bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2024–07–28
five papers selected by
Joanna Zawacka, Karolinska Institutet
  1. TP53 p.R337H Germline Variant among Women at Risk of Hereditary Breast Cancer in a Public Health System of Midwest Brazil.
  2. Germline variants in patients diagnosed with pediatric soft tissue sarcoma.
  3. Functional evaluation of germline TP53 variants identified in Brazilian families at-risk for Li-Fraumeni syndrome.
  4. Pancreatic cancer screening is effective in individuals at risk with predisposing germline gene variants, but not in gene variant-negative familial pancreatic cancer families.
  5. The CRISPR-Cas System and Clinical Applications of CRISPR-Based Gene Editing in Hematology with a Focus on Inherited Germline Predisposition to Hematologic Malignancies.
  1. Genes (Basel). 2024 Jul 16. pii: 928. [Epub ahead of print]15(7):
    TP53 p.R337H Germline Variant among Women at Risk of Hereditary Breast Cancer in a Public Health System of Midwest Brazil.
    Tatiana Strava Corrêa, Paula Fontes Asprino, Eduarda Sabá Cordeiro de Oliveira, Ana Carolina Rathsam Leite, Luiza Weis, Maria Isabel Achatz, Claudiner Pereira de Oliveira, Renata Lazari Sandoval, Romualdo Barroso-Sousa.
      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.
    Keywords:  Li–Fraumeni syndrome; TP53 p.R337H; breast cancer; hereditary cancer
    DOI:  https://doi.org/10.3390/genes15070928
  2. Acta Oncol. 2024 Jul 22. 63 586-591
    Germline variants in patients diagnosed with pediatric soft tissue sarcoma.
    Synnøve Yndestad, Hans Kristian Haugland, Dorota Goplen, Dorota Wojcik, Stian Knappskog, Per Eystein Lønning.
       BACKGROUND: While soft tissue sarcomas affect younger patients, few studies have assessed the distribution of underlying pathogenic germline variants.
    PATIENTS AND METHODS: We retrospectively identified all pediatric and young adult patients (0-22 years) at Haukeland University Hospital, Norway (1981-2019), through clinical and pathological records. We identified n = 46 eligible patients. From these 46 patients, adequate material representing normal tissue was available for n = 41 cases (n = 24 diagnosed with rhabdomyosarcoma, 9 with synovial sarcomas, 2 with Ewing sarcomas, and 6 without further classification), with matching tumor tissue for n = 40. Normal tissue samples were analyzed for germline pathogenic variants (PVs) by targeted sequencing of 360 cancer genes.
    RESULTS: Out of the 41 analyzed cases, we found PVs or likely PVs in 7 (17%). These variants were found in TP53, MUTYH, FANCC, DICER1, FANCA, MYO3A, and MYO5B. Supporting the causality of these PVs, four cases revealed loss of heterozygosity (LOH) of the wild-type allele in the tumor tissue, one patient with a PV in DICER1 had a second somatic variant in DICER1, and a patient with a PV in TP53 had the altered allele amplified in the tumor. For three out of five with available family history, a history of other cancers in relatives was recorded. Among genes with variants of uncertain significance, CHD1L was of particular interest, revealing a stop-gain and a missense variant.
    INTERPRETATION: A high fraction of young patients with soft tissue sarcoma harbor PVs. Among the genes affected, we substantiate a potential role of MYO5B and propose a potential role for MYO3A.
    DOI:  https://doi.org/10.2340/1651-226X.2024.40730
  3. Sci Rep. 2024 Jul 26. 14(1): 17187
    Functional evaluation of germline TP53 variants identified in Brazilian families at-risk for Li-Fraumeni syndrome.
    Renata B V Abreu, Ariane S Pereira, Marcela N Rosa, Patricia Ashton-Prolla, Viviane A O Silva, Matias E Melendez, Edenir I Palmero.
      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.
    Keywords:   TP53 ; DNA repair; Functional analysis; Li–Fraumeni syndrome; Transcription factor; Variants of uncertain significance
    DOI:  https://doi.org/10.1038/s41598-024-67810-3
  4. United European Gastroenterol J. 2024 Jul 19.
    Pancreatic cancer screening is effective in individuals at risk with predisposing germline gene variants, but not in gene variant-negative familial pancreatic cancer families.
    Elisabeth Maurer, Bettina Lehman, Elvira Matthäi, Ulrike Denzer, Jens Figiel, Moritz Jesinghaus, Emily P Slater, Ulrich Stefenelli, Thomas M Gress, Detlef K Bartsch.
       OBJECTIVE: To evaluate the diagnostic yield of pancreatic cancer screening in individuals at risk (IAR) from familial pancreatic cancer (FPC) families with respect to the presence or absence of pathogenic germline variants predisposing to pancreatic adenocarcinoma (PDAC).
    DESIGN: In a 20 years period, IAR from FPC families were enrolled in a prospective screening program of the national case collection for FPC of Germany, including magnet resonance imaging (MRI) and endoscopic ultrasound (EUS). The diagnostic yield was analyzed regarding significant pancreatic lesions such as PDAC, high-grade pancreatic-intraepithelial-neoplasia (PanIN3) and intraductal-papillary-mucinous-neoplasia (IPMN) with high-grade dysplasia. Screening results were compared between carriers of pathogenic variants and variant-negative IAR.
    RESULTS: 337 IAR, including 74 (22%) variant-carriers and 263 IAR of variant-negative FPC families (mean age 49; standard deviation [SD] + 8.9) were followed 64 (SD + 55) months. IAR underwent 5.1 (SD + 3.9) screening visits with 1733 MRI (5.1,SD + 3.9 per IAR) and 728 EUS (2.2,SD + 1.7 per IAR). In 12 (4%) cases, significant pancreatic lesions were detected, including 4 PDAC, 3 PanIN3 and 5 high-grade IPMN. Three of 4 IAR with PDAC died after a mean of 27 months postoperatively, and one IAR is alive without evidence of disease after 31 months. The diagnostic yield for significant lesions was 13.5% (10/74) for variant carriers compared to 0.8% (2/263) for IAR of variant-negative FPC families (p < 0.001). Logistic regression analysis revealed that a negative variant status was almost always accompanied by the absence of a significant lesion over time with a negative predictive value of 99.2% (95% CI 97.3%-99.9%).
    CONCLUSION: The diagnostic yield seems to justify PDAC screening in IAR of FPC-families with pathogenic germline variants in PDAC predisposing genes, not in IAR of variant-negative families.
    Keywords:  IPMN; PDAC; adenocarcinoma; diagnosis; familiar; genetic; high; increased; intraepithelial; neoplasia
    DOI:  https://doi.org/10.1002/ueg2.12631
  5. Genes (Basel). 2024 Jul 01. pii: 863. [Epub ahead of print]15(7):
    The CRISPR-Cas System and Clinical Applications of CRISPR-Based Gene Editing in Hematology with a Focus on Inherited Germline Predisposition to Hematologic Malignancies.
    Rina Kansal.
      Clustered regularly interspaced short palindromic repeats (CRISPR)-based gene editing has begun to transform the treatment landscape of genetic diseases. The history of the discovery of CRISPR/CRISPR-associated (Cas) proteins/single-guide RNA (sgRNA)-based gene editing since the first report of repetitive sequences of unknown significance in 1987 is fascinating, highly instructive, and inspiring for future advances in medicine. The recent approval of CRISPR-Cas9-based gene therapy to treat patients with severe sickle cell anemia and transfusion-dependent β-thalassemia has renewed hope for treating other hematologic diseases, including patients with a germline predisposition to hematologic malignancies, who would benefit greatly from the development of CRISPR-inspired gene therapies. The purpose of this paper is three-fold: first, a chronological description of the history of CRISPR-Cas9-sgRNA-based gene editing; second, a brief description of the current state of clinical research in hematologic diseases, including selected applications in treating hematologic diseases with CRISPR-based gene therapy, preceded by a brief description of the current tools being used in clinical genome editing; and third, a presentation of the current progress in gene therapies in inherited hematologic diseases and bone marrow failure syndromes, to hopefully stimulate efforts towards developing these therapies for patients with inherited bone marrow failure syndromes and other inherited conditions with a germline predisposition to hematologic malignancies.
    Keywords:  CRISPR-Cas; DNA repair; acute myeloid leukemia; bone marrow failure; gene editing; gene therapy; hematologic cancers; inherited germline predisposition to cancer; myelodysplastic syndromes; myeloid neoplasms
    DOI:  https://doi.org/10.3390/genes15070863
This page is being maintained by Thomas Krichel. It was last updated on 2026‒05‒17 at 11:44.