Pilot study of the prevalence of autoimmune disorders in Li-Fraumeni syndrome.
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ABSTRACT:
SUBMITTER: Obregon IH
PROVIDER: S-EPMC10277222 | biostudies-literature | 2023 Jul
REPOSITORIES: biostudies-literature
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Pilot study of the prevalence of autoimmune disorders in Li-Fraumeni syndrome.
Obregón Ixtaccihuatl H IH de Andrade Kelvin C KC Bremer Renee C RC Khincha Payal P PP Savage Sharon A SA
Familial cancer 20230111 3
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Project description:Li-Fraumeni syndrome (LFS) is a classic cancer predisposition disorder that is commonly associated with germline mutations of the p53 tumor suppressor gene. Examination of the wide spectrum of adult-onset and childhood cancers and the distribution of p53 mutations has led to a greater understanding of cancer genotype-phenotype correlations. However, the complex LFS phenotype is not readily explained by the simple identification of germline p53 mutations in affected individuals. Recent work has identified genetic events that modify the LFS phenotype. These include intragenic polymorphisms, mutations/polymorphisms of genes in the p53 regulatory pathway, as well as more global events such as aberrant copy number variation and telomere attrition. These genetic events may, in part, explain the breadth of tumor histiotypes within and across LFS families, the apparent accelerated age of onset within families, and the range of clinical outcomes among affected family members. This review will examine the clinical and genetic definitions of LFS and offer insight into how lessons learned from the study of this rare disorder may inform similar questions in other familial cancer syndromes.
| S-EPMC3135649 | biostudies-literature
Project description:BackgroundLi-Fraumeni syndrome (LFS) is a highly penetrant autosomal dominant cancer predisposition disorder caused by germline TP53 pathogenic variants. Patients with LFS have increased oxidative phosphorylation capacity in skeletal muscle and oxidative stress in blood. Metformin inhibits oxidative phosphorylation, reducing available energy for cancer cell proliferation and decreasing production of reactive oxygen species that cause DNA damage. Thus, metformin may provide pharmacologic risk reduction for cancer in patients with LFS, but its safety in nondiabetic patients with germline TP53 pathogenic variants has not been documented.MethodsThis study assessed safety and tolerability of metformin in nondiabetic LFS patients and measured changes in metabolic profiles. Adult patients with LFS and germline TP53 variant received 14 weeks of metformin. Blood samples were obtained for measurement of serum insulin-like growth factor-1, insulin, and insulin-like growth factor binding protein 3. Hepatic mitochondrial function was assessed with fasting exhaled CO2 after ingestion of 13C-labeled methionine. Changes in serum metabolome were measured. All statistical tests were 2-sided.ResultsWe enrolled 26 participants: 20 females and 6 males. The most common adverse events were diarrhea (50.0%) and nausea (46.2%). Lactic acidosis did not occur, and there were no changes in fasting glucose. Cumulative mean 13C exhalation was statistically significantly suppressed by metformin (P = .001). Mean levels of insulin-like growth factor binding protein 3 and insulin-like growth factor-1 were statistically significantly lowered (P = .02). Lipid metabolites and branched-chain amino acids accumulated.ConclusionsMetformin was safe and tolerable in patients with LFS. It suppressed hepatic mitochondrial function as expected in these individuals. This study adds to the rationale for development of a pharmacologic risk-reduction clinical trial of metformin in LFS.
| S-EPMC7746650 | biostudies-literature
Project description:Li-Fraumeni syndrome (LFS) is an autosomal dominant condition associated with a high risk of a broad range of childhood- and adult-onset cancers. LFS is related to germline mutations of the tumor-suppressor gene TP53 The most common reported leukemia associated with LFS is hypodiploid acute lymphoblastic leukemia, but myeloid malignancies including acute myeloid leukemia (AML), chronic myeloid leukemia, and myelodysplastic syndrome (MDS) are also reported, often in the setting of therapy-related disease. We reviewed the clinicopathologic characteristics including cytogenetics and molecular analysis for seven adult patients with LFS and hematologic malignancies evaluated at the Hereditary Hematologic Malignancy Clinic (HHMC) at MD Anderson Cancer Center. We present this LFS review series to increase awareness of LFS for the appropriate diagnosis of both patients and potentially affected relatives, as well as provide experience with patient outcomes in this difficult to treat population.
| S-EPMC6371746 | biostudies-literature
Project description:ImportanceEstablishment of an optimal cancer surveillance program is important to reduce cancer-related morbidity and mortality in individuals with Li-Fraumeni syndrome, a rare, highly penetrant cancer predisposition syndrome.ObjectiveTo determine the feasibility and efficacy of a comprehensive cancer screening regimen in Li-Fraumeni syndrome, using multiple radiologic techniques, including rapid whole-body magnetic resonance imaging (MRI) and laboratory measurements.Design, setting, and participantsBaseline evaluation of a prospective cancer screening study was conducted from June 1, 2012, to July 30, 2016, at the National Cancer Institute, National Institutes of Health (an academic research facility). Participants included 116 individuals with Li-Fraumeni syndrome with a germline TP53 pathogenic variant who were aged 3 years or older at the time of baseline screening and had not received active cancer therapy at least 6 months prior to screening.Main outcomes and measuresDetection of prevalent cancer with multimodal screening techniques and the need for additional evaluation.ResultsOf the 116 study participants, 77 (66.4%) were female; median age was 37.6 years (range, 3-68 years). Baseline cancer screening led to the diagnosis of cancer in 8 (6.9%) individuals (2 lung adenocarcinomas, 1 osteosarcoma, 1 sarcoma, 1 astrocytoma, 1 low-grade glioma, and 2 preinvasive breast cancers [ductal carcinoma in situ]); all but 1 required only resection for definitive treatment. A total of 40 (34.5%) participants required additional studies to further investigate abnormalities identified on screening, with 32 having incidental, benign, or normal findings, resulting in a false-positive rate of 29.6%. Non-MRI techniques, including baseline blood tests, abdominal ultrasonography in children, mammography, and colonoscopy, did not lead to a diagnosis of prevalent cancer in our cohort.Conclusions and relevanceThis study describes the establishment and feasibility of an intensive cancer surveillance protocol for individuals with Li-Fraumeni syndrome. Prevalent cancers were detected at an early stage with baseline whole-body, brain, and breast MRI. Prospective screening of the participants is under way.
| S-EPMC5824271 | biostudies-literature
Project description:There is growing evidence that alterations in metabolism may contribute to tumorigenesis. Here, we report on members of families with the Li-Fraumeni syndrome who carry germline mutations in TP53, the gene encoding the tumor-suppressor protein p53. As compared with family members who are not carriers and with healthy volunteers, family members with these mutations have increased oxidative phosphorylation of skeletal muscle. Basic experimental studies of tissue samples from patients with the Li-Fraumeni syndrome and a mouse model of the syndrome support this in vivo finding of increased mitochondrial function. These results suggest that p53 regulates bioenergetic homeostasis in humans. (Funded by the National Heart, Lung, and Blood Institute and the National Institutes of Health; ClinicalTrials.gov number, NCT00406445.).
| S-EPMC4123210 | biostudies-literature
Project description:Li-Fraumeni syndrome (LFS) is a highly penetrant, autosomal dominant, human familial cancer predisposition. Although a key role for the tumor suppressor p53 has been implicated in LFS, the genetic and cellular mechanisms underpinning this disease remain unknown. Therefore, modeling LFS in a vertebrate system that is accessible to both large-scale genetic screens and in vivo cell biological studies will facilitate the in vivo dissection of disease mechanisms, help identify candidate genes, and spur the discovery of therapeutic compounds. Here, we describe a forward genetic screen in zebrafish embryos that was used to identify LFS candidate genes, which yielded a p53 mutant (p53(I166T)) that as an adult develops tumors, predominantly sarcomas, with 100% penetrance. As in humans with LFS, tumors arise in heterozygotes and display loss of heterozygosity (LOH). This report of LOH indicates that Knudson's two-hit hypothesis, a hallmark of human autosomal dominant cancer syndromes, can be modeled in zebrafish. Furthermore, as with some LFS mutations, the zebrafish p53(I166T) allele is a loss-of-function allele with dominant-negative activity in vivo. Additionally, we demonstrate that the p53 regulatory pathway, including Mdm2 regulation, is evolutionarily conserved in zebrafish, providing a bona fide biological context in which to systematically uncover novel modifier genes and therapeutic agents for human LFS.
| S-EPMC2806900 | biostudies-literature
Project description:Li-Fraumeni syndrome (LFS) is a complex hereditary cancer predisposition disorder associated with early-onset cancers in diverse tissues of origin. Germline TP53 mutations are identified in 75% of patients with classic LFS. The lifetime likelihood of a TP53 mutation carrier developing cancer approaches 75% in males and almost 100% in females. Several genetic modifiers have been implicated to account for the phenotypic variability within and across LFS families; however, efforts to develop predictive algorithms of age of onset and type of cancers in individual patients have not yet found clinical use. Although it is not possible to prevent cancers from forming in LFS patients, novel protocols have been developed for surveillance for early tumor detection, leading to improvements in survival. Comprehensive studies of the genome and epigenome in LFS families in the context of germline TP53 mutations is anticipated to shed light on this intriguing, yet devastating, disease and to transform the clinical management of patients.
| S-EPMC5378014 | biostudies-literature
Project description:PurposeLi-Fraumeni syndrome (LFS) is a hereditary disorder caused by germline mutation in TP53. Owing to the rarity of LFS, data on its clinical features are limited. This study aimed to evaluate the clinical characteristics and prognosis of Korean patients with LFS.Materials and methodsPatients who underwent genetic counseling and confirmed with germline TP53 mutation in the National Cancer Center in Korea between 2011 and 2022 were retrospectively reviewed. Data on family history with pedigree, types of mutation, clinical features, and prognosis were collected.ResultsFourteen patients with LFS were included in this study. The median age at diagnosis of the first tumor was 32 years. Missense and nonsense mutations were observed in 13 and one patients, respectively. The repeated mutations were p.Arg273His, p.Ala138Val, and pPro190Leu. The sister with breast cancer harbored the same mutation of p.Ala138Val. Seven patients had multiple primary cancers. Breast cancer was most frequently observed, and other types of tumor included sarcoma, thyroid cancer, pancreatic cancer, brain tumor, adrenocortical carcinoma, ovarian cancer, endometrial cancer, colon cancer, vaginal cancer, skin cancer, and leukemia. The median follow-up period was 51.5 months. Two and four patients showed local recurrence and distant metastasis, respectively. Two patients died of leukemia and pancreatic cancer 3 and 23 months after diagnosis, respectively.ConclusionThis study provides information on different characteristics of patients with LFS, including types of mutation, types of cancer, and prognostic outcomes. For more appropriate management of these patients, proper genetic screening and multidisciplinary discussion are required.
| S-EPMC10789946 | biostudies-literature
Project description:PURPOSE:In the past 5 years, new screening protocols have been developed that provide improved cancer screening options for individuals with Li-Fraumeni syndrome (LFS). Very little has been published on the psychosocial impact of these screening protocols. The goals of this study were to determine how participation in screening impacts individuals psychosocially, to examine the benefits and drawbacks of screening, and to evaluate possible barriers to continued screening. METHODS:We performed a qualitative study consisting of semistructured phone interviews conducted from December 2015 to February 2016 with 20 individuals attending the LFS screening program at MD Anderson Cancer Center. RESULTS:Data analysis showed that benefits of screening include early detection, peace of mind, centralized screening, knowledge providing power, and screening making LFS seem more livable. Perceived drawbacks included logistical issues, difficulty navigating the system, screening being draining, and significant negative emotional reactions such as anxiety, fear, and skepticism. Regardless of the emotions that were present, 100% of participants planned on continuing screening in the program. CONCLUSION:Our data indicate that the perceived benefits of screening outweigh the drawbacks of screening. Individuals in this screening program appeared to have improved psychosocial well-being because of their access to the screening program.Genet Med advance online publication 16 March 2017.
| S-EPMC5875687 | biostudies-literature
Project description:Li-Fraumeni syndrome (LFS) is a hereditary tumor that exhibits autosomal dominant inheritance. LFS develops in individuals with a pathogenic germline variant of the cancer-suppressor gene, TP53 (individuals with TP53 pathogenic variant). The number of individuals with TP53 pathogenic variant among the general population is said to be 1 in 500 to 20,000. Meanwhile, it is found in 1.6% (median value, range of 0-6.7%) of patients with pediatric cancer and 0.2% of adult patients with cancer. LFS is diagnosed by the presence of germline TP53 pathogenic variants. However, patients can still be diagnosed with LFS even in the absence of a TP53 pathogenic variant if the familial history of cancers fit the classic LFS diagnostic criteria. It is recommended that TP53 genetic testing be promptly performed if LFS is suspected. Chompret criteria are widely used for the TP53 genetic test. However, as there are a certain number of cases of LFS that do not fit the criteria, if LFS is suspected, TP53 genetic testing should be performed regardless of the criteria. The probability of individuals with TP53 pathogenic variant developing cancer in their lifetime (penetrance) is 75% for men and almost 100% for women. The LFS core tumors (breast cancer, osteosarcoma, soft tissue sarcoma, brain tumor, and adrenocortical cancer) constitute the majority of cases; however, various types of cancers, such as hematological malignancy, epithelial cancer, and pediatric cancers, such as neuroblastoma, can also develop. Furthermore, approximately half of the cases develop simultaneous or metachronous multiple cancers. The types of TP53 pathogenic variants and factors that modify the functions of TP53 have an impact on the clinical presentation, although there are currently no definitive findings. There is currently no cancer preventive agent for individuals with TP53 pathogenic variant. Surgical treatments, such as risk-reducing bilateral mastectomy warrant further investigation. Theoretically, exposure to radiation could induce the onset of secondary cancer; therefore, imaging and treatments that use radiation should be avoided as much as possible. As a method to follow-up LFS, routine cancer surveillance comprising whole-body MRI scan, brain MRI scan, breast MRI scan, and abdominal ultrasonography (US) should be performed immediately after the diagnosis. However, the effectiveness of this surveillance is unknown, and there are problems, such as adverse events associated with a high rate of false positives, overdiagnosis, and sedation used during imaging as well as negative psychological impact. The detection rate of cancer through cancer surveillance is extremely high. Many cases are detected at an early stage, and treatments are low intensity; thus, cancer surveillance could contribute to an improvement in QOL, or at least, a reduction in complications associated with treatment. With the widespread use of genomic medicine, the diagnosis of LFS is unavoidable, and a comprehensive medical care system for LFS is necessary. Therefore, clinical trials that verify the feasibility and effectiveness of the program, comprising LFS registry, genetic counseling, and cancer surveillance, need to be prepared.
| S-EPMC8595164 | biostudies-literature