Early Cancer Detection in Li-Fraumeni Syndrome with Cell-Free DNA.

People with Li-Fraumeni syndrome (LFS) harbor a germline pathogenic variant in the TP53 tumor suppressor gene, face a near 100% lifetime risk of cancer, and routinely undergo intensive surveillance protocols. Liquid biopsy has become an attractive tool for a range of clinical applications, including early cancer detection. Here, we provide a proof-of-principle for a multimodal liquid biopsy assay that integrates a targeted gene panel, shallow whole-genome, and cell-free methylated DNA immunoprecipitation sequencing for the early detection of cancer in a longitudinal cohort of 89 LFS patients. Multimodal analysis increased our detection rate in patients with an active cancer diagnosis over uni-modal analysis and was able to detect cancer-associated signal(s) in carriers prior to diagnosis with conventional screening (positive predictive value = 67.6%, negative predictive value = 96.5%). Although adoption of liquid biopsy into current surveillance will require further clinical validation, this study provides a framework for individuals with LFS. SIGNIFICANCE: By utilizing an integrated cell-free DNA approach, liquid biopsy shows earlier detection of cancer in patients with LFS compared with current clinical surveillance methods such as imaging. Liquid biopsy provides improved accessibility and sensitivity, complementing current clinical surveillance methods to provide better care for these patients. See related commentary by Latham et al., p. 23. This article is featured in Selected Articles from This Issue, p. 5.

Li-Fraumeni Syndrome-Associated Dimer-Forming Mutant p53 Promotes Transactivation-Independent Mitochondrial Cell Death.

Cancer-relevant mutations in the oligomerization domain (OD) of the p53 tumor suppressor protein, unlike those in the DNA binding domain, have not been well elucidated. Here, we characterized the germline OD mutant p53(A347D), which occurs in cancer-prone Li-Fraumeni syndrome (LFS) patients. Unlike wild-type p53, mutant p53(A347D) cannot form tetramers and exists as a hyperstable dimeric protein. Further, p53(A347D) cannot bind or transactivate the majority of canonical p53 target genes. Isogenic cell lines harboring either p53(A347D) or no p53 yield comparable tumorigenic properties, yet p53(A347D) displays remarkable neomorphic activities. Cells bearing p53(A347D) possess a distinct transcriptional profile and undergo metabolic reprogramming. Further, p53(A347D) induces striking mitochondrial network aberration and associates with mitochondria to drive apoptotic cell death upon topoisomerase II inhibition in the absence of transcription. Thus, dimer-forming p53 demonstrates both loss-of-function (LOF) and gain-of-function (GOF) properties compared with the wild-type form of the protein. SIGNIFICANCE: A mutant p53 (A347D), which can only form dimers, is associated with increased cancer susceptibility in LFS individuals. We found that this mutant wields a double-edged sword, driving tumorigenesis through LOF while gaining enhanced apoptogenic activity as a new GOF, thereby yielding a potential vulnerability to select therapeutic approaches. See related commentary by Stieg et al., p. 1046. See related article by Gencel-Augusto et al., p. 1230. This article is highlighted in the In This Issue feature, p. 1027.

Germline TP53 pathogenic variants and breast cancer: A narrative review.

Approximately 10% of breast cancers are associated with the inheritance of a pathogenic variant (PV) in one of the breast cancer susceptibility genes. Multiple breast cancer predisposing genes, including TP53, are responsible for the increased breast cancer risk. Tumor protein-53 (TP53) germline PVs are associated with Li-Fraumeni syndrome, a rare autosomal dominant inherited cancer predisposition syndrome associated with early-onset pediatric and multiple primary cancers such as soft tissue and bone sarcomas, breast cancer, brain tumors, adrenocortical carcinomas and leukemias. Women harboring a TP53 PV carry a lifetime risk of developing breast cancer of 80-90%. The aim of the present narrative review is to provide a comprehensive overview of the criteria for offering TP53 testing, prevalence of TP53 carriers among patients with breast cancer, and what is known about its prognostic and therapeutic implications. A summary of the current indications of secondary cancer surveillance and survivorship issues are also provided. Finally, the spectrum of TP53 alteration and testing is discussed. The optimal strategies for the treatment of breast cancer in patients harboring TP53 PVs poses certain challenges. Current guidelines favor the option of performing mastectomy rather than lumpectomy to avoid adjuvant radiotherapy and subsequent risk of radiation-induced second primary malignancies, with careful consideration of radiation when indicated post-mastectomy. Some studies suggest that patients with breast cancer and germline TP53 PV might have worse survival outcomes compared to patients with breast cancer and wild type germline TP53 status. Annual breast magnetic resonance imaging (MRI) and whole-body MRI are recommended as secondary prevention.

Surveillance imaging and early surgical intervention for improved CNS tumor outcomes in children with Li-Fraumeni syndrome: Children's National Hospital experience and literature review.

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).

TP53 Variant in the Blood of a Patient with Gastric Cancer Undergoing Tumor Profiling Tests Diagnosed as Clonal Hematopoiesis.

BACKGROUND Clonal hematopoiesis is the production of a specific single clonal type of cell in the blood and is often found in cancer genomic profiling tests. When the clone carries a pathogenic variant, it may be important to differentiate between somatic or germline origin. The variant in the blood that has a lower minor allele frequency could reflect heterozygous germline origin, somatic mosaicism, and clonal hematopoiesis. It is important to evaluate suspected variants to determine the course of treatment and follow-up of the patient, depending on the patient's medical condition and family situation. CASE REPORT We report a 53-year-old Japanese man with gastric cancer who underwent a cancer genomic profiling test searching for therapeutic agents. The profiling test detected a variant, TP53 c.559+2T>G minor allele frequencies of 9% (168/1865) in tumor tissue and 29.1% (58/199) in paired blood. Since the TP53 variant has the possibility of Li-Fraumeni syndrome, ancillary testing was performed using fingernails, buccal swab, and blood specimens. The genomic analysis revealed no TP53 variant in his fingernails. The patient had previously received platinum-based chemotherapies, suggesting that the variant reflected treatment-induced clonal hematopoiesis. CONCLUSIONS Identifying clonal hematopoiesis when performing genomic profiling tests for patients with cancer is important. Examining multiple tissues to determine whether a variant arises from clonal hematopoiesis or is of germline origin can provide more accurate genetic information and improve patient follow-up care.

p53 mutants G245S and R337H associated with the Li-Fraumeni syndrome regulate distinct metabolic pathways.

Li-Fraumeni and Li-Fraumeni-like syndromes (LFS/LFL) are hereditary cancer predisposition disorders associated with germline mutations in the TP53 tumor suppressor gene. Here, we stably expressed LFS/LFL-associated p53 mutants R337H and G245S in p53-null H1299 cells to study their cellular and molecular effects. Mutant proteins showed distinct oligomerization states and opposing effects on cell proliferation and viability. Stable expression of p53G245S enhanced cell proliferation and spheroid formation, while cells stably expressing p53R337H showed reduced proliferation and clonogenicity, along with increased cell death. Mass spectrometry analysis revealed that proteins whose expression was induced by p53R337H or p53G245S expression were related to distinct metabolic profiles. Proteins upregulated by p53G245S expression were associated with a Warburg phenotype, while proteins upregulated by p53R337H expression were related to oxidative phosphorylation and fatty acid oxidation. Differences in mitochondrial mass and activity between cells stably expressing p53R337H or p53G245S were further corroborated by High Resolution Respirometry, flow cytometry and qPCR assays. The implications of the different oncogenic properties of p53R337H and p53G245S on the clinical manifestation and treatment of LFS/LFL patients carrying these mutations are discussed.

Inherited TP53 Variants and Risk of Prostate Cancer.

BACKGROUND: Inherited germline TP53 pathogenic and likely pathogenic variants (gTP53) cause autosomal dominant multicancer predisposition including Li-Fraumeni syndrome (LFS). However, there is no known association of prostate cancer with gTP53. OBJECTIVE: To determine whether gTP53 predisposes to prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: This multi-institutional retrospective study characterizes prostate cancer incidence in a cohort of LFS males and gTP53 prevalence in a prostate cancer cohort. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We evaluated the spectrum of gTP53 variants and clinical features associated with prostate cancer. RESULTS AND LIMITATIONS: We identified 31 prostate cancer cases among 163 adult LFS males, including 26 of 54 aged ≥50 yr. Among 117 LFS males without prostate cancer at the time of genetic testing, six were diagnosed with prostate cancer over a median (interquartile range [IQR]) of 3.0 (1.3-7.2) yr of follow-up, a 25-fold increased risk (95% confidence interval [CI] 9.2-55; p < 0.0001). We identified gTP53 in 38 of 6850 males (0.6%) in the prostate cancer cohort, a relative risk 9.1-fold higher than that of population controls (95% CI 6.2-14; p < 0.0001; gnomAD). We observed hotspots at the sites of attenuated variants not associated with classic LFS. Two-thirds of available gTP53 prostate tumors had somatic inactivation of the second TP53 allele. Among gTP53 prostate cancer cases in this study, the median age at diagnosis was 56 (IQR: 51-62) yr, 44% had Gleason ≥8 tumors, and 29% had advanced disease at diagnosis. CONCLUSIONS: Complementary analyses of prostate cancer incidence in LFS males and gTP53 prevalence in prostate cancer cohorts suggest that gTP53 predisposes to aggressive prostate cancer. Prostate cancer should be considered as part of LFS screening protocols and TP53 considered in germline prostate cancer susceptibility testing. PATIENT SUMMARY: Inherited pathogenic variants in the TP53 gene are likely to predispose men to aggressive prostate cancer.

A Functional Precision Medicine Pipeline Combines Comparative Transcriptomics and Tumor Organoid Modeling to Identify Bespoke Treatment Strategies for Glioblastoma.

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.

Cancer incidence, patterns, and genotype-phenotype associations in individuals with pathogenic or likely pathogenic germline TP53 variants: an observational cohort study.

BACKGROUND: Li-Fraumeni syndrome, caused primarily by pathogenic or likely pathogenic germline TP53 variants, is a rare, variably penetrant, cancer predisposition syndrome with very high risks of cancer starting in childhood, including the risk of multiple primary malignancies over an individual's lifespan. We aimed to characterise and quantify cancer incidence, patterns, and genotype-phenotype associations in individuals with pathogenic or likely pathogenic germline TP53 variants. METHODS: This observational cohort study was done in 480 carriers of pathogenic or likely pathogenic germline TP53 variants enrolled in the National Cancer Institute's referral-based longitudinal Li-Fraumeni syndrome study between Aug 1, 2011, and March 24, 2020. Data on personal and family history of cancer were obtained through study questionnaires and validated by medical records. Variants were categorised on the basis of both loss-of-function (LOF) and dominant-negative effect (DNE) properties. Cancer incidence associated with Li-Fraumeni syndrome was compared with that of the general population using the Surveillance, Epidemiology, and End Results (SEER) 1975-2017 registry. Cancer incidence was evaluated with family-clustered Cox regression models and competing risk methods. This study is registered with ClinicalTrials.gov, NCT01443468. FINDINGS: Individuals with Li-Fraumeni syndrome had a nearly 24 times higher incidence of any cancer than the general population (standardised incidence ratio 23·9; 95% CI 21·9-26·0), with the highest comparative incidence from childhood to 30 years of age. The overall cancer incidence remained 10·3 (95% CI 7·9-13·2) times higher than that of the general population after age 50 years. In women, when considering breast cancer as a competing risk, the probability of a first diagnosis of a non-breast cancer malignancy was substantially lower than that of any first cancer (24·4% [95% CI 19·6-30·5] vs 50·4% [43·5-56·5] by age 33·7 years). Overall, DNE_LOF and notDNE_LOF variants were associated with earlier age at first and second cancer compared with notDNE_notLOF and DNE_notLOF variants. The time interval from first to second cancer was shorter among carriers whose first cancer diagnoses were later in life. Multiple cancers were diagnosed within a short timeframe in some individuals, regardless of the order of cancer occurrence. INTERPRETATION: This study adds granularity to the understanding of cancer incidence and patterns in individuals with pathogenic or likely pathogenic germline TP53 variants. Integration of age range-specific cancer incidence estimates, cancer-free survival by functional variant group, the potential impact of risk-reducing mastectomy on female cancer incidence, and data on subsequent malignancies will be important for the development of strategies to optimise cancer screening and management for these individuals. FUNDING: Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Institutes of Health.

Clinical and molecular characterization of patients fulfilling Chompret criteria for Li-Fraumeni syndrome in Southern Brazil.

Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition syndrome caused by pathogenic germline variants in the TP53 gene, characterized by a predisposition to the development of a broad spectrum of tumors at an early age. The core tumors related to LFS are bone and soft tissue sarcomas, premenopausal breast cancer, brain tumors, adrenocortical carcinomas (ACC), and leukemias. The revised Chompret criteria has been widely used to establish clinical suspicion and support TP53 germline variant testing and LFS diagnosis. Information on TP53 germline pathogenic variant (PV) prevalence when using Chompret criteria in South America and especially in Brazil is scarce. Therefore, the aim of this study was to characterize patients that fulfilled these specific criteria in southern Brazil, a region known for its high population frequency of a founder TP53 variant c.1010G>A (p.Arg337His), as known as R337H. TP53 germline testing of 191 cancer-affected and independent probands with LFS phenotype identified a heterozygous pathogenic/likely pathogenic variant in 26 (13.6%) probands, both in the DNA binding domain (group A) and in the oligomerization domain (group B) of the gene. Of the 26 carriers, 18 (69.23%) were R337H heterozygotes. Median age at diagnosis of the first tumor in groups A and B differed significantly in this cohort: 22 and 2 years, respectively (P = 0.009). The present study shows the clinical heterogeneity of LFS, highlights particularities of the R337H variant and underscores the need for larger collaborative studies to better define LFS prevalence, clinical spectrum and penetrance of different germline TP53 pathogenic variants.

A Novel Germline TP53 Mutation in a Patient With Li-Fraumeni Syndrome: Resolving a Variant of Uncertain Significance.

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.

Reducing Fatty Acid Oxidation Improves Cancer-free Survival in a Mouse Model of Li-Fraumeni Syndrome.

Germline mutations of TP53, which cause the cancer predisposition disorder Li-Fraumeni syndrome (LFS), can increase mitochondrial activity as well as fatty acid ß-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 (p53172H/H , homolog of the human TP53 R175H LFS mutation) with myoglobin-knockout (MB-/- ) mice known to have decreased FAO. MB-/- p53172H/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 p53172H/H mice using a Cre-loxP-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.

Histopathologic features of breast cancer in Li-Fraumeni syndrome.

Breast cancer is the most common malignancy in female patients with Li-Fraumeni syndrome (LFS), a rare autosomal dominant hereditary syndrome characterized by germline TP53 mutations. Recent studies have shown that the majority of these tumors are estrogen receptor (ER) positive with frequent HER2 co-expression. However, the morphologic features of these tumors have not been as well studied as other germline-associated breast cancers. We evaluated the pathologic features of 27 invasive and in situ carcinomas from patients with known germline TP53 mutations collected through the Li-Fraumeni Consortium. Overall, 60% of cases were HER2 positive and 44% showed ER co-expression. Most DCIS was high nuclear grade with central necrosis and associated periductal fibrosis and lymphocytic response. Invasive carcinomas were mostly of ductal type (NOS), modified Scarff-Bloom-Richardson (mSBR) high grade, with marked nuclear atypia and high mitotic rate. Prominent tumor infiltrating lymphocytes, syncytial growth pattern, or pushing borders were not seen in these tumors. High p53 IHC expression was seen in tumors from individuals with germline TP53 missense mutations whereas little or no protein expression (<1% nuclear expression, null pattern) was seen in tumors from carriers of non-missense mutations. In this study, we report in detail the morphologic features of invasive and in situ carcinomas in LFS. We found that these tumors share features with cancers harboring somatic TP53 mutations but are distinct from BRCA-associated breast cancers.

Genotype-phenotype correlations among TP53 carriers: Literature review and analysis of probands undergoing multi-gene panel testing and single-gene testing.

Pathogenic germline variants in the TP53 gene predispose to a wide range of cancers, known collectively as Li-Fraumeni syndrome (LFS). There has been much research aimed to identify genotype-phenotype correlations, that is, differences between variant location and/or effect and cancer spectrum. These correlations, should they exist, have potential to impact clinical management of carriers. Review of previously published studies showed a variety of study designs and inconsistency in reported findings. Here, we used pooled data from 427 TP53 carriers who had undergone multigene panel testing and 154 TP53 carriers identified by single-gene testing to investigate correlations between TP53 genotype (truncating variants, hotspot variants, other missense variants with dominant-negative effect, missense variants without dominant-negative effect) and a number of LFS-selected malignancies. Our results suggest that carriers of truncating and hotspot variants might be more likely to present with LFS cancers and have shorter time to first cancer diagnosis compared to carriers of other variant types. However, the differences observed were minor, and we conclude that there is currently insufficient evidence to consider location and/or molecular effect of pathogenic variants to assist with clinical management of TP53 carriers. Larger studies are necessary to confirm the correlations suggested by our analysis.

Mutant p53 induces Golgi tubulo-vesiculation driving a prometastatic secretome.

TP53 missense mutations leading to the expression of mutant p53 oncoproteins are frequent driver events during tumorigenesis. p53 mutants promote tumor growth, metastasis and chemoresistance by affecting fundamental cellular pathways and functions. Here, we demonstrate that p53 mutants modify structure and function of the Golgi apparatus, culminating in the increased release of a pro-malignant secretome by tumor cells and primary fibroblasts from patients with Li-Fraumeni cancer predisposition syndrome. Mechanistically, interacting with the hypoxia responsive factor HIF1α, mutant p53 induces the expression of miR-30d, which in turn causes tubulo-vesiculation of the Golgi apparatus, leading to enhanced vesicular trafficking and secretion. The mut-p53/HIF1α/miR-30d axis potentiates the release of soluble factors and the deposition and remodeling of the ECM, affecting mechano-signaling and stromal cells activation within the tumor microenvironment, thereby enhancing tumor growth and metastatic colonization.

Cancer surveillance and distress among adult pathogenic TP53 germline variant carriers in Germany: A multicenter feasibility and acceptance survey.

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.

Cutaneous pleomorphic fibromas arising in patients with germline TP53 mutations.

Pleomorphic fibromas are rare benign cutaneous neoplasms associated with deletion/loss of chromosomes 13q and 17p, where RB1 and TP53 are located, respectively. Herein, we report five cases of pleomorphic fibroma arising in patients with germline TP53 mutations, suggesting a potential link with Li-Fraumeni syndrome. All three patients were female and young (mean age 27) with a strong personal and/or family oncologic history and confirmed pathogenic germline TP53 mutations. In two patients, multiple pleomorphic fibromas were diagnosed. Clinically, the lesions arose at various cutaneous sites and were small (≤2 cm) and raised (4/5). Histopathologically, the tumors were paucicellular, composed of atypical spindled to stellate cells with hyperchromatic and variably pleomorphic nuclei. Mitotic activity was exceedingly low, although rare atypical mitotic figures were seen in one case. Immunohistochemically, the tumor cells were diffusely positive for p16 (3/3) and showed loss of Rb expression (5/5). All cases showed aberrant p53 expression (overexpression in 4, complete loss in 1). The tumors have followed a benign clinical course with no evidence of progression or recurrence. In conclusion, the development of multiple pleomorphic fibromas in a young patient may be a clue to an underlying genetic cancer syndrome involving TP53.

[Hereditary predisposition to tumors of the central and peripheral nervous systems]. / Prédisposition héréditaire aux tumeurs des systèmes nerveux central et périphérique.

Some tumors of the central and peripheral nervous system may be associated with a cancer predisposition syndrome, either hereditary or occurring de novo. Such a syndrome is usually associated with multiple tumors occurring early in life. Patients with neurofibromatosis type 1 present with multiple neurofibromas, especially of the plexiform type (which may transform into malignant peripheral nerve sheath tumor), and pilocytic astrocytomas of the optic pathways. Neurofibromatosis type 2 patients present with multiple schwannomas (typically bilateral vestibular schwannomas), meningiomas, and ependymomas. Li-Fraumeni syndrome (germline TP53 mutation) is associated with choroid plexus tumors (carcinomas), medulloblastomas, and diffuse astrocytomas. Multiple hemangioblastomas are characteristic of von Hippel-Lindau syndrome while subependymal giant cell astrocytomas are pathognomonic of tuberous sclerosis complex. Dysplastic cerebellar gangliocytomas of adult patients occur in Cowden syndrome. Turcot syndrome overlaps with constitutional mismatch repair deficiency syndrome (CMMRD), which is associated with giant cell glioblastomas. Rhabdoid tumor predisposition syndrome (germline mutation of SMARCB1/INI1) is associated with atypical teratoid/rhabdoid tumors. Tumors arising in the setting of a cancer predisposition syndrome develop along specific genetic pathways. Some histopathological and immunohistochemical characteristics of these tumors may point toward such a syndrome. The diagnosis of a cancer predisposition syndrome is of tremendous importance to the patients and their families who require genetic counseling and long-term follow-up.