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Accurate diagnosis is the foundation of clinical care but accurate diagnosis is not easily reached in some cases. In rare instances, even a sophisticated multidisciplinary team at an academic medical center cannot reliably reach an accurate diagnosis after extensive testing and imaging, and has to wait until histological diagnosis or even autopsy results are available. The underlying reason of challenging diagnoses is mostly conflicting data from history, tests, and imaging that point to different diagnoses. In this issue of World Journal of Clinical Cases, Huffaker et al reported such a challenging case of a tricuspid mass in a patient with Li-Fraumeni syndrome. The case by Huffaker et al powerfully illustrates the occasional diagnostic challenges inherent in our current diagnostic approach and the current technology. Clinicians should realize that in rare situations, agnosticism in diagnosis is unavoidable but a treatment has to be initiated so long as the principle of primum non nocere is upheld.

Choroid plexus carcinomas (CPC) are early childhood cancers characterized by loss of TP53 function and poor survival. We are analyzing data on TP53 status, survival, and second cancers from the largest cohort of CPC receiving chemotherapy followed by consolidation with marrow-ablative chemotherapy (HDCx). Additionally, we discuss the rationale for targeted therapies for CPC patients. Currently, 8 of the 13 with Li-Fraumeni Syndrome-associated CPC were treated and continued CPC-free, indicating that HDCx improves CPC-free survival in young children with TP53-mutated CPC. These data justify the inclusion of HDCx in the planned prospective international trial for children with TP53-mutated CPC.

Germline and somatic TP53 variants play a crucial role during tumorigenesis. However, genetic variations that solely affect the alternatively spliced p53 isoforms, p53β and p53γ, are not fully considered in the molecular diagnosis of Li-Fraumeni syndrome and cancer. In our search for additional cancer predisposing variants, we identify a heterozygous stop-lost variant affecting the p53β isoforms (p.*342Serext*17) in four families suspected of an autosomal dominant cancer syndrome with colorectal, breast and papillary thyroid cancers. The stop-lost variant leads to the 17 amino-acid extension of the p53β isoforms, which increases oligomerization to canonical p53α and dysregulates the expression of p53's transcriptional targets. Our study reveals the capacity of p53β mutants to influence p53 signalling and contribute to the susceptibility of different cancer types. These findings underscore the significance of p53 isoforms and the necessity of comprehensive investigation into the entire TP53 gene in understanding cancer predisposition. Pathogenic germline variants in TP53 predispose to a variety of cancers, but variants solely affecting alternatively spliced isoforms of TP53 are understudied. Here, the authors identify a heterozygous stop-lost variant that specifically affects p53β isoforms and predisposes to familial cancer using germline whole-exome sequencing and functional genomics assays. [ABSTRACT FROM AUTHOR]

Background: Li-Fraumeni syndrome (LFS), a hereditary condition attributed to TP53 pathogenic variants,(PV), is associated with high risks for various malignant tumors, including breast cancer. Notably, individuals harboring TP53 PVs are more likely (67–83%) to develop HER2 + breast cancer than noncarriers (16–25%). In this retrospective study, we evaluated the associations between TP53 variants and breast cancer phenotype. Methods: We conducted a retrospective review of the medical records of patients with LFS treated at a single institution and reviewed the literature on TP53 functions and the mechanisms underlying HER2 + breast cancer development in LFS. Results: We analyzed data for 10 patients with LFS from 8 families. The median age at the onset of the first tumor was 35.5 years. Only case 2 met the classic criteria; this patient harbored a nonsense variant, whereas the other patients carried missense variants. We observed that 9 of 10 patients developed breast cancer. Immunohistochemical analyses revealed that 40% of breast cancers in patients with LFS were HR − /HER2 +. The median age at the onset of breast cancer was slightly younger in HR − /HER2 + tumors than in HR + /HER2 − tumors (31 years and 35.5 years, respectively). Conclusions: The occurrence of HER2 + breast cancer subtype was 40% in our LFS case series, which is greater than that in the general population (16–25%). Some TP53 PVs may facilitate HER2-derived oncogenesis in breast cancer. However, further studies with larger sample sizes are warranted to clarify the oncogenic mechanisms underlying each subtype of breast cancer in TP53 PV carriers. [ABSTRACT FROM AUTHOR]

Acknowledging the increasing use of whole-body magnetic resonance imaging (WB-MRI) in the oncological setting, we conducted a narrative review focusing on practical aspects of the examination and providing a synthesis of various acquisition protocols described in the literature. Firstly, we addressed the topic of patient preparation, emphasizing methods to enhance examination acceptance. This included strategies for reducing anxiety and patient distress, improving staff–patient interactions, and increasing overall patient comfort. Secondly, we analysed WB-MRI acquisition protocols recommended in existing imaging guidelines, such as MET-RADS-P, MY-RADS, and ONCO-RADS, and provided an overview of acquisition protocols reported in the literature regarding other expanding applications of WB-MRI in oncology, in patients with breast cancer, ovarian cancer, melanoma, colorectal and lung cancer, lymphoma, and cancers of unknown primary. Finally, we suggested possible acquisition parameters for whole-body images across MR systems from three different vendors. [ABSTRACT FROM AUTHOR]

Metformin is best known as a foundational therapy for type 2 diabetes but is also used in other contexts in clinical medicine with a number of emerging and potential indications. Many of its beneficial effects may be mediated by modest effects on weight loss and insulin sensitivity, but it has multiple other known mechanisms of action. Current clinical uses beyond type 2 diabetes include: polycystic ovarian syndrome; diabetes in pregnancy/gestational diabetes; prevention of type 2 diabetes in prediabetes; and adjunct therapy in type 1 diabetes. As metformin has been in clinical use for almost 70 years, much of the underpinning evidence for its use in these conditions is, by definition, based on trials conducted before the advent of contemporary evidence‐based medicine. As a result, some of the above‐established uses are 'off‐label' in many regulatory territories and their use varies accordingly in different countries. Going forward, several current 'repurposing' investigational uses of metformin are also being investigated: prevention of cancer (including in Li Fraumeni syndrome), renal protection, Alzheimer's disease, metabolic dysfunction‐associated steatotic liver disease and promotion of healthy ageing. Despite the longevity of metformin and its important current roles beyond type 2 diabetes in clinical medicine, it has further potential and much research is ongoing. [ABSTRACT FROM AUTHOR]

Background TP53 alterations are common in certain pediatric cancers, making identification of putative germline variants through tumor genomic profiling crucial for disease management. Methods We analyzed TP53 alterations in 3123 tumors from 2788 pediatric patients sequenced using tumor-only or tumor-normal paired panels. Germline confirmatory testing was performed when indicated. Somatic and germline variants were classified based on published guidelines. Results In 248 tumors from 222 patients, 284 tier 1/2 TP53 sequence and small copy number variants were detected. Following germline classification, 86.6% of 142 unique variants were pathogenic or likely pathogenic. Confirmatory testing on 118 patients revealed germline TP53 variants in 28 of them (23 pathogenic or likely pathogenic and 5 of uncertain significance), suggesting a minimum Li-Fraumeni syndrome incidence of 0.8% (23/2788) in this cohort, 10.4% (23/222) in patients with TP53 variant–carrying tumors, and 19.5% (23/118) with available normal samples. About 25% (7/28) of patients with germline TP53 variants did not meet Li-Fraumeni syndrome diagnostic or testing criteria, while 20.9% (28/134) with confirmed or inferred somatic origins did. TP53 biallelic inactivation occurred in 75% of germline carrier tumors and was also prevalent in other groups, causing an elevated tumor-observed variant allelic fraction. Somatic evidence, however, including low variant allele fraction correctly identified only 27.8% (25/90) of patients with confirmed somatic TP53 variants. Conclusion The high incidence and variable phenotype of Li-Fraumeni syndrome in this cohort highlights the importance of assessing germline status of TP53 variants identified in all pediatric tumors. Without clear somatic evidence, distinguishing somatic from germline origins is challenging. Classifying germline and somatic variants should follow appropriate guidelines. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The increased use of next‐generation sequencing has led to the detection of pathogenic TP53 variants in the germline setting in patients without a personal or family history consistent with Li–Fraumeni syndrome (LFS). These variants can represent low‐penetrance LFS, mosaic LFS, or clonal hematopoiesis of indeterminate potential. Additionally, TP53 variants of uncertain significance can be detected in patients with a history suspicious for LFS. The interpretation of the significance of these variants can be challenging but is crucial for an accurate diagnosis and appropriate medical management. This retrospective case review provides illustrative examples of the interpretation of challenging TP53 results through multidisciplinary expertise and use of a flowchart. The authors describe eight patients with TP53 variants associated with ambiguous diagnoses and, for each case, describe how the results were interpreted and the medical care that was implemented. This report presents illustrative cases to help guide clinicians to reach definitive diagnoses for patients when confronted with TP53 variants that are inconsistent with the clinical picture and to add to the body of literature regarding interpretation and medical management of TP53 variants discovered on germline testing. [ABSTRACT FROM AUTHOR]

Abstract Germline TP53 pathogenic variants can lead to a cancer susceptibility syndrome known as Li–Fraumeni (LFS). Variants affecting its activity can drive tumorigenesis altering p53 pathways and their identification is crucial for assessing individual risk. This study explored the functional impact of TP53 missense variants on its transcription factor activity. We selected seven TP53 missense variants (c.129G > C, c.320A > G, c.417G > T, c.460G > A, c,522G > T, c.589G > A and c.997C > T) identified in Brazilian families at-risk for LFS. Variants were created through site-directed mutagenesis and transfected into SK-OV-3 cells to assess their transcription activation capabilities. Variants K139N and V197M displayed significantly reduced transactivation activity in a TP53-dependent luciferase reporter assay. Additionally, K139N negatively impacted CDKN1A and MDM2 expression and had a limited effect on GADD45A and PMAIP1 upon irradiation-induced DNA damage. Variant V197M demonstrated functional impact in all target genes evaluated and loss of Ser15 phosphorylation. K139N and V197M variants presented a reduction of p21 levels after irradiation. Our data show that K139N and V197M negatively impact p53 functions, supporting their classification as pathogenic variants. This underscores the significance of conducting functional studies on germline TP53 missense variants classified as variants of uncertain significance to ensure proper management of LFS-related cancer risks.

Background/Objective: Li-Fraumeni syndrome (LFS) is an inherited sequence variant in TP53 characterized by the early onset of various core malignancies including adrenocortical carcinoma (ACC), sarcomas, breast cancer, leukemias, and central nervous system tumors. We present a case of a patient with LFS who developed endocrine neoplasms not classically seen in LFS in addition to developing ACC. Case Report: A 26-year-old nonbinary individual assigned female at birth with a history of LFS complicated by osteosarcoma of the jaw was incidentally found to have thyroid and sellar masses on surveillance magnetic resonance imaging. Fine-needle aspiration of thyroid mass confirmed papillary thyroid carcinoma, and the patient underwent total thyroidectomy. Pituitary workup was notable for laboratory test results consistent with adrenocorticotropic hormone-dependent hypercortisolism; the patient underwent resection of the pituitary lesion. The patient was subsequently noted on abdominal imaging to have a new left adrenal mass; they underwent left adrenalectomy with pathology consistent with ACC. Discussion: There is limited literature on the relationship between LFS and thyroid and pituitary neoplasms. Genetic testing has suggested that TP53 sequence variants may play a role in tumorigenesis in thyroid and pituitary neoplasms; however, most of the current literature is based on evidence of somatic rather than germline sequence variants. Conclusion: This case highlights a patient with LFS with neoplasia of multiple endocrine organs including ACC, which is a classic finding, as well as papillary thyroid carcinoma and Cushing disease. Further investigation may be necessary to assess if patients with LFS are at a higher risk of various endocrine neoplasms in addition to the core malignancies classically described because this could affect future screening protocols.

Germline TP53 pathogenic variants can lead to a cancer susceptibility syndrome known as Li–Fraumeni (LFS). Variants affecting its activity can drive tumorigenesis altering p53 pathways and their identification is crucial for assessing individual risk. This study explored the functional impact of TP53 missense variants on its transcription factor activity. We selected seven TP53 missense variants (c.129G > C, c.320A > G, c.417G > T, c.460G > A, c,522G > T, c.589G > A and c.997C > T) identified in Brazilian families at-risk for LFS. Variants were created through site-directed mutagenesis and transfected into SK-OV-3 cells to assess their transcription activation capabilities. Variants K139N and V197M displayed significantly reduced transactivation activity in a TP53-dependent luciferase reporter assay. Additionally, K139N negatively impacted CDKN1A and MDM2 expression and had a limited effect on GADD45A and PMAIP1 upon irradiation-induced DNA damage. Variant V197M demonstrated functional impact in all target genes evaluated and loss of Ser15 phosphorylation. K139N and V197M variants presented a reduction of p21 levels after irradiation. Our data show that K139N and V197M negatively impact p53 functions, supporting their classification as pathogenic variants. This underscores the significance of conducting functional studies on germline TP53 missense variants classified as variants of uncertain significance to ensure proper management of LFS-related cancer risks. [ABSTRACT FROM AUTHOR]

Li-Fraumeni syndrome (LFS) is caused by a pathogenic germline variant at the TP53 locus and is associated with an increased predisposition to a variety of cancers. The neoplasms most frequently associated with LFS are sarcomas, breast cancer, brain tumors, and adrenocortical carcinomas. In this case report, we present a 43-year-old male diagnosed with an ocular adnexal sebaceous carcinoma of the right upper eyelid who was confirmed to have LFS with subsequent genetic testing. The mutational profile of both the patient’s genetic screen and tumor sequencing were congruent, demonstrating the same pathogenic loss-of-function TP53 variant. This case report highlights the importance of pursuing genetic testing in patients with a history of multiple tumor types, particularly those with uncommon diagnoses. In this case, confirmation of LFS had important implications for personalized patient care, including identification of contraindicated treatment interventions and the imaging modalities necessary for vigilant follow-up screening. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is the most common malignancy in female patients with Li-Fraumeni syndrome (LFS), a condition associated with an increased risk of various malignancies, including radiation therapy (RT)–induced malignancies (RIM) within previously irradiated areas. Our study aimed to assess the incidence of RIM in patients with LFS and early-stage BC treated with adjuvant RT, including the effect of RT dose and technique. We examined patients with a germline pathogenic/likely pathogenic TP53 variant diagnosed with early-stage BC and monitored by a hereditary cancer team at a single cancer center. The study endpoints included RIM frequency, the association of RIM with the dose and type of RT (2-dimensional [2D] RT, 3-dimensional [3D] RT, and intensity modulated RT [IMRT]), and BC recurrence. We analyzed 48 patients with a median age of 39 years (range, 21-62). The majority (71%) had the TP53 R337H variant, and 87% were unaware of their LFS diagnosis at the time of BC treatment. Treatment modalities included mastectomy (62%), (neo)adjuvant chemotherapy (66%), and RT (62%), with RT being more common after breast-conserving surgery (87% vs 46% with mastectomy, P =.010). Among the 30 patients treated with RT, 10% developed RIM in the irradiated field, consisting of 3 soft tissue malignancies. RT dose (≤40.8 or >40.8 Gy) did not influence RIM occurrence, but the type of RT did. RIM was observed in 100% of cases with 2D RT (2/2), 50% with IMRT (1/2), and 0% with 3D RT (0/16) (P =.004). Our study underscores a concerning rate of RIM after adjuvant RT, emphasizing the importance of a thorough risk-benefit evaluation before recommending RT, with preference for its avoidance if possible. Although subgroup sizes were limited, the risk of RIM appeared to be influenced by the RT technique, with higher rates observed with 2D RT and IMRT compared with 3D RT. Early TP53 testing is essential to guide the BC treatment plan. [ABSTRACT FROM AUTHOR]

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. The mechanisms behind therapy-related myeloid neoplasms (t-MN) occurring after chemotherapy treatment remain poorly understood, particularly for paediatric patients. Here, the authors analyse t-MN in children using single-cell genomics, showing how t-MN founding cells can expand after cessation of therapy and how the platinum-induced growth inhibition is TP53-dependent. [ABSTRACT FROM AUTHOR]

Despite the high prevalence of TP53 pathogenic variants (PV) carriers in the South and Southeast regions of Brazil, germline genetic testing for hereditary breast cancer (HBC) is not available in the Brazilian public health system, and the prevalence of Li-Fraumeni syndrome (LFS) is not well established in other regions of Brazil. We assessed the occurrence of TP53 p.R337H carriers among women treated for breast cancer (BC) between January 2021 and January 2022 at public hospitals of Brasilia, DF, Brazil. A total of 180 patients who met at least one of the NCCN criteria for HBC underwent germline testing; 44.4% performed out-of-pocket germline multigene panel testing, and 55.6% were tested for the p.R337H variant by allelic discrimination PCR. The median age at BC diagnosis was 43.5 years, 93% had invasive ductal carcinoma, 50% had estrogen receptor-positive/HER2 negative tumors, and 41% and 11% were diagnosed respectively at stage III and IV. Two patients (1.11%) harbored the p.R337H variant, and cascade family testing identified 20 additional carriers. The TP53 p.R337H detection rate was lower than that reported in other studies from south/southeast Brazil. Nonetheless, identifying TP53 PV carriers through genetic testing in the Brazilian public health system could guide cancer treatment and prevention. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A case series evaluating efficacy and safety of immune checkpoint blockade in Li-Fraumeni syndrome [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

For patients with hereditary breast and ovarian cancer, the probability of carrying two pathogenic variants (PVs) in dominant cancer-predisposing genes is rare. Using targeted next-generation sequencing (NGS), we investigated a 49-year-old Caucasian woman who developed a highly aggressive breast tumor. Our analyses identified an intragenic germline heterozygous duplication in BRCA1 with an additional likely PV in the TP53 gene. The BRCA1 variant was confirmed by multiplex ligation probe amplification (MLPA), and genomic breakpoints were characterized at the nucleotide level (c.135-2578_442-1104dup). mRNA extracted from lymphocytes was amplified by RT-PCR and then Sanger sequenced, revealing a tandem duplication r.135_441dup; p.(Gln148Ilefs*20). This duplication results in the synthesis of a truncated and, most likely, nonfunctional protein. Following functional studies, the TP53 exon 5 c.472C > T; p.(Arg158Cys) missense variant was classified as likely pathogenic by the Li-Fraumeni Syndrome (LFS) working group. This type of unexpected association will be increasingly identified in the future, with the switch from targeted BRCA sequencing to hereditary breast and ovarian cancer (HBOC) panel sequencing, raising the question of how these patients should be managed. It is therefore important to record and investigate these rare double-heterozygous genotypes. [ABSTRACT FROM AUTHOR]

• Identification of TP53 pathogenic variants at lower-than-expected variant allele frequencies (VAF) for Li Fraumeni Syndrome (LFS) may reflect postzygotic mosaicism (PZM) or clonal hematopoiesis (CH). • Constitutional mosaic LFS and clonal hematopoiesis (CH) represent completely different entities with regards to cancer risk, family implications and management. • In a cancer genetics specialty clinic, approximately 17 % of TP53 genetic testing results were "mosaic". • Ancillary tissue testing can help confirm a diagnosis of mosaic LFS. • Half of mosaic TP53 results may be postzygotic mosaicism (PZM) and half clonal hematopoiesis (CH). Germline heterozygous TP53 pathogenic variants (PVs) cause Li Fraumeni Syndrome (LFS, OMIM#151623). TP53 PVs at lower-than-expected variant allele frequencies (VAF) may reflect postzygotic mosaicism (PZM) or clonal hematopoiesis (CH); however, no guidelines exist for workup and clinical management. Retrospective analysis of probands who presented to an academic cancer genetics program with a TP53 PV result on germline genetic testing. Twenty-one of 125 unrelated probands (17 %) were found to harbor a TP53 PV with VAF<30 % or a designation of "mosaic". A diagnosis of PZM was made in nine (43 %) due to a clinical phenotype consistent with LFS with (n = 8) or without (n = 1) positive ancillary tissue testing. Twelve patients (57 %) were diagnosed with presumed CH (pCH) due to a diagnosis of a myeloproliferative neoplasm, negative ancillary tissue testing, clinical phenotype not meeting LFS criteria, no cancer, and/or no first cancer age<50. Of the 19 patients with biological offspring, nine had either partial or complete offspring testing, all negative. Determining the etiology of low VAF TP53 PVs requires ancillary tissue testing and incorporation of clinical phenotype. Discerning PZM versus CH is important to provide optimal care and follow-up. [Display omitted] [ABSTRACT FROM AUTHOR]

Objective: Li-Fraumeni syndrome (LFS) is a rare hereditary cancer predisposition syndrome that significantly increases one's lifetime cancer risk from infancy to late adulthood. LFS is primarily caused by pathogenic autosomal dominant germline TP53 variants. Consequently, each naturally conceived biological child of an individual with a pathogenic variant has a 50% chance of inheriting it. This study examines the connections between family cancer history and reproductive beliefs within multigenerational family units including at least one member with TP53 -positive LFS. Method: Forty-five families enrolled in a protocol-specific cancer screening study completed 66 group interviews. An interdisciplinary team constructed a thematic codebook of inductive and deductive codes using interpretive description and modified ground theory to analyze data and then implemented a framework method to organize themes. Results: The following major themes were related to reproductive beliefs in the context of LFS: (a) tension between morality and generational cancer experiences, (b) discriminating between multiple moral frames (i.e., religion and risk reduction), and (c) impossible choices between one's own health and future children. Conclusions: Reproductive beliefs associated with LFS are distinct from other well-studied hereditary cancer syndromes. Families with LFS experience novel reproductive beliefs that may trigger moral distress. Reproductive LFS-tailored psychoeducational interventions and clinician awareness are needed. [ABSTRACT FROM AUTHOR]

Li-Fraumeni syndrome is caused by inherited TP53 tumor suppressor gene mutations. MicroRNA miR-34a is a p53 target and modifier gene. Interestingly, miR-34 triple-null mice exhibit normal p53 responses and no overt cancer development, but the lack of miR-34 promotes tumorigenesis in cancer-susceptible backgrounds. miR-34 genes are highly conserved and syntenic between zebrafish and humans. Zebrafish miR-34a and miR-34b/c have similar expression timing in development, but miR-34a is more abundant. DNA damage by camptothecin led to p53-dependent induction of miR-34 genes, while miR-34a mutants were adult-viable and had normal DNA damage-induced apoptosis. Nevertheless, miR-34a-/- compound mutants with a gain-of-function tp53R217H/ R217H or tp53-/- mutants were more cancer-prone than tp53 mutants alone, confirming the tumor-suppressive function of miR-34a. Through transcriptomic comparisons at 28 hours post-fertilization (hpf), we characterized DNA damage-induced transcription, and at 8, 28 and 72 hpf we determined potential miR-34a-regulated genes. At 72 hpf, loss of miR-34a enhanced erythrocyte levels and up-regulated myb-positive hematopoietic stem cells. Overexpression of miR-34a suppressed its reporter mRNA, but not p53 target induction, and sensitized injected embryos to camptothecin but not to γ-irradiation. Author summary: Li-Fraumeni syndrome, rooted in inherited mutations of the TP53 tumor suppressor gene, presents a complex interplay with microRNA34a (miR-34a), a known p53 target and modifier gene. Notably, miR-34 triple-null mice, despite exhibiting typical p53 responses and no evident cancer development, unveil a crucial role for miR-34 genes in suppressing tumorigenesis, particularly in predisposed conditions. The evolutionary conservation of miR-34 genes across zebrafish and humans underscores their significance. Studying zebrafish embryos reveals intriguing insights into miR-34a dynamics during development and its response to DNA damage, illuminating its involvement in cancer susceptibility. Additionally, experiments involving miR-34a mutants further confirm its tumor-suppressive function, especially when coupled with tp53 mutations. Transcriptomic analysis at different developmental stages uncover potential genes regulated by miR-34a, shedding light on its broader regulatory role. These findings enhance our understanding of the intricate mechanisms underlying cancer susceptibility and highlight miR-34a as a potential therapeutic target for Li-Fraumeni syndrome and related malignancies. [ABSTRACT FROM AUTHOR]

Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with a high, lifetime risk of a broad spectrum of cancers caused by pathogenic germline TP53 mutations. Numerous different germline TP53 mutations have been associated with LFS, which has an exceptionally diverse clinical spectrum in terms of tumor type and age of onset. Our patient has developed six asynchronous tumors to date: a phyllode tumor of the breast, a pheochromocytoma, a rosette-forming glioneuronal tumor (RGNT), an adrenocortical carcinoma (ACC), a ductal carcinoma of the breast, and a thymoma. The occurrence of such a number of rare tumors is sporadic even among in the population of patients living with cancer predisposition syndromes. In this instance, the omission of pretest genetic counseling and thorough family tree analysis prior to selecting the test led to the oversight of an underlying TP53 likely pathogenic mutation (classified as Class 4). This emphasizes the necessity for such counseling to prevent overlooking crucial genetic information. Neglecting this step could have had profound implications on the patient's treatment, particularly considering the early onset and occurrence of multiple tumors, which typically raise suspicion of a hereditary component. The implications for family members must be considered. [ABSTRACT FROM AUTHOR]

Introduction: In 1969, Li-Fraumeni syndrome (LFS), which is a rare cancer predisposition syndrome, was reported for the first time. The main problem in LFS is the mutation in the TP53 gene, which is a crucial tumor suppressor gene in the cell cycle. A hereditary syndrome is inherited in an autosomal dominant pattern. There is a significant correlation between this syndrome and various cancers such as sarcoma, breast cancer, brain tumors, and different other types of malignancies. This study aimed to identify the possibility of LFS in cancer patients in the East Azarbaijan, Iran. Methods: In this experimental study, 45 children with cancer in the Northwest of Iran were investigated for LFS. DNA was extracted from the whole blood cells using the salting-out method. The region within the exons 5-8 of the TP53 gene has been replicated via Polymerase Chain Reaction (PCR) method. The PCR products were sent for Sanger sequencing, and finally, the data were analyzed by Chromas software. Results: In the studied probands, in 12 (26.67%) cases, polymorphisms in Exon 6 and Introns 6 and Intron 7 were identified, and no mutation was observed in exons 5-8 of the TP53 gene. Conclusion: Our results show that there were no mutations in exons 5-8 of the TP53 gene as an indication of LFS possibility in these families. Further studies are needed to be done in a bigger population, and Next-Generation Sequencing (NGS) needs to be done to evaluate the whole genome of these patients to complete our data. [ABSTRACT FROM AUTHOR]

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Li–Fraumeni syndrome (LFS) is a hereditary disorder characterized by an increased risk of developing multiple early-onset cancers, primarily due to germline TP53 mutations. Women and men with this mutation face lifetime cancer risks of 90% and 70%, respectively. This report describes the first documented case of LFS with clinical information in Vietnam involving a 9-year-old child diagnosed with osteosarcoma who had multiple first- and second-degree relatives with cancer. Whole-genome sequencing (WGS) revealed a heterozygous, pathogenic, autosomal dominant TP53 variant NM_000546.6:c.733G>A (p.Gly245Ser) and a translocation in the 3’UTR of the ATMIN gene with unknown pathogenicity in both the patient and her mother. Sanger sequencing confirmed the presence of the TP53 c.733G>A mutation, which was subsequently detected in extended family members. Of the 17 family members invited for testing, only 8, none of whom currently have cancer, agreed to participate: all tested negative for the mutation. This case highlights the importance of genetic testing for the early detection and management of cancers in LFS patients. It also underscores significant barriers to genetic screening in Vietnam, including limited access and the psychosocial consequences of testing, which emphasize the need for improved genetic counseling and surveillance strategies that are tailored to local contexts.

The article discusses the use of genomic profiling in cancer treatment and its potential to identify germline genetic variants associated with an increased risk of cancer. The study focuses on TP53 mutations, which are found in more than half of all cancers and can cause Li-Fraumeni syndrome (LFS), a cancer predisposition syndrome. The authors report the results of their somatic sequencing pipeline, which detected germline TP53 variants in a cohort of pediatric cancer patients. The accurate diagnosis of LFS is crucial due to the significantly higher cancer risk it confers. The article also highlights the importance of understanding germline genetic susceptibility to cancer in pediatrics, as a significant percentage of children with cancer have an underlying cancer predisposition syndrome. The authors discuss the implications of genetic testing for families and the challenges associated with universal testing. They emphasize the need for genetic counseling and the involvement of children in the decision-making process. The article concludes by highlighting the potential of somatic-germline integrative genomics in pediatric oncology and the importance of further research in this field. [Extracted from the article]

Abstract Li-Fraumeni syndrome (LFS) is an autosomal dominant tumor predisposition syndrome caused by heterozygous germline mutations or deletions in the TP53 tumor suppressor gene. Central nervous system tumors, such as choroid plexus tumors, medulloblastomas, and diffuse gliomas, are frequently found in patients with LFS. Although molecular profiles of diffuse gliomas that develop in pediatric patients with LFS have been elucidated, those in adults are limited. Recently, diffuse gliomas have been divided into pediatric- and adult-type gliomas, based on their distinct molecular profiles. In the present study, we investigated the molecular profiles of high-grade gliomas in three adults with LFS. These tumors revealed characteristic histopathological findings of high-grade glioma or glioblastoma and harbored wild-type IDH1/2 according to whole exome sequencing (WES). However, these tumors did not exhibit the key molecular alterations of glioblastoma, IDH-wildtype such as TERT promoter mutation, EGFR amplification, or chromosome 7 gain and 10 loss. Although WES revealed no other characteristic gene mutations or copy number alterations in high-grade gliomas, such as those in histone H3 genes, PDGFRA amplification was found in all three cases together with uniparental disomy of chromosome 17p, where the TP53 gene is located. DNA methylation analyses revealed that all tumors exhibited DNA methylation profiles similar to those of pediatric-type high-grade glioma H3-wildtype and IDH-wildtype (pHGG H3-/IDH-wt), RTK1 subtype. These data suggest that high-grade gliomas developed in adult patients with LFS may be involved in pHGG H3-/IDH-wt. PDGFRA and homozygous alterations in TP53 may play pivotal roles in the development of this type of glioma in adult patients with LFS.

Abstract Background Li-Fraumeni syndrome (LFS) is a rare autosomal dominant disease caused by inherited or de novo germline pathogenic variants in TP53. Individuals with LFS have a 70–100% lifetime risk of developing cancer. The current standard of care involves annual surveillance with whole-body and brain MRI (WB-MRI) and clinical review; however, there are no chemoprevention agents licensed for individuals with LFS. Preclinical studies in LFS murine models show that the anti-diabetic drug metformin is chemopreventive and, in a pilot intervention trial, short-term use of metformin was well-tolerated in adults with LFS. However, metformin’s mechanism of anticancer activity in this context is unclear. Methods Metformin in adults with Li-Fraumeni syndrome (MILI) is a Precision-Prevention phase II open-labelled unblinded randomised clinical trial in which 224 adults aged ≥ 16 years with LFS are randomised 1:1 to oral metformin (up to 2 mg daily) plus annual MRI surveillance or annual MRI surveillance alone for up to 5 years. The primary endpoint is to compare cumulative cancer-free survival up to 5 years (60 months) from randomisation between the intervention (metformin) and control (no metformin) arms. Secondary endpoints include a comparison of cumulative tumour-free survival at 5 years, overall survival at 5 years and clinical characteristics of emerging cancers between trial arms. Safety, toxicity and acceptability of metformin; impact of metformin on quality of life; and impact of baseline lifestyle risk factors on cancer incidence will be assessed. Exploratory end-points will evaluate the mechanism of action of metformin as a cancer preventative, identify biomarkers of response or carcinogenesis and assess WB-MRI performance as a diagnostic tool for detecting cancers in participants with LFS by assessing yield and diagnostic accuracy of WB-MRI. Discussion Alongside a parallel MILI study being conducted by collaborators at the National Cancer Institute (NCI), MILI is the first prevention trial to be conducted in this high-risk group. The MILI study provides a unique opportunity to evaluate the efficacy of metformin as a chemopreventive alongside exploring its mechanism of anticancer action and the biological process of mutated P53-driven tumourigenesis. Trial registration ISRCTN16699730. Registered on 28 November 2022. URL: https://www.isrctn.com/ EudraCT/CTIS number 2022-000165-41.

Li-Fraumeni syndrome (LFS) is a rare autosomal dominant inherited genetic disorder that greatly increases the risk of developing several types of cancer, including young children and young adults. LFS is primarily caused by specific mutations in the tumor suppressor gene TP53. In this study, we successfully generated two human induced pluripotent stem cell (iPSC) lines derived from patients diagnosed with LFS, each carrying a distinct heterozygous mutation in the TP53 gene. These LFS patient-derived iPSC lines exhibited robust expression of key pluripotency markers, demonstrated the capacity to differentiate into all three germ layers (endoderm, mesoderm, and ectoderm), and maintained a normal karyotype. The establishment of these iPSC lines provides a valuable tool for modeling LFS in vitro, enabling researchers to investigate the underlying pathological mechanisms associated with the disease across various cell types and tissues.

Backgroud Li-Fraumeni syndrome is a hereditary tumor syndrome characterized by an elevated risk of malignancy, particularly acute lymphoblastic leukemia (ALL), which can be caused by the heterozygous germline mutation. TP53 gene germline mutation is considered a potential risk factor and crucial prognostic parameter for acute leukemia development and diagnosis, but rarely occurs in adults, and its specific pathogenic significance in acute leukemia is unclear.Case presentation We describes a case of a 45-year-old woman diagnosed with ALL. Whole-exome sequencing approach identified one of the TP53 germline mutations from her bone marrow sample with possible pathogenic significance, c.848G>A (p.Arg283His) heterozygous missense mutation located on exon 8, which was further verified in her hair, oral mucous and nail samples. Family pedigree screening revealed that the same TP53 genetic variant was present in the patient's father and non-donor son, whereas not in the donor. Digital PCR observed that this point mutation frequency dropped post-transplantation but remained low during maintenance therapy when the patient was leukemia-free.Conclusion This suspected Li-Fraumeni syndrome case report with a likely pathogenic heterozygous TP53 variant expands the cancer genetic spectrum. Screening her family members for mutations facilitates identifying the optimal relative donor and avoids unnecessary treatment by monitoring TP53 germline mutations for minimal residual disease following hematopoietic stem cell transplantation. Its potential roles in hematological malignant tumor development and clinical pathogenic implications necessitate further probing.

Li-Fraumeni syndrome (LFS) is an autosomal dominant tumor predisposition syndrome caused by heterozygous germline mutations or deletions in the TP53 tumor suppressor gene. Central nervous system tumors, such as choroid plexus tumors, medulloblastomas, and diffuse gliomas, are frequently found in patients with LFS. Although molecular profiles of diffuse gliomas that develop in pediatric patients with LFS have been elucidated, those in adults are limited. Recently, diffuse gliomas have been divided into pediatric- and adult-type gliomas, based on their distinct molecular profiles. In the present study, we investigated the molecular profiles of high-grade gliomas in three adults with LFS. These tumors revealed characteristic histopathological findings of high-grade glioma or glioblastoma and harbored wild-type IDH1/2 according to whole exome sequencing (WES). However, these tumors did not exhibit the key molecular alterations of glioblastoma, IDH-wildtype such as TERT promoter mutation, EGFR amplification, or chromosome 7 gain and 10 loss. Although WES revealed no other characteristic gene mutations or copy number alterations in high-grade gliomas, such as those in histone H3 genes, PDGFRA amplification was found in all three cases together with uniparental disomy of chromosome 17p, where the TP53 gene is located. DNA methylation analyses revealed that all tumors exhibited DNA methylation profiles similar to those of pediatric-type high-grade glioma H3-wildtype and IDH-wildtype (pHGG H3-/IDH-wt), RTK1 subtype. These data suggest that high-grade gliomas developed in adult patients with LFS may be involved in pHGG H3-/IDH-wt. PDGFRA and homozygous alterations in TP53 may play pivotal roles in the development of this type of glioma in adult patients with LFS. [ABSTRACT FROM AUTHOR]

Introduction: Medulloblastoma is the most common malignant brain tumor in children, often requiring intensive multimodal therapy, including chemotherapy with alkylating agents. However, therapy-related complications, such as therapyrelated myeloid neoplasms (t-MNs), can arise, particularly in patients with genetic predisposition syndromes. This case report presents three pediatric cases of medulloblastoma with subsequent development of t-MNs, highlighting the potential role of genetic predisposition and the importance of surveillance for hematological abnormalities in long-term survivors. Case presentation: We describe three cases of pediatric medulloblastoma who developed t-MNs after receiving chemotherapy, including alkylating agents. Two of the patients had underlying genetic predisposition syndromes (TP53 pathologic variants). The latency period between initial diagnosis of medulloblastoma and the development of secondary cancer varied among the cases, ranging from 17 to 65 months. The three cases eventually succumbed from secondary malignancy, therapy-related complications and progression of primary disease, respectively. Conclusions: This report highlights the potential association between genetic predisposition syndromes and the development of therapy-related myeloid neoplasms in pediatric medulloblastoma survivors. It underscores the importance of surveillance for hematological abnormalities among such patients. [ABSTRACT FROM AUTHOR]

Purpose: Individuals with cancer predisposition syndromes (CPS) inherit elevated cancer risks. Medical supply gaps for people at risk of CPS cause insufficient outreach and miss potential benefits of individualized care strategies. Increased awareness of CPS and progress in the eHealth sector are untapped sources of health care improvement for affected individuals. Methods and results: This study addressed German–speaking medical students with an online questionnaire in respect to their knowledge of CPS, their medical education, and perspectives. The study population (n = 404) reported interest in and knowledge of CPS, supported by a satisfactory and sustainable education for their prospective patient care. The next generation of doctors would implement eHealth to improve medical services. Skepticism about digitization was claimed by students. They were especially concerned about deterioration in the physician–patient relationship, data abuse, dependence on technology, and incorrect diagnoses. Conclusion: Due to increasing diagnosing of CPS and deeper knowledge, this topic is essential for the curriculum in medical schools. In particular, care providers need know-how on identifying patients at risk for a CPS, certain diagnostic and therapeutic steps, surveillance and prophylactic strategies to improve patients' outcomes. Education in medical school as well as implemented eHealth seems to have potential to meet this demand in an upcoming era of personalized medicine. What does this study add to the clinical work. Medical teaching on cancer predisposition syndromes should be expanded to improve knowledge and individualized and personalized healthcare. [ABSTRACT FROM AUTHOR]

Copyright of Pediatric Endocrinology, Diabetes & Metabolism is the property of Termedia Publishing House and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Adrenocortical carcinoma (ACC) and pheochromocytoma/paraganglioma (PPGL) are two rare types of adrenal gland malignancies. Regarding hereditary tumors, some patients with ACC are associated with with Li-Fraumeni syndrome (LFS), and those with PPGL with multiple endocrine neoplasia type 2. Recent studies have expanded this spectrum to include other types of hereditary tumors, such as Lynch syndrome or familial adenomatous polyposis. Individuals harboring germline TP53 pathogenic variants that cause LFS have heterogeneous phenotypes depending on the respective variant type. As an example, R337H variant found in Brazilian is known as low penetrant. While 50–80% of pediatric ACC patients harbored a LFS, such a strong causal relationship is not observed in adult patients, which suggests different pathophysiologies between the two populations. As for PPGL, because multiple driver genes, such as succinate dehydrogenase (SDH)-related genes, RET, NF1, and VHL have been identified, universal multi-gene germline panel testing is warranted as a comprehensive and cost-effective approach. PPGL pathogenesis is divided into three molecular pathways (pseudohypoxia, Wnt signaling, and kinase signaling), and this classification is expected to result in personalized medicine based on genomic profiles. It remains unknown whether clinical characteristics differ between cases derived from genetic predisposition syndromes and sporadic cases, or whether the surveillance strategy should be changed depending on the genetic background or whether it should be uniform. Close cooperation among medical genomics experts, endocrinologists, oncologists, and early investigators is indispensable for improving the clinical management for multifaceted ACC and PPGL. [ABSTRACT FROM AUTHOR]

Thyroid cancer is the most common endocrine malignancy, accounting for 1 % of all cancers 1. The genetic syndromes associated with differentiated thyroid cancers(DTC) are Cowden syndrome, Familial Adenomatous Polyposis(FAP), Carney's complex, Pendred syndrome and Werner syndrome2. The incidence of synchronous second primary tumors(SSPC) associated with oropharyngeal malignancies was 1 to 10 %3. The incidence of other malignancies other than the above syndromes occurring synchronously with DTC is very rare. Only a few case reports and series are available. The incidence of synchronous second primary cancer(SSPC) with Differentiated Thyroid Cancers(DTC) is a very rare entity. Very few case reports and case series were published in the literature. The current study is aimed to enumerate the clinicopathological data of patients with DTC with SSPC. This is a single-center retrospective study. All the patients diagnosed with DTC and SSPC from January 2016 to July 2023 were included in the study. The demographic, clinicopathological data and survival data were collected from the institute's database. Patients were followed up telephonically and survival status was documented. Synchronous cancers are defined as more than one independent primary malignancy when the second(or third) cancer occurs within six months of diagnosis of the first malignancy4. [Display omitted] A total of 1395 patients were diagnosed with thyroid cancer during the study period. Twelve patients were found to have DTC with SSPC. All the patients had papillary thyroid cancer as primary DTC. Ten patients had head and neck squamous cell carcinoma, one had malignant phyllodes tumor, and another patient with endometrioid adenocarcinoma as the SSPC. Six patients diagnosed during preoperative evaluation, one patient diagnosed 3 months after the oral malignancy diagnosis and five patients were diagnosed to have PTC in cervical nodes after neck dissection. Complete thyroid removal was done in six patients and hemithyroidectomy in two patients. Among the patients who underwent total thyroidectomy, four patients had undergone radioactive iodine scan followed by radioactive iodine ablation for two patients. Three patients had died during follow-up, two patients was lost to follow-up and the rest of the seven patients were alive. Out of those alive one patient had a follow-up of less than six months and was excluded from the survival calculation. The median follow up was 25.55 months. The median overall survival was 40.97 months. DTC constitute 95% of thyroid malignancies. Five to fifteen percent of DTC has familial disease. The genetic syndromes associated with DTC are FAP, PTEN syndromes(Cowden syndrome, Bannayan- Riley-Ruvalcaba syndrome, PTEN hamartoma tumor syndrome), Werner syndrome, Carney complex, DICER1 syndrome, Pendred syndrome, Ataxia telangiectasia, Li Fraumeni syndrome, and Peutz Jeghers syndrome5. But, synchronous occurrence of a second malignancy with DTC is a rare phenomenon. In the present study, the most common SSPC was SCC of the head and neck region(83.3%). 5 patients had incidental detection of thyroid cancer in cervical lymph nodes which were dissected during neck dissection done for other causes. L J Fliegelman et al published a paper on four cases of incidentally detected thyroid malignancy in cervical nodes6. Ansari-Lari et al also published cases of incidentally diagnosed PTC on cervical lymph nodes7. In the present study, one patient had synchronous papillary thyroid carcinoma with a malignant phyllodes tumor of the breast. No such case was found reported in the literature during our literature search. In the present study, we reported a case of synchronous endometrioid adenocarcinoma with PTC. Badan Marius-loan et al reported one case of PTC with endometrioid carcinoma8. Patients with Cowden syndrome can have thyroid carcinoma and endometrial carcinoma9. The overall survival of the study group was 40.97 months. Biopsy-proven SCC recurrence was seen in two patients out of four patients with clinically documented recurrence. In the literature review on case series and case reports, it was concluded that the prognosis of the patient depends on the staging of oral synchronous primary and the treatment of thyroid cancer must be decided based on oral malignancy staging and treatment. In conclusion SSPC with DTC is a very rare phenomenon. SCC of the head and neck region is the most common synchronous second primary malignancy associated with DTC. As there are no published guidelines for this clinical scenario, a multi-disciplinary panel discussion is a must to decide regarding management considering the staging and weighing the treatment benefit for both malignancies. [ABSTRACT FROM AUTHOR]

Purpose: This systematic review evaluated whole-body MRI (WB-MRI) as a cancer screening tool for individuals carrying germline TP53 mutations, a population known to be at a significantly elevated risk of malignancy. The primary objective is to assess the diagnostic performance of WB-MRI in detecting cancer in this cohort. Methods: PubMed, MEDLINE, EMBASE and the Cochrane Central Registry of Controlled Trials were searched until 18 August 2023. Eligible studies were selected based on predefined inclusion criteria. The data extracted included information on study characteristics, patient demographics, and the WB-MRI diagnostic performance. Results: This systematic review identified eight eligible studies, comprising 506 TP53 mutation carriers. The mean age was 34.6 ± 16.3 (range 1–74) years. In total, 321/506 (63.4%) of the patients were female and 185/506 (36.6%) were male. In addition, 267/506 (52.8%) had a previous oncological diagnosis. Thirty-six new cancers were diagnosed with WB-MRI (36/506 (7.1%)). The overall pooled proportion of cancer detected on MRI was 7% (95% confidence interval 5–10). In total, 44 new lesions were picked up, as multiple lesions were found in some patients. Conclusion: WB-MRI is an effective cancer screening tool for TP53 mutation carriers. While these findings suggest the potential for WB-MRI to contribute to early cancer detection in this high-risk population, further research and the standardisation of protocols internationally are warranted to optimise its clinical utility. [ABSTRACT FROM AUTHOR]