant disease with high penetrance caused by a germline variant of TP53 gene. We report the first case of endometrial cancer after yolk sac tumor with LFS., Case Presentation: The presented female patient underwent right adnexectomy at age 23 because of a yolk sac tumor of the ovary. At the age of 27, the patient was diagnosed with endometrial adenocarcinoma, received cytoreductive surgery and chemotherapy. Given that her personal cancer history along with a strong family history of cancer, her father passing away from lung cancer at age 48 and her grandmother dying of ovarian cancer at age 50, the patient was referred for genetic counseling and testing. Genetic screening revealed a heterozygous pathogenic TP53 c.844C > T, p.( R282 W) with NM_000546.5 variant, a class 5 (C5) variant. This is the first reported case of a yolk sac tumor accompanied by subsequent endometrial cancer that is associated with LFS., Conclusions: We reported a first case of an endometrial cancer after yolk sac tumor patient with a tumor family history of harboring the germline TP53 pathogenic variation which expanded types of tumor that can be presented in patients with LFS. This case highlights the importance of genetic testing for patients with malignant tumors, as well as patients with a family history of malignant tumors. And our case highlights the necessity of screening for gynecologic tumor in LFS patients., (© 2023. The Author(s).)

Introduction: Pure androgen-secreting adrenocortical tumors are a rare but important cause of peripheral precocious puberty., Case Presentation: Here, we report a pure androgen-secreting adrenocortical tumor in a 2.5-year-old boy presenting with penile enlargement, pubic hair, frequent erections, and rapid linear growth. We confirmed the diagnosis through laboratory tests, medical imaging, and histology. Furthermore, genetic testing detected a pathogenic germline variant in the TP53 gene, molecularly confirming underlying Li-Fraumeni syndrome., Discussion: Only 15 well-documented cases of pure androgen-secreting adrenocortical tumors have been reported so far. No clinical or imaging signs were identified to differentiate adenomas from carcinomas, and no other cases of Li-Fraumeni syndrome were diagnosed in the four patients that underwent genetic testing. However, diagnosing Li-Fraumeni syndrome is important as it implies a need for intensive tumor surveillance and avoidance of ionizing radiation., Conclusion: In this article, we emphasize the need to screen for TP53 gene variants in children with androgen-producing adrenal adenomas and report an association with arterial hypertension., (© 2023. The Author(s).)

Introduction: Breast cancer (BC) is the most common type of cancer in premenopausal women with germline TP53 pathogenic variants (mTP53) (Li Fraumeni syndrome - LFS). However, little is known about the BC prognosis in these patients. This study analyzed the BC-related oncologic outcomes of patients with LFS., Methods: We evaluated a cohort of LFS patients with BC in comparison with a control cohort of BC patients with no pathogenic variant in a hereditary cancer panel. The primary endpoint was recurrence-free survival (RFS). Due to the risk of second malignancies in LFS, only locoregional and distant recurrences were considered events for RFS. Secondary endpoints included rates of contralateral BC, overall survival (OS), and breast cancer-specific survival (BCSS)., Results: Forty-one patients were evaluated in the mTP53 group and 82 in the control group. Median age at BC diagnosis was 40 and 41 years, respectively. The mTP53 group received less adjuvant radiotherapy than the control group (63.4% vs 93.9%, P < 0.001). Other relevant baseline characteristics and treatment received were similar between groups. 5y-RFS rates were 79.4% in the mTP53 versus 93.6% in the control group (HR 2.43, 95%CI 0.74-8.01, P = 0.143); and were not impacted by the use of adjuvant radiotherapy. 5y-BCSS rates were 92.2% and 98.6%, respectively (HR 1.87, IC95% 0.25-13.48, P = 0.534)., Conclusions: Our results showed no statistically significant difference in BC-related RFS and BCSS between patients with mTP53 and a control group with no pathogenic variant. Larger multicentric studies are warranted to confirm these results., Competing Interests: Declaration of competing interest VP: Speaker fees and/or honoraria for consultancy or advisory functions: AstraZeneca, Daiichi-Sankyo, Novartis; Financial support for educational programs and symposia: Daiichi-Sankyo. RCB: Speaker fees and/or honoraria for consultancy or advisory functions: Daiichi-Sankyo, Nestle; Financial support for educational programs and symposia: AstraZeneca, Daiichi-Sankyo; Institutional Research Funding: Novartis, AstraZeneca. LT: Consulting or Advisory Role: Lilly, Novartis, MSD, AstraZeneca, Daiichi-Sankyo; Educational Support: Pfizer, Lilly, Zodiac, AstraZeneca; Speaker: Novartis, Roche, Pfizer, Zodiac, Lilly, MSD, AstraZeneca, Daichii-Sankyo; Institutional Research Funding: Novartis. DJBHC: Speaker fees and/or honoraria for consultancy or advisory functions: Novartis, Daiichi-Sankyo, AstraZeneca; Financial support for educational programs and symposia: Gilead. AC: Speaker fees and/or honoraria for consultancy or advisory functions: AstraZeneca, Libbs. RGC: Speaker fees and/or honoraria for consultancy or advisory functions: AstraZeneca, MSD, GSK; Financial support for educational programs and symposia: AstraZeneca., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome caused by germline mutations in the TP53 gene. CNS tumors are the fourth most common tumor type in LFS, and recent screening guidelines demonstrate that early tumor detection is associated with improved long-term survival. However, there is a paucity of data regarding surgical intervention when lesions are identified in asymptomatic patients on surveillance imaging. The authors investigated this through their cohort and literature review., Methods: The cohort consisted of children seen in the Pediatric Cancer Genetics Program at Children's National Hospital between August 2012 and August 2021. The authors also include a PubMed (MEDLINE) literature search of articles from 2006 to 2021 related to surveillance and CNS tumors in patients with LFS. Studies in which CNS tumors were not identified or detailed patient information was not provided were excluded. Patients from the selected articles and the authors' cohort were added for further analysis., Results: Between August 2012 and August 2021, 10 children with LFS and CNS tumors were assessed at Children's National Hospital: 4 who were known carriers of the TP53 mutation had CNS lesions found on surveillance imaging, whereas 6 presented with symptomatic CNS lesions and were either known or subsequently found to have germline TP53 mutations. The literature search identified 148 articles, 7 of which were included in this review. Patients from the literature and the present cohort were added for a total of 56 CNS lesions. A majority of the low-grade CNS lesions (22/24, 92%) were found on surveillance protocols in asymptomatic patients, whereas the majority of the high-grade lesions (22/26, 85%) presented in symptomatic patients who were not undergoing routine surveillance or as the initial diagnosis of LFS. The authors noted a significant survival advantage in pediatric patients with low-grade lesions, with an overall survival of 100% at 30 months. Minor limitations of the study include patient sample size and limitations in the patient cohort due to this being a retrospective rather than a prospective study., Conclusions: Data presented in this study support surveillance protocols in LFS and demonstrate the importance of dedicated CNS imaging and early surgical intervention when lesions are identified. Systematic review registration no.: CRD42022372610 (www.crd.york.ac.uk/prospero).

Background: Leiomyosarcoma is a rare malignant tumor of smooth muscle origin and represents 10-20% of all soft tissue sarcomas. Primary colon and rectal sarcomas constitute < 0.1% of all large bowel malignancies. In Li-Fraumeni syndrome, sarcomas are the second most frequent cancer (25%). Li-Fraumeni syndrome is a genetic disease with a familial predisposition to multiple malignant neoplasms. This syndrome has an autosomal dominant pattern of inheritance and high penetrance characterized by germline TP53 mutations. Patients with a history of cancer who do not meet all the "classic" criteria for Li-Fraumeni syndrome are considered to have Li-Fraumeni-like syndrome. To the best of our knowledge, this article is the first report of a patient with rectal leiomyosarcoma as the initial phenotypic manifestation of Li-Fraumeni-like syndrome. The authors also present a literature review., Case Presentation: A 67-year-old Brazilian woman underwent anterior rectosigmoidectomy and panhysterectomy secondary to rectal leiomyosarcoma. She subsequently developed carcinomatosis and died 2 years after the operation. Her family medical history consisted of a daughter who died at 32 years of age from breast cancer, a granddaughter diagnosed with adrenocortical carcinoma at 6 years of age and two siblings who died from prostate cancer. A genetic study was carried out to identify a pathogenic variant of Li-Fraumeni syndrome. In the DNA extracted from the peripheral blood leukocyte, restriction fragment length polymorphism was analyzed to search for mutations in the TP53 gene. The DNA sequencing identified the germline pathogenic variant p. R337H heterozygous in exon 10 of TP53. The patient was classified as having Li-Fraumeni-like syndrome., Conclusion: In patients with rectal leiomyosarcoma, it is advisable to investigate the family history of cancer and perform genetic studies to screen for Li-Fraumeni syndrome., (© 2022. The Author(s).)

Background: Germline TP53 mutations have been frequently reported in patients with Li-Fraumeni syndrome (LFS), resulting in a predisposition to various malignancies. Mutations other than germline TP53 mutations can also cause LFS-associated malignancies, but their details remain unclear. We describe a novel c-myc amplification in a unique liposarcoma in a patient with LFS., Case Presentation: A female patient with LFS developed breast cancer twice at the age of thirty; both were invasive ductal carcinomas harboring HER2 amplifications. Computed tomography revealed an anterior mediastinal mass, which was surgically resected. Histological analysis revealed three different lesions corresponding to myxoid liposarcoma-, pleomorphic liposarcoma-, and well-differentiated liposarcoma-like lesions. Fluorescence in-situ hybridization (FISH) analysis did not detect MDM2 amplification, Rb1 deletion, break apart signals of EWS, FUS, DDIT3, or c-myc, or c-myc-IGH fusion signals, but it did detect more c-myc signals. Further FISH analysis and comprehensive genomic profiling revealed c-myc amplification. We considered two differential diagnoses, dedifferentiated liposarcoma lacking MDM2 amplification and myxoid pleomorphic liposarcoma (MPLPS), and determined that this case is most likely MPLPS. However, definite diagnosis could not be made because a clear-cut differentiation of the case from liposarcomas was not possible., Conclusions: A previous study demonstrated that c-myc amplification could not be detected in various liposarcomas, but the present unique liposarcoma showed c-myc amplification, so the c-myc amplification may indicate that the present liposarcoma is an LFS-related tumor. The present case further clarifies the pathological features of MPLPS and LFS-related liposarcomas by broadening their histopathological and genetic diversities., (© 2022. The Author(s).)

Li-Fraumeni syndrome(LFS)is a hereditary cancer disorder caused by germline variant in TP53 and characterized by various malignancies. Multidisciplinary treatment is needed for tumors of LFS, however, radiation therapy is a relative contraindication because of frequent development of secondary malignancy such as sarcoma in the irradiated field. Case 1: A 22- year-old woman who was diagnosed with LFS by genetic test when she developed upper rectal cancer. Her rectal tumor with marked bilateral lateral lymph node dissection was successfully removed by low anterior resection with extensive lateral lymph node dissection. She underwent resection for ovarian metastasis followed by chemotherapy and radiotherapy but subsequently died by the disease 32 months postoperatively. Case 2(elder sister of Case 1): A brain tumor was identified in the left high frontal lobe to the parietal lobe because of consciousness disorder, after the genetic diagnosis of LFS. The brain tumor was successfully resected. Histological examination revealed diffuse astrocytoma(WHO grade Ⅱ). Local recurrence was observed 46 months later, and radiation therapy was performed. Six months have passed since radiation therapy, no exacerbation of local recurrence has been observed.

Objectives: This qualitative-descriptive study explored adolescent and young adult (AYA) perspectives, experiences, and challenges with openness and closedness in family communication about Li-Fraumeni syndrome (LFS)., Methods: We conducted interviews with AYAs (aged 15-39 years) with LFS enrolled in the National Cancer Institute's LFS study (NCT01443468). An interprofessional clinician-researcher team analyzed transcribed data using the constant comparative method and interpretive description., Results: AYAs (N = 38; 26 females, 12 males, mean age=29 years) reported navigating openness and closedness about LFS in their families, which varied by LFS topic, relationship, disease trajectory, and developmental phase. AYAs described communication challenges, including broaching difficult topics (e.g., reproductive decision-making, end-of-life), balancing information-sharing with emotionally protecting family and self, and struggling with interactions that cause relational tensions., Conclusions: AYAs reported experiencing LFS family communication challenges that disrupted their psychosocial well-being. LFS-related stressors and life transitions complicated and were complicated by these challenging family interactions., Practice Implications: Clinicians may support AYAs with LFS by inquiring about family communication, responding empathically to communication concerns, providing resources to support difficult conversations, and engaging mental health providers as needed. Researchers could partner with AYAs to develop tailored communication skills training and social support tools., Competing Interests: Declaration of Competing Interest The authors report no declarations of interest., (Published by Elsevier B.V.)

In humans, germline TP53 mutations predispose carriers to a wide spectrum of cancers, which is known as Li-Fraumeni syndrome (LFS). To date, the association of melanomas with LFS remains unestablished. No melanomas have been reported in any P53-modified mouse models either. In this study, we show that targeted disruption of P53 at the DNA-binding domain in Xenopus tropicalis recapitulates LFS, with the formation of soft-tissue sarcomas and pancreatic ductal adenocarcinoma. Interestingly, 19% of the 14-month-old tp53 Δ7/Δ7 homozygotes and 18% of tp53 +/Δ7 heterozygotes spontaneously developed small nevi and non-invasive melanomas. Large invasive melanomas were also observed in other older homozygous mutants, with about 7.9% penetrance. Our data suggest that more dermatologic investigation of LFS patients should be able to settle the association of melanoma with LFS in epidemiology. Our model is also valuable for further investigation of the molecular mechanism underlying melanoma progression upon germline alteration of the tp53 locus., (© 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Li-Fraumeni syndrome is a cancer predisposition condition associated with various tumor types. We present the case of a 6-year-old boy who initially presented with a pituitary adenoma that was successfully treated with surgery. It ultimately recurred, requiring further surgical intervention followed by proton beam therapy. He later developed a medulloblastoma, and genetic testing revealed TP53 germline mutation. The patient underwent gross total resection of this medulloblastoma, followed by proton-based craniospinal irradiation and adjuvant chemotherapy. He remained disease-free 12 months after radiation and 7 months after chemotherapy. Current literature does not report pituitary adenoma as the initial central nervous manifestation in Li-Fraumeni syndrome. Early genetic testing should be considered in pediatric patients who present with such rare tumor types to help identify cancer predisposing conditions. Furthermore, as evidenced by our case, the management of multiple brain tumors in the pediatric population poses challenges. A multidisciplinary approach involving neurosurgery, pediatric oncology, pathology, and radiation oncology remains crucial to optimize patient outcomes., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Atypical teratoid/rhabdoid tumor (AT/RT) is a malignant central nervous system tumor predominantly affecting infants. Mutations of SMARCB1 or (rarely) SMARCA4 causing loss of nuclear SMARCB1 or SMARCA4 protein expression are characteristic features, but further recurrent genetic alterations are lacking. Most AT/RTs occur de novo, but secondary AT/RTs arising from other central nervous system tumors have been reported. Malignant gliomas, IDH wild-type, arising in patients with Li-Fraumeni syndrome typically show somatic mutations of TP53 as well as complex copy number alterations, but little is known about the loss of SMARCB1 or SMARCA4 protein expression in this context. Here, we report 2 children in whom malignant supratentorial brain tumors with SMARCB1 deficiency, complex copy number alterations, and somatic TP53 mutations lead to the discovery of pathogenic/likely pathogenic TP53 variants in the germline. Screening of the molecularneuropathology.org dataset for cases with similar genetic and epigenetic alterations yielded another case with SMARCA4 deficiency in a young adult with Li-Fraumeni syndrome. In conclusion, SMARCB1-deficient or SMARCA4-deficient malignant brain tumors with complex copy number alterations and somatic TP53 mutations in children and young adults may represent the first clinical manifestation of Li-Fraumeni syndrome and should prompt genetic counseling and investigation for TP53 germline status., Competing Interests: Conflicts of Interest and Source of Funding: Supported by IZKF Münster (Ha3/017/20). C.P.K. has been supported by the Deutsche Kinderkrebsstiftung (DKS2019.13) and BMBF ADDRess (01GM1909A). B.B. is supported by the Deutsche Kinderkrebsstiftung (DKS 2020.05). M.C.F. and R.S. are supported Deutsche Krebshilfe (DKH 70113981, 70114040). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Li-Fraumeni syndrome (LFS), a rare autosomal-dominant inheritance condition, is associated with a family cancer history as well as pathogenic/likely-pathogenic TP53 germline variants (P/LP TP53 GV). The current clinical methods for detecting LFS are limited. Here, we retrospectively investigate P/LP TP53 GV among Chinese cancer patients by next-generation sequencing and evaluate its relationship with a family cancer history. A total of 270 out of 19,226 cancer patients have TP53 GV, including 53 patients with P/LP TP53 GV. Patients with P/LP TP53 GV are mainly found in male with glioma, lung cancer or sarcoma. The median age of diagnosis for P/LP TP53 GV patients is significantly lower than that of non-P/LP TP53 GV patients (31-years vs. 53-years; P < 0.01). One LFS patient and 3 Li-Fraumeni-like syndrome (LFL) patients are among the 26 followed-up P/LP TP53 GV patients. Among 25 types of P/LP TP53 GV, the highest variant frequencies occurred at codon 175 and 248. p.M237I, p.R158H, p.C238Y and p.C275R, are firstly identified among the Chinese LFS/LFL patients. This study reports the (P/LP) TP53 GV characteristics of Chinese pan-cancer patients. These findings suggest analyzing the P/LP TP53 GV in cancer patients is an effective strategy for identifying cancer predisposition syndrome., Competing Interests: Conflict of interest Xiaoyan Zhang, Yu Fang, Hongling Yuan, Wei Li, Honglin Zhu, Fangping Zhao, Sizhen Wang, Tonghui Ma were employed by Genetron Health (Beijing) Technology, Co. Ltd., and did this work as part of their employment. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Ltd. All rights reserved.)

Comprehensive annual screening reduces cancer-related mortality in Li-Fraumeni syndrome (LFS), a cancer-prone disorder caused by pathogenic germline TP53 variants. Blood tests at months 4 and 8 between annual screening are recommended but their effectiveness in early cancer detection has not been established. Interim blood counts and inflammatory biomarkers were evaluated in 132 individuals with LFS (112 adults, 87 female, median age 36 years [range 3-68], median follow-up 37 months [range 2-70]) and test abnormalities were observed in 225 (35%). Thirteen cancers in 12 individuals were diagnosed between annual screenings but only one cancer (colorectal adenocarcinoma) was diagnosed due to an abnormal interim blood test. Fisher's exact test and generalized estimating equation models found no statistical associations between cancer diagnoses and any test abnormality. Four- and 8-monthly interim screening blood tests may not be of independent benefit for cancer detection in LFS, but annual cancer screening and personalized follow-up remain essential., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Introduction: Experiences of illness change the physical body and embodiments, or the ways in which the world and the self are known through the body. When illness is anticipated, such as with inherited cancer predisposition syndromes, risk becomes embodied and shared in family groups. Embodied risk is experienced whether or not symptoms have manifested. To examine how individuals and families with genetic risk experience the world and understand their disease through their bodies, we employ Li-Fraumeni syndrome (LFS) as an exemplar. LFS is a rare, genetic, cancer predisposition syndrome with nearly 100% lifetime cancer risk starting from birth, limited opportunities for prevention, rigorous screening protocols, and early mortality., Methods: Forty-five families, including 117 individuals aged 13-81 years, enrolled in the National Cancer Insitute's LFS study (NCT01443468) completed 66 open-ended interviews regarding LFS experiences. An interdisciplinary team used modified grounded theory to explore physical aspects of living with LFS in psychosocial contexts., Findings: The physicality of living with LFS included constant monitoring of LFS bodies across the family to identify physical change that might indicate carcinogenesis. Cancer screening, risk reduction, and treatment acted as dually protective and invasive, and as an unavoidable features of LFS. Connections between family members with similar embodiments normalized aesthetic changes and supported coping with visible markers of difference. In some circumstances, participants objectified the body to preserve the self and important relationships. In others, intense pain or loss created thresholds beyond which the self could no longer be separated from the body to support coping., Discussion: This paper focuses on Li-Fraumeni syndrome, a familial condition with a well-established genetic identity in which the body-self is experienced in relation to important others, to medical imaging, and to historical experiences with cancer. We expand on theories of embodied risk and inter-embodiment to describe experiences across disease trajectories, with attention to division and union between body, self, and other., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Patients with germline TP53 mutations are characterized by the occurrence of multiple early-onset malignancies. The characteristic syndrome is Li-Fraumeni syndrome (OMIM # 151623), an autosomal dominant disorder typified by premenopausal breast carcinoma, adrenal cortical tumors, bone and soft tissue sarcomas, leukemias, and tumors of the brain and spinal cord. Gynecologic malignancies are uncommonly reported in families harboring TP53 mutations, and the predominant tumor type reported is ovarian. Uterine carcinoma has been reported only a handful of times in patients with germline TP53 mutations, none as a presenting tumor in a teenager. We report on an 18-year-old patient who presented with grade 3, high-stage endometrioid endometrial carcinoma. Sequencing detected a single-nucleotide substitution in the TP53 gene (NM&#95;000546.6:c.818G>A), encoding the missense substitution p.Arg273His (R273H) in both the tumor and normal tissue, consistent with a germline mutation. We discuss the biology of the TP53 gene and p53 protein, with emphasis on the R273H mutation. We also review the literature on endometrial carcinoma in patients with germline TP53 mutations., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 by the International Society of Gynecological Pathologists.)

Competing Interests: The authors declare no conflicts of interest.

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Li Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome caused by germline mutations in TP53. TP53 is the most common mutated gene in human cancer, occurring in 30-50% of glioblastomas (GBM). Here, we highlight a precision medicine platform to identify potential targets for a GBM patient with LFS. We used a comparative transcriptomics approach to identify genes that are uniquely overexpressed in the LFS GBM patient relative to a cancer compendium of 12,747 tumor RNA sequencing data sets, including 200 GBMs. STAT1 and STAT2 were identified as being significantly overexpressed in the LFS patient, indicating ruxolitinib, a Janus kinase 1 and 2 inhibitors, as a potential therapy. The LFS patient had the highest level of STAT1 and STAT2 expression in an institutional high-grade glioma cohort of 45 patients, further supporting the cancer compendium results. To empirically validate the comparative transcriptomics pipeline, we used a combination of adherent and organoid cell culture techniques, including ex vivo patient-derived organoids (PDOs) from four patient-derived cell lines, including the LFS patient. STAT1 and STAT2 expression levels in the four patient-derived cells correlated with levels identified in the respective parent tumors. In both adherent and organoid cultures, cells from the LFS patient were among the most sensitive to ruxolitinib compared to patient-derived cells with lower STAT1 and STAT2 expression levels. A spheroid-based drug screening assay (3D-PREDICT) was performed and used to identify further therapeutic targets. Two targeted therapies were selected for the patient of interest and resulted in radiographic disease stability. This manuscript supports the use of comparative transcriptomics to identify personalized therapeutic targets in a functional precision medicine platform for malignant brain tumors.

Increasing availability of genomic testing poses new challenges to clinicians, particularly where variant interpretation from commercial sources may be equivocal. The authors report a patient with recurrent rhabdomyosarcoma and subsequent bilateral breast cancer who was found to harbor a previously undescribed germline TP53 sequence alteration annotated by the commercial laboratory as a variant of uncertain significance. By investigating publicly available databases of aggregated normal germline and malignant somatic genomic sequences, the authors conclude that this missense variant, c.476C>T (p.A159V), is a novel, pathogenic Li-Fraumeni syndrome mutation and demonstrate the utility of these resources in clinical pediatric hematology and oncology practice., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Women with Li-Fraumeni syndrome (LFS) have elevated breast cancer (BC) risk. Optimal BC treatment strategies in this population are yet unknown., Methods: BC subtypes and treatment were retrospectively investigated between December 2016 and January 2019 in a multicentre study. BC risks were evaluated according to the type of surgery., Results: Thirty-five women of our study population (35/44; 79.5%) had developed 36 breast lesions at first diagnosis at a mean age of 34 years. Those breast lesions comprised 32 invasive BCs (89%), three ductal carcinoma in situ alone (8%) and one malignant phyllodes tumour (3%). BCs were mainly high-grade (18/32), of no special type (NST; 31/32), HER2-enriched (11/32) or luminal-B-(like)-type (10/32). Affected women (n = 35) received breast-conserving surgery (BCS, n = 17) or a mastectomy (ME, n = 18) including seven women with simultaneous contralateral prophylactic mastectomy (CPM) at first diagnosis. Nineteen women suffered 20 breast or locoregional axillary lesions at second diagnosis with mean age of 36. Median time between first and second diagnosis was 57 months; median time to contra- and ipsilateral recurrence depended on surgical strategies (BCS: 46 vs. unilateral ME: 93 vs. bilateral ME > 140 months). Women with a primary treatment of solitaire therapeutic ME suffered from contralateral BC earlier compared to those with therapeutic ME and CPM (median: 93 vs. >140 months)., Conclusion: Aggressive BC subtypes occur among women with LFS. Surgical treatment, i.e. ME and CPM, may prolong time to a second BC diagnosis. Conclusion on long-term survival benefit is pending. Individual competing tumour risks and long-term outcomes need to be taken into consideration., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

We traced the neoplastic history (from 5 to 11 years of age) of a child with concomitant Fanconi anemia and Li-Fraumeni syndrome. Interestingly, the patient developed a highly malignant T-cell non-Hodgkin lymphoma (NHL), which does not represent the typical tumor type in the two aforementioned syndromes, presumably due to the underlying genomic instability. By using a combination of molecular and immunohistochemical approaches, we characterized the accumulation of multiple genetic alterations in a single patient, with both germline (parentally inherited biallelic FANCA variants and a likely de novo nonsense variant in TP53) and somatic (TP53 loss of heterozygosity and 5q interstitial deletion) contributions. Our findings support the interplay of TP53 and FANC genes in DNA damage response pathways and further highlight the genetic heterogeneity of lymphomas as well as the contribution of genomic instability to lymphomagenesis., Competing Interests: Declaration of Competing Interest The authors have no potential conflicts of interest to declare., (Copyright © 2020. Published by Elsevier Inc.)

Breast cancer is the most common tumor among women with inherited variants in the TP53 tumor suppressor, but onset varies widely suggesting interactions with genetic or environmental factors. Rodent models haploinsufficent for Trp53 also develop a wide variety of malignancies associated with Li-Fraumeni syndrome, but BALB/c mice are uniquely susceptible to mammary tumors and is genetically linked to the Suprmam1 locus on chromosome 7. To define mechanisms that interact with deficiencies in p53 to alter susceptibility to mammary tumors, we fine mapped the Suprmam1 locus in females from an N2 backcross of BALB/cMed and C57BL/6J mice. A major modifier was localized within a 10 cM interval on chromosome 7. The effect of the locus on DNA damage responses was examined in the parental strains and mice that are congenic for C57BL/6J alleles on the BALB/cMed background (SM1-Trp53 +/- ). The mammary epithelium of C57BL/6J-Trp53 +/- females exhibited little radiation-induced apoptosis compared to BALB/cMed-Trp53 +/- and SM1-Trp53 +/- females indicating that the Suprmam1 B6/B6 alleles could not rescue repair of radiation-induced DNA double-strand breaks mostly relying on non-homologous end joining. In contrast, the Suprmam1 B6/B6 alleles in SM1-Trp53 +/- mice were sufficient to confer the C57BL/6J-Trp53 +/- phenotypes in homology-directed repair and replication fork progression. The Suprmam1 B6/B6 alleles in SM1-Trp53 +/- mice appear to act in trans to regulate a panel of DNA repair and replication genes which lie outside the locus., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Breast cancer is the most frequent event in Li-Fraumeni syndrome associated with germline TP53 variants. Some studies have shown that breast cancers in women with Li-Fraumeni syndrome are commonly HER2-positive, suggesting that HER2 amplification or over-expression in a young woman may be a useful criterion to test for germline variants in the TP53 gene. We assessed the prevalence of germline TP53 variants by Sanger sequencing or next-generation sequencing in 149 women with HER2-positive breast cancer diagnosed until age 40. The pattern of HER2 amplification was evaluated with dual-probe FISH in a subset of breast carcinomas from patients with germline TP53 variants as compared with those of noncarriers. Among 149 women tested, three presented a deleterious TP53 germline variant (2%), with one patient diagnosed at age 31 and the other two with bilateral breast cancer at ages 29/33 and 28/32, respectively. Three of the 36 patients (8.3%) with the first breast cancer diagnosed at age 31 or younger presented a pathogenic TP53 variant. Additionally, all TP53 deleterious variant carriers had a first degree relative diagnosed with different early-onset cancers (frequently not belonging to the Li-Fraumeni syndrome tumor spectrum) diagnosed at age 45 or younger. Higher levels of HER2 amplification were found in breast carcinomas of TP53 pathogenic variant carriers than in those of noncarriers. Deleterious germline TP53 variants account for a small proportion of early-onset HER2-positive breast cancers, but these seem to have higher HER2 amplification ratios. All TP53 pathogenic variant carriers found in this study had the first breast carcinoma diagnosed at age 31 or younger and a first-degree relative with early-onset cancer. Further studies are needed to clarify if HER2 status in early-onset breast cancer patients, in combination with other personal and/or familial cancer history, is useful to update the TP53 testing criteria.

Cemento-osseous dysplasia (COD) is the most common benign fibro-osseous lesion of the jaws and generally considered non-neoplastic and self-limited. Here, we present a 30-year old female who noticed a bilateral swelling of her posterior mandible with irregular periapical mineralization and incomplete root resorption on panoramic radiographs. A biopsy revealed florid COD and no further treatment was initiated. 9 years later, she presented with a progressive expansion of her left posterior mandible after being treated for bilateral breast cancer 4 and 8 years before. CT scans showed expansile and densely mineralized lesions in all four quadrants with the left posterior mandible showing a focal penetration of the buccal cortical bone. Biopsies revealed an osteoblastic high-grade osteosarcoma in the left and a COD in the right mandible, notably with cellular atypia in the spindle cell component. The patient underwent segmental resection of the left mandible with clear margins and adjuvant chemotherapy. Subsequent genetic testing identified a heterozygous germline TP53 mutation (p.V173G) which confirmed the clinically suspected Li-Fraumeni syndrome (LFS). 3 years after the resection, the patient is free of disease and the other foci of COD remained stable in size on follow-up imaging analyses. Our case illustrates LFS-related osteosarcoma developing within florid COD. Given the rarity of this coincidence, a causative relation between the two lesions seems unlikely but in patients with tumor predisposition syndromes it might be advisable to closely monitor even benign lesions like COD.

Germline mutations of TP53 , which cause the cancer predisposition disorder Li-Fraumeni syndrome (LFS), can increase mitochondrial activity as well as fatty acid β-oxidation (FAO) in mice. Increased fatty acid metabolism can promote cancer malignancy, but its specific contribution to tumorigenesis in LFS remains unclear. To investigate this, we crossed LFS mice carrying the p53 R172H knock-in mutation ( p53 172H/H , homolog of the human TP53 R175H LFS mutation) with myoglobin-knockout ( MB -/- ) mice known to have decreased FAO. MB -/- p53 172H/H double-mutant mice also showed mildly reduced FAO in thymus, a common site of T lymphoma development in LFS mice, in association with an approximately 40% improvement in cancer-free survival time. RNA sequencing profiling revealed that the p53 R172H mutation promotes mitochondrial metabolism and ribosome biogenesis, both of which are suppressed by the disruption of MB . The activation of ribosomal protein S6, involved in protein translation and implicated in cancer promotion, was also inhibited in the absence of MB . To further confirm the role of FAO in lymphomagenesis, mitochondrial FAO enzyme, carnitine palmitoyltransferase 2 (CPT2), was specifically disrupted in T cells of p53 172H/H mice using a Cre- lox P-mediated strategy. The heterozygous knockout of CPT2 resulted in thymus FAO haploinsufficiency and an approximately 30% improvement in survival time, paralleling the antiproliferative signaling observed with MB disruption. Thus, this study demonstrates that moderating FAO in LFS can suppress tumorigenesis and improve cancer-free survival with potential implications for cancer prevention. PREVENTION RELEVANCE: Mildly inhibiting the increased fatty acid oxidation observed in a mouse model of Li-Fraumeni syndrome, a cancer predisposition disorder caused by inherited mutations of TP53 , dampens aberrant pro-tumorigenic cell signaling and improves the survival time of these mice, thereby revealing a potential strategy for cancer prevention in patients., (©2020 American Association for Cancer Research.)

Introduction: To assess the upper gastrointestinal (UGI) cancer risk and surveillance outcomes in Li-Fraumeni syndrome (LFS)., Methods: Analysis of the International Agency for Research on Cancer database and a single-center adult LFS cohort., Results: UGI cancer was present in 7.2% of families and 3.9% of individuals with a pathogenic/likely pathogenic TP53 mutation in International Agency for Research on Cancer; 29% occurred before age 30. Our institutional cohort had 35 individuals (31% of the LFS cohort) with 48 cumulative upper endoscopies; 3 (8.5%) individuals had concerning UGI findings., Discussion: UGI cancer is observed in LFS. Upper endoscopy should be part of a comprehensive LFS surveillance program.

Germline mutations of TP53 are responsible for Li-Fraumeni syndrome in its 60-80%. We found a novel germline mutation, TP53: c.997del:p.R333Vfs*12 (NM&#95;000546.6, GRCh, 17:7670713..7670713). The proband is a 40-year-old female, who was suffered from osteosarcoma in her right forearm at her age of 11. She was also suffered from lung adenocarcinoma in her right upper lobe and bone metastasis in her right scapula at her age of 37. She was treated with gefitinib, an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) because of EGFR mutation (L747-S752 del). Her bone metastasis became resistant after 1-year treatment. Bone metastasis had an additional EGFR mutation (T790M). The secondary treatment with osimertinib, an another EGFR-TKI, can successfully control the tumors for over 2 years. This TP53 mutation (R333Vfs*12) was first found in lung adenocarcinomas. The therapeutic effect of osimertinib for this triple mutant lung adenocarcinoma is better than the previous report., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Background: Li-Fraumeni syndrome (LFS) is a high-risk cancer predisposition syndrome caused by pathogenic germline variants of TP53. Cancer surveillance has noted a significant survival advantage in individuals with LFS; however, little is known about the feasibility, acceptance, and psychosocial effects of such a program., Methods: Pathogenic TP53 germline variant carriers completed a 7-part questionnaire evaluating sociodemographics, cancer history, surveillance participation, reasons for nonadherence, worries, and distress adapted from the Cancer Worry Scale. Counselees' common concerns and suggestions were assessed in MAXQDA Analytics Pro 12., Results: Forty-nine participants (46 females and 3 males), aged 40.0 ± 12.6 years, formed the study population; 43 (88%) had a personal cancer history (including multiple cancers in 10 [20%]). Forty-three individuals participated (88%) in surveillance during the study or formerly. Willingness to undergo surveillance was influenced by satisfaction with genetic testing and counseling (P = .019 [Fisher-Yates test]) but not by sociodemographics, cancer history, or distress level. Almost one-third of the participants reported logistical difficulties in implementing surveillance because of the high frequency of medical visits, scheduling difficulties, and the travel distance to their surveillance providers. Self-reported distress and perceived emotional burden for family members and partners were moderate (median for self-reported distress, 3.3; median for perceived emotional burden, 3.0). For both, the interquartile range was moderate to very high (2.7-3.7 and 3.0-3.7, respectively)., Conclusions: Individuals with LFS require efficient counseling as well as an accessible, well-organized, interdisciplinary, standardized surveillance program to increase adherence and psychological coping., (© 2020 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Purpose: Women with Li-Fraumeni syndrome (LFS), a cancer predisposition syndrome caused by germline mutations in TP53, have an over 50% risk of developing breast cancer by age 70. Patients with LFS are at risk for radiation-induced malignancies; however, only small case series have prior investigated radiation risks in the treatment of breast cancer. We therefore aimed to investigate the risk of malignancy in breast cancer patients with LFS following adjuvant radiotherapy., Methods: A single-institution retrospective chart review was conducted for female breast cancer patients with confirmed germline TP53 mutation. The frequency of radiation-induced malignancies in LFS patients was compared to non-LFS breast cancer cases reported in the Penn Medicine Cancer Registry via statistical analyses., Results: We identified 51 female LFS breast cancer patients with 74 primary diagnoses. Fifty-seven% had a history of breast cancer only, and 25% had breast cancer as their presenting diagnosis of LFS. LFS-associated breast cancers were predominantly invasive ductal carcinoma (48%) and HER2+ (58%). Twenty patients underwent adjuvant radiotherapy with a median follow-up of 12.5 (2-20) years. Of 18 patients who received radiation in a curative setting, one (6%) patient developed thyroid cancer, and one (6%) patient developed sarcoma in the radiation field. This risk for radiation-induced malignancy associated with LFS was higher for both sarcoma and thyroid cancer in comparison with the control cohort., Conclusions: We found a lower risk of radiation-induced secondary malignancies in LFS breast cancer patients than previously reported in the literature (33% risk of radiation-induced sarcoma). These findings suggest that LFS may not be an absolute contraindication for radiotherapy in breast cancer. The potential risk for locoregional recurrence without radiotherapy must be weighed against the long-term risk for radiation-induced malignancies in consideration of adjuvant radiotherapy for LFS breast cancer patients.

Li-Fraumeni syndrome (LFS), caused by the germline mutations in the TP53 gene, leads to significant lifetime risk to cancer in the central nervous system. Recognition of LFS, and elucidating its underlying cause has had a remarkable effect on our knowledge of the biology of brain tumors and represents a significant opportunity for cancer surveillance and screening. In this review, we discuss the historical context of the LFS with an emphasis on the clinicopathologic implications in clincal diagnosis, germline testing, and clinical management of brain tumor patients.

Pleomorphic myxoid liposarcoma is an extremely rare, clinically aggressive subtype of liposarcoma that has been primarily reported in young patients. In this article, we report a case of a pleomorphic myxoid liposarcoma that presented as a second primary neoplasm in a 34-year-old man with history of primary mediastinal large B-cell lymphoma. During the clinical workup, the patient was diagnosed with a germline TP53 gene mutation and Li-Fraumeni syndrome. The tumor, a 2.9 × 2.3 × 2.0 cm well-demarcated and solid mass, was centered in the anterior chest wall soft tissue. Histologically, most of the tumor displayed abundantly myxoid stroma, low cellularity of mostly bland spindle cells, delicate branching capillaries, and lipoblasts; these areas transitioned to small areas whose features were reminiscent of pleomorphic liposarcoma. As assessed by fluorescence in situ hybridization, the tumor showed no DDIT3 ( CHOP ) (12q13) rearrangements or MDM2 gene amplification. Clinically, the tumor progressed with multiple recurrences and metastasis to the humerus bone. To our knowledge, this is the first case of pleomorphic myxoid liposarcoma diagnosed in an adult with Li-Fraumeni syndrome.