Case Report: Identification of a Novel Pathogenic Germline TP53 Variant in a Family With Li-Fraumeni Syndrome.
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SUBMITTER: Paduano F
PROVIDER: S-EPMC8440986 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Li-Fraumeni syndrome (LFS) is an inherited, autosomal-dominant condition that predisposes individuals to a wide-spectrum of tumors at an early age. Approximately 70% of families with classic LFS have pathogenic variants in the tumor suppressor gene TP53 that disrupt protein function or stability. While more than 70% of pathogenic variants in TP53 are missense variants, the vast majority occur very infrequently, and thus their clinical significance is uncertain or conflicting. Here, we report an extremely rare TP53 missense variant, c.799C?>?T (p.Arg267Trp), identified in a 2-year-old Saudi proband diagnosed with choroid plexus carcinoma (CPC) and six of his first- and second-degree relatives. CPC is frequently found in families with LFS, and this is the first detailed report of a family with this variant. Intriguingly, the proband's father is homozygous for TP53 c.799C?>?T and phenotypically normal at 39 years of age. While loss of TP53 heterozygosity is often observed in tumors from individuals with LFS, homozygous germline TP53 pathogenic variants are rare. Based on our analysis of this single family, we hypothesize that TP53 c.799C?>?T has low or variable penetrance for LFS, with predisposition to the development of CPC. The observations from this family have furthered our understanding of the phenotypic variability that may be caused by one variant of TP53, even in the same family, and suggest that other factors (genetic and/or environmental) may play a role in mechanism of disease manifestation in LFS.
| S-EPMC6300601 | biostudies-literature
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
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:IntroductionHeritable lung cancer may occur in the context of germline TP53 mutations (Li-Fraumeni syndrome). Limited cases of intrafamily tumor genomic characteristics have been reported.Main concerns important clinical findings primary diagnoses interventions outcomesA 40-year-old woman with no smoking history or known environmental exposure risk was incidentally found to have stage II (T2N1) NSCLC harboring an EGFR exon 19 p.Glu746_Ala750 deletion. Family history was notable for an identical twin sister with colorectal cancer (diagnosed at age 31 y) and a mother with stage I NSCLC harboring an EGFR exon 21 c.2573T>G (p.Leu858Arg) mutation (diagnosed at age 69 y). Genetic testing revealed a germline TP53 c.542G>A (p.Arg181His) mutation in the patient, her mother, and her sister, consistent with Li-Fraumeni syndrome. No germline EGFR mutations were detected.ConclusionShared germline TP53 mutations may be associated with distinct NSCLC somatic EGFR mutations within families with Li-Fraumeni syndrome. Further understanding of the association between genetic cancer syndromes and lung cancer risk may improve early lung cancer detection in populations not otherwise meeting screening eligibility.
| S-EPMC9304605 | biostudies-literature
Project description:Breast cancer is the most common tumor in women with Li-Fraumeni Syndrome (LFS), an inherited cancer syndrome associated with germline mutations in the TP53 tumor suppressor gene. Their lifetime breast cancer risk is 49% by age 60. Breast cancers in TP53 mutation carriers recently have more often been reported to be hormone receptor and HER-2 positive by immunohistochemistry and FISH in small series. We seek to complement the existing small literature with this report of a histopathologic analysis of breast cancers from women with documented LFS. Unstained slides and paraffin-embedded tumor blocks from breast cancers from 39 germline TP53 mutation carriers were assembled from investigators in the LFS consortium. Central histology review was performed on 93% of the specimens by a single breast pathologist from a major university hospital. Histology, grade, and hormone receptor status were assessed by immunohistochemistry; HER-2 status was defined by immunohistochemistry and/or FISH. The 43 tumors from 39 women comprise 32 invasive ductal carcinomas and 11 ductal carcinomas in situ (DCIS). No other histologies were observed. The median age at diagnosis was 32 years (range 22-46). Of the invasive cancers, 84% were positive for ER and/or PR; and 81% were high grade. Sixty three percent of invasive and 73% of in situ carcinomas were positive for Her2/neu (IHC 3+ or FISH amplified). Of the invasive tumors, 53% were positive for both ER and HER2+; other ER/PR/HER2 combinations were observed. The DCIS were positive for ER and HER2 in 27% of the cases. This report of the phenotype of breast cancers from women with LFS nearly doubles the literature on this topic. Most DCIS and invasive ductal carcinomas in LFS are hormone receptor positive and/or HER-2 positive. These findings suggest that modern treatments may result in improved outcomes for women with LFS-associated breast cancer.
| S-EPMC3709568 | biostudies-literature
Project description:Li-Fraumeni Syndrome (LFS), which is a rare dominantly inherited cancer predisposition syndrome, is associated with germline P53 mutations. Mutations of the tumor suppressor protein P53 are associated with more than 50% of human cancers; however, almost 30% of P53 mutations occur rarely and this has raised questions about their significance. It therefore appeared of particular interest that we identified a novel mutation in a patient suffering from breast cancer and fulfilling the diagnostic criteria of LFS. In this study, a patient with remarkable family history developed breast cancer and was diagnosed with LFS. By performing next-generation sequencing on the patient and subsequent verification by Sanger sequencing among other family members, a new germ-line P53 replication error, a trinucleotide repeat mutation in the coding region, was identified in two generations of this Li-Fraumeni family.
| S-EPMC5794730 | biostudies-literature
Project description:BackgroundLi-Fraumeni syndrome is a cancer predisposition syndrome caused by germline TP53 tumor suppressor gene mutations, with no previous association with pancreatic neuroendocrine tumors (PNETs). Here we present the first case of PNET associated with Li-Fraumeni syndrome.Case presentationThis is a 43-year-old female who underwent laparoscopic distal pancreatectomy at age 39 for a well-differentiated grade 2 cystic PNET. When the patient was 41 years old, her seven-year-old daughter was found to have an astrocytoma and a germline TP53 mutation. While undergoing surveillance with 68Gallium-DOTATATE positron emission tomography/computed tomography for her PNET, the patient was found to have a large choroid plexus papilloma in her right temporal lobe. She underwent genetic counseling and testing that identified a germline pathogenic variant in TP53, leading to the diagnosis of Li-Fraumeni syndrome. Her PNET had a hemizygous pathogenic TP53 mutation with loss of the wild-type alternate allele, consistent with loss of heterozygosity and the two-hit hypothesis. She was enrolled in a Li-Fraumeni syndrome protocol and continues surveillance screening with our service.ConclusionsThis is the first PNET reported in association with Li-Fraumeni syndrome. Pancreatic cancer risk is elevated in this syndrome, and our case highlights the need for vigilance in screening for pancreatic neoplasms in these patients.
| S-EPMC7106707 | biostudies-literature
Project description:BackgroundLi-Fraumeni syndrome (LFS) is a rare autosomal dominant cancer predisposition syndrome caused by germline TP53 gene mutations. It is characterized by high risk of early-onset cancer, and has been confirmed as associated with multiple tumors clinically. So pediatricians should be more alert to LFS in children with tumors. Choroid plexus carcinoma (CPC) is a rare, malignant tumor which account for less than 1% of all central nervous system (CNS) tumors. However, when such tumorigenesis occurs, it is important to be vigilant for the presence of LFS.Case presentationThe first patient is a 32-month-old boy admitted for convulsions and then was found intracranial space-occupying lesion. Underwent operation, he was diagnosis as choroid plexus carcinoma (WHO Grade III). After 5 months, his elder sister, a 13-year-old girl, was brought to emergency department for confusion and intermittent convulsions. Surgery was performed immediately after head CT examination found the lesion. The pathology result indicated glioblastoma. Because the siblings of the same family have successively suffered from malignant tumors, we performed genetic testing on this family. TP53 gene mutation occurred in both children of these two cases from their father, and their other brother was not spared either. So the two siblings both met the diagnostic criteria of LFS. Then they all received systematic anti-tumor therapy, and follow-up hitherto.ConclusionHere we reported a rare LFS case that two siblings were inherited the same TP53 germline mutations from their father. They suffered from choroid plexus carcinoma and glioblastoma and were finally diagnosed with LFS. In this LFS family, the primary tumors of the two children were both central nervous system tumors, which were not reported in the previous literature. It is suggested that clinicians should be alert to LFS related tumors, which is helpful for early diagnosis. Timely detection of TP53 gene is an important way for early diagnosis of LFS, especially in children with tumor. The incidence of secondary tumor in LFS patients is significantly higher, and other family members of the LFS patient also have an increased risk of suffering from the tumors. Therefore, early diagnosis and timely tumor surveillance can obtain better therapeutic effect and prognosis for both proband and their family.
| S-EPMC8711161 | biostudies-literature
Project description:BackgroundLi-Fraumeni is a rare autosomal dominant cancer predisposition syndrome. The basis is a germline mutation of TP53 gene which encodes tumor suppressor protein resulting in early onset of tumors, most often breast cancer, soft tissue sarcomas, brain tumors, adrenocortical carcinomas, and leukemia.Case reportWe present a case of a young woman with a positive family history for cancer diagnosed with malignant solitary fibrous tumor and luminal B-like invasive breast cancer. Breast cancer and sarcomas account for the majority of tumors associated with Li-Fraumeni syndrome, yet solitary fibrous tumor is a rare clinical entity with no established guidelines for treatment. Even though both primary tumors were successfully resected, the sarcoma relapsed in the form of lung metastases. The NGS analysis revealed single nucleotide variant (c.1101-1G>A) in TP53 gene, affecting the acceptor splice site at intron 10. Until now, only one case of this genetic variant has been documented with conflicting interpretations of pathogenicity.ConclusionsThe knowledge of TP53 mutation status is essential since the management of these patients requires different approach to avoid excessive toxicity due to the risk of developing secondary malignancy. Using the clinical criteria to screen for affected individuals facilitates appropriate early genetic counseling of patients and their families. Following the American College of Medical Genetics criteria, we believe that the reported single nucleotide variant (c.1101-1G>A) in TP53 gene should be considered pathogenic.
| S-EPMC8399826 | biostudies-literature
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