bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2020‒11‒08
three papers selected by
Joanna Zawacka-Pankau
University of Warsaw


  1. BMC Cancer. 2020 Nov 02. 20(1): 1053
    Kwong A, Shin VY, Ho CYS, Au CH, Slavin TP, Weitzel JN, Chan TL, Ma ESK.
      BACKGROUND: Germline TP53 mutations are associated with Li-Fraumeni syndrome, a severe and rare hereditary cancer syndrome. Despite the rarity of germline TP53 mutations, the clinical implication for mutation carriers and their families is significant. The risk management of TP53 germline mutation carriers is more stringent than BRCA carriers, and radiotherapy should be avoided when possible.METHODS: TP53 gene mutation screening was performed in 2538 Chinese breast cancer patients who tested negative for BRCA mutations.
    RESULTS: Twenty TP53 mutations were identified with high next-generation sequencing concerning for germline mutations in Chinese breast cancer families. The majorities of the TP53 carriers had early-onset, hormone receptor-positive breast cancer, and had strong family history of cancer. Among all, 11 patients carried a germline mutation and 6 of which were likely de novo germline mutations. In addition, 1 case was suspected to be induced by chemotherapy or radiation, as this patient had no significant family history of cancer and aberrant clonal expansion can commonly include TP53 mutations. Furthermore, we have identified one mosaic LFS case. Two novel mutations (c.524_547dup and c.529_546del) were identified in patients with early-onset.
    CONCLUSIONS: In view of the high lifetime risk of malignancy, identification of patients with germline TP53 mutations are important for clinicians to aid in accurate risk assessment and offer surveillance for patients and their families.
    Keywords:  Breast cancer risk; Chinese; Hereditary breast cancer; TP53 mutation
    DOI:  https://doi.org/10.1186/s12885-020-07476-y
  2. Front Oncol. 2020 ;10 571330
    Grasel RS, Felicio PS, de Paula AE, Campacci N, Garcia FAO, de Andrade ES, Evangelista AF, Fernandes GC, Sabato CDS, De Marchi P, Souza CP, de Paula CAA, Torrezan GT, Galvão HCR, Carraro DM, Palmero EI.
      The use of gene panels introduces a new dilemma in the genetics field due to the high frequency of variants of uncertain significance (VUS). The objective of this study was to provide evidence that may help in the classification of these germline variants in terms of their clinical impact and association with the disease in question. A total of 52 unrelated women at-risk for HBOC and negative for BRCA1/BRCA2 pathogenic variants were evaluated through a gene panel comprising 14 breast and/or ovarian cancer susceptibility genes. Of the 453 germline variants identified, 15 variants (classes 3, 4, and 5) in the ATM, BRIP1, CHEK2, MRE11A, MUTHY, PALB2, RAD50, and RAD51C genes were evaluated via databases, co-segregation studies and loss of heterozygosity in the tumor. The co-segregation analysis allowed the establishment of an association with the presence of variants and the risk of cancer for variant c.316C>T in the BRIP1 gene. Four variants of uncertain significance showed loss of heterozygosity in the tumor (ATM c.4709T>C; CHEK2 c.1036C>T; PALB2 c.1001A>G, and RAD50 c.281T>C), which is an indication of pathogenicity. Thus, the present study provides novel evidence that favors the association of variants in moderate-risk genes with the development of hereditary breast cancer.
    Keywords:  genetics; hereditary breast and ovarian cancer predisposition syndrome; hereditary cancer; segregation analysis; variant of unknown significance
    DOI:  https://doi.org/10.3389/fonc.2020.571330
  3. Cancer Genet. 2020 Oct 24. pii: S2210-7762(20)30277-5. [Epub ahead of print]
    Vasta LM, McMaster ML, Harney LA, Ling A, Kim J, Harris AK, Carr AG, Damrauer SM, Rader DJ, Kember RL, Kanetsky PA, Nathanson KL, Pyle LC, Greene MH, Schultz KA, Stewart DR, .
      BACKGROUND: Several studies have reported conflicting evidence on the inclusion of testicular germ cell tumors (TGCT) in the DICER1 tumor-predisposition phenotype. We evaluated the relationship between DICER1 and TGCT by reviewing scrotal ultrasounds of males with pathogenic germline variants in DICER1 and queried exome data from TGCT-affected men for DICER1 variants.METHODOLOGY: Fifty-four male DICER1-carriers and family controls (n=41) enrolled in the National Cancer Institute (NCI) DICER1 Natural History Study were offered scrotal ultrasounds. These studies were examined by a single radiologist for abnormalities. In parallel, DICER1 variants from two large exome-sequenced TGCT cohorts were extracted. We used previously published AMG-AMP criteria to characterize rare DICER1 variants.
    RESULTS: There was no observed difference in frequency of testicular cystic structures in DICER1-carriers versus controls. DICER1 variation was not associated with TGCT in the NCI DICER1-carriers. In 1,264 exome-sequenced men with TGCT, none harbored ClinVar- or InterVar-determined pathogenic or likely pathogenic variants in DICER1. Three DICER1 variants of uncertain significance (one case and two controls) were predicted "damaging" based on a priori criteria.
    CONCLUSION: Using two complementary approaches, we found no evidence of an association between pathogenic DICER1 variants and TGCT.
    Keywords:  DICER1; Exome sequencing; Scrotal ultrasound; Testicular cancer; miRNA
    DOI:  https://doi.org/10.1016/j.cancergen.2020.10.002