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A mutation in the POT1 gene is responsible for cardiac angiosarcoma in TP53-negative Li-Fraumeni-like families.

ABSTRACT: Cardiac angiosarcoma (CAS) is a rare malignant tumour whose genetic basis is unknown. Here we show, by whole-exome sequencing of a TP53-negative Li-Fraumeni-like (LFL) family including CAS cases, that a missense variant (p.R117C) in POT1 (protection of telomeres 1) gene is responsible for CAS. The same gene alteration is found in two other LFL families with CAS, supporting the causal effect of the identified mutation. We extend the analysis to TP53-negative LFL families with no CAS and find the same mutation in a breast AS family. The mutation is recently found once in 121,324 studied alleles in ExAC server but it is not described in any other database or found in 1,520 Spanish controls. In silico structural analysis suggests how the mutation disrupts POT1 structure. Functional and in vitro studies demonstrate that carriers of the mutation show reduced telomere-bound POT1 levels, abnormally long telomeres and increased telomere fragility.

SUBMITTER: Calvete O

PROVIDER: S-EPMC4598567 | biostudies-literature |

REPOSITORIES: biostudies-literature

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A MUTATION IN THE POT1 GENE IS RESPONSIBLE FOR CARDIAC ANGIOSARCOMA IN TP53-NEGATIVE LI-FRAUMENI-LIKE FAMILIES

Project description:Whole Exome sequencing of two patients with Cardiac angiosarcoma in Li-Fraumeni-like families discovers that a mutation in the pot1 gene is responsible for cardiac angiosarcoma in tp53-negative li-fraumeni-like families

2015-09-14 | E-MTAB-3858 | biostudies-arrayexpress

A MUTATION IN THE POT1 GENE IS RESPONSIBLE FOR CARDIAC ANGIOSARCOMA IN TP53-NEGATIVE LI-FRAUMENI-LIKE FAMILIES

Project description:A MUTATION IN THE POT1 GENE IS RESPONSIBLE FOR CARDIAC ANGIOSARCOMA IN TP53-NEGATIVE LI-FRAUMENI-LIKE FAMILIES

| PRJEB10670 | ENA

Estimating TP53 Mutation Carrier Probability in Families with Li-Fraumeni Syndrome Using LFSPRO.

Project description:Background: Li-Fraumeni syndrome (LFS) is associated with germline TP53 mutations and a very high lifetime cancer risk. Algorithms that assess a patient's risk of inherited cancer predisposition are often used in clinical counseling. The existing LFS criteria have limitations, suggesting the need for an advanced prediction tool to support clinical decision making for TP53 mutation testing and LFS management.Methods: Based on a Mendelian model, LFSPRO estimates TP53 mutation probability through the Elston-Stewart algorithm and consequently estimates future risk of cancer. With independent datasets of 1,353 tested individuals from 867 families, we evaluated the prediction performance of LFSPRO.Results: LFSPRO accurately predicted TP53 mutation carriers in a pediatric sarcoma cohort from MD Anderson Cancer Center in the United States, the observed to expected ratio (OE) = 1.35 (95% confidence interval, 0.99-1.80); area under the receiver operating characteristic curve (AUC) = 0.85 (0.75-0.93); a population-based sarcoma cohort from the International Sarcoma Kindred Study in Australia, OE = 1.62 (1.03-2.55); AUC = 0.67 (0.54-0.79); and the NCI LFS study cohort, OE = 1.28 (1.17-1.39); AUC = 0.82 (0.78-0.86). LFSPRO also showed higher sensitivity and specificity than the classic LFS and Chompret criteria. LFSPRO is freely available through the R packages LFSPRO and BayesMendel.Conclusions: LFSPRO shows good performance in predicting TP53 mutations in individuals and families in varied situations.Impact: LFSPRO is more broadly applicable than the current clinical criteria and may improve clinical management for individuals and families with LFS. Cancer Epidemiol Biomarkers Prev; 26(6); 837-44. ©2017 AACR.

| S-EPMC5457344 | biostudies-literature

The contribution of CHEK2 to the TP53-negative Li-Fraumeni phenotype.

Project description:BACKGROUND:CHEK2 has previously been excluded as a major cause of Li-Fraumeni syndrome (LFS). One particular CHEK2 germline mutation, c.1100delC, has been shown to be associated with elevated breast cancer risk. The prevalence of CHEK2*1100delC differs between populations and has been found to be relatively high in the Netherlands. The question remains nevertheless whether CHEK2 germline mutations contribute to the Li-Fraumeni phenotype. METHODS:We have screened 65 Dutch TP53-negative LFS/LFL candidate patients for CHEK2 germline mutations to determine their contribution to the LFS/LFL phenotype. RESULTS:We identified six index patients with a CHEK2 sequence variant, four with the c.1100delC variant and two sequence variants of unknown significance, p.Phe328Ser and c.1096-?_1629+?del. CONCLUSION:Our data show that CHEK2 is not a major LFS susceptibility gene in the Dutch population. However, CHEK2 might be a factor contributing to individual tumour development in TP53-negative cancer-prone families.

| S-EPMC2664322 | biostudies-literature

Germline TP53 Mutation and Clinical Characteristics of Korean Patients With Li-Fraumeni Syndrome.

Project description:BackgroundLittle is known of the mutation and tumor spectrum of Korean patients with Li-Fraumeni syndrome (LFS). Owing to the rarity of LFS, few cases have been reported in Korea thus far. This study aimed to retrospectively review the mutations and clinical characteristics of Korean patients with LFS.MethodsTP53 mutation was screened in 89 unrelated individuals at the Samsung Medical Center in Korea, from 2004 to 2015. Six additional mutation carriers were obtained from the literature.ResultsWe identified nine different mutations in 14 Korean patients (male to female ratio=0.3:1). Two such frameshift mutations (p.Pro98Leufs*25, p.Pro27Leufs*17) were novel. The recurrent mutations were located at codons 31 (n=2; p.Val31Ile), 175 (n=3; p.Arg175His), and 273 (n=4; p.Arg273His and p.Arg273Cys). The median age at the first tumor onset was 25 yr. Ten patients (71%) developed multiple primary tumors. A diverse spectrum of tumors was observed, including breast (n=6), osteosarcoma (n=4), brain (n=4), leukemia (n=2), stomach (n=2), thyroid (n=2), lung (n=2), skin (n=2), bladder (n=1), nasal cavity cancer (n=1), and adrenocortical carcinoma (n=1).ConclusionsThere was considerable heterogeneity in the TP53 mutations and tumor spectrum in Korean patients with LFS. Our results suggest shared and different LFS characteristics between Caucasian and Korean patients. This is the first report on the mutation spectrum and clinical characteristics from the largest series of Korean LFS patients.

| S-EPMC4940490 | biostudies-literature

Inherited TP53 Mutations and the Li-Fraumeni Syndrome.

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

Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li-Fraumeni syndrome cohort.

Project description:BACKGROUND:Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition syndrome characterized by a very high lifetime cancer risk and an early age at diagnosis of a wide cancer spectrum. Precise estimates for the risk of first and subsequent cancers are lacking. METHODS:The National Cancer Institute's Li-Fraumeni Syndrome Study includes families meeting the diagnostic criteria for LFS or Li-Fraumeni-like syndrome, and individuals with a germline TP53 mutation, choroid plexus carcinoma, adrenocortical carcinoma, or ?3 cancers. Herein, we estimated the cumulative risk and annual hazards for first and second cancers among TP53 mutation carriers (TP53 positive [TP53+]) using MATLAB statistical software. RESULTS:This study evaluated 286 TP53+ individuals from 107 families. The cumulative cancer incidence was 50% by age 31 years among TP53+ females and 46 years among males, and nearly 100% by age 70 years for both sexes. Cancer risk was highest after age 20 years for females, mostly due to breast cancer, whereas among males the risk was higher in childhood and later adulthood. Among females, the cumulative incidence rates by age 70 years for breast cancer, soft tissue sarcoma, brain cancer, and osteosarcoma were 54%, 15%, 6%, and 5%, respectively. Among males, the incidence rates were 22%, 19%, and 11%, respectively, for soft tissue sarcoma, brain cancer, and osteosarcoma. Approximately 49% of those with 1 cancer developed at least another cancer after a median of 10 years. The average age-specific risk of developing a second cancer was comparable to that of developing a first cancer. CONCLUSIONS:The cumulative cancer risk in TP53?+?individuals was very high and varied by sex, age, and cancer type. Additional work, including prospective risk estimates, is needed to better inform personalized risk management. Cancer 2016;122:3673-81. © 2016 American Cancer Society.

| S-EPMC5115949 | biostudies-literature

Identification of a novel germ-line mutation in the TP53 gene in a Mexican family with Li-Fraumeni syndrome.

Project description:BACKGROUND: Germ-line mutations of the TP53 gene are known to cause Li-Fraumeni syndrome, an autosomal, dominantly inherited, high-penetrance cancer-predisposition syndrome characterized by the occurrence of a variety of cancers, mainly soft tissue sarcomas, adrenocortical carcinoma, leukemia, breast cancer, and brain tumors. METHODS: Mutation analysis was based on Denaturing high performance liquid chromatography (DHPLC) screening of exons 2-11 of the TP53 gene, sequencing, and cloning of DNA obtained from peripheral blood lymphocytes. RESULTS: We report herein on Li Fraumeni syndrome in a family whose members are carriers of a novel TP53 gene mutation at exon 4. The mutation comprises an insertion/duplication of seven nucleotides affecting codon 110 and generating a new nucleotide sequence and a premature stop codon at position 150. With this mutation, the p53 protein that should be translated lacks the majority of the DNA binding domain. CONCLUSION: To our knowledge, this specific alteration has not been reported previously, but we believe it is the cause of the Li-Fraumeni syndrome in this family.

| S-EPMC2806269 | biostudies-literature

Genomic alterations associated with loss of heterozygosity for TP53 in Li-Fraumeni syndrome fibroblasts.

Project description:Studies of Li-Fraumeni syndrome fibroblasts heterozygous for germline TP53 mutations have shown that loss of heterozygosity (LOH) occurs during passaging and is associated with genomic instability, such as chromosomal aberrations and aneuploidy to investigate the genomic changes associated with LOH in Li-Fraumeni (LF) fibroblasts, we have analysed cell strains at increasing population doublings (PD) using Comparative Genomic Hybridization (CGH). We have looked at three groups of cell strains: LF mutation-carrying strains which showed LOH for TP53, LF mutation-carrying strains which did not show LOH, and strains from normal individuals. Using CGH, we have detected loss of distinct chromosomal regions associated with LOH in 4 out of 5 mutation-carrying strains. In particular we have found loss of chromosomal regions containing genes involved in cell cycle control or senescence, including loss of 9p and 17p in these strains. Other recurrent changes included loss of chromosomes 4q and 6q, regions shown to contain one or more tumour suppressor genes. No genomic alterations were detected at cumulative PD in the normal strains or in the LF mutation-carrying strains which did not show LOH for TP53. We have also analysed the three groups of strains for microsatellite instability and somatic TP53 mutations, and have found genetic alterations in only one strain.

| S-EPMC2374657 | biostudies-other

Frequency of Thyroid Carcinoma in Brazilian TP53 p.R337H Carriers With Li Fraumeni Syndrome.

Project description:ImportanceLi Fraumeni syndrome (LFS) is associated with a wide variety of tumors; nevertheless, thyroid carcinoma has not been evaluated in this syndrome. Due to the Brazilian founder mutation p.R337H, some tumors that have not been described in the classic LFS have been observed in a higher-than-expected prevalence in Brazil.ObjectiveTo determine the frequency of thyroid carcinoma in Brazilian carriers of a founder TP53 p.R337H mutation.Design, setting, and participantsWe reviewed medical records of patients with LFS with germline TP53 p.R337H mutation. For a better understanding of the correlation between thyroid carcinoma and LFS, tumor profile data of Brazilian carriers were analyzed. We included data from 193 patients with LFS with the TP53 p.R337H mutation from the database of the Department of Oncogenetics from the A.C. Camargo Cancer Center.Main outcomes and measuresThyroid tumors found in this population were reviewed with regard to age at diagnosis, sex, histologic subtype, and other tumors presented by these patients.ResultsOverall, 101 of 193 TP53 p.R337H mutation carriers with LFS from 58 families were cancer affected and, among them, thyroid carcinoma presented a prevalence of 10.9% (3 men and 8 women). The mean age at diagnosis was 44 years (median [SD], 43 [14.77] years). All the cases were histologically classified as papillary carcinomas, with 2 of them exhibiting follicular variant. The most common other cancers in the patients with thyroid carcinoma were breast cancer (5 patients) and soft-tissue sarcoma (2 patients).Conclusions and relevanceThyroid carcinoma may be associated with the Brazilian founder TP53 p.R337H mutation. Knowledge about this genotype/phenotype correlation is relevant to adjusting the LFS screening recommendations to these specific carriers.

| S-EPMC5824314 | biostudies-literature

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