bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2023‒08‒06
three papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet
  1. CHEK2 is not a Li-Fraumeni syndrome gene: time to update public resources.
  2. Germline mutations in 32 cancer susceptibility genes by Next-Generation Sequencing among breast cancer patients.
  3. Germline HPF1 retrogene insertion in RB1 gene involved in cancer predisposition.
  1. J Med Genet. 2023 Aug 03. pii: jmg-2023-109464. [Epub ahead of print]
    CHEK2 is not a Li-Fraumeni syndrome gene: time to update public resources.
    Cristina Fortuno, Marcy Richardson, Tina Pesaran, Amal Yussuf, Carolyn Horton, Paul A James, Amanda B Spurdle.
      The gene-disease relationship for CHEK2 remains listed as 'Li-Fraumeni syndrome 2' in public resources such as OMIM and MONDO, despite published evidence to the contrary, causing frustration among Li-Fraumeni syndrome (LFS) clinical experts. Here, we compared personal cancer characteristics of 2095 CHEK2 and 248 TP53 pathogenic variant carriers undergoing multigene panel testing at Ambry Genetics against 15 135 individuals with no known pathogenic variant. Our results from a within-cohort logistic regression approach highlight obvious differences between clinical presentation of TP53 and CHEK2 pathogenic variant carriers, with no evidence of CHEK2 being associated with any of the TP53-related core LFS cancers. These findings emphasise the need to replace 'Li-Fraumeni syndrome 2' as the CHEK2-associated disease name, thereby limiting potential confusion.
    Keywords:  Genetic Predisposition to Disease; Genetic Variation; Genetics; Germline Mutation; Human Genetics
    DOI:  https://doi.org/10.1136/jmg-2023-109464
  2. Oncology. 2023 Jul 29.
    Germline mutations in 32 cancer susceptibility genes by Next-Generation Sequencing among breast cancer patients.
    Yu Yang, Chang Liu, Zhong-Ling Zhuo, Fei Xie, Ke Wang, Shu Wang, Xiao-Tao Zhao.
      INTRODUCTION: BRCA1/2 germline mutations are the most well-known genetic determinants for breast cancer. However, the distribution of germline mutations in non-BRCA1/2 cancer susceptibility genes in Chinese breast cancer patients is unclear. The association between clinical characteristics and germline mutations remains to be explored.METHODS: Consecutive breast cancer patients from Peking University People's Hospital were enrolled. Clinical characteristics were collected and next-generation sequencing (NGS) was performed using blood samples of participants to identify pathogenic/likely pathogenic (P/LP) germline mutations in 32 cancer susceptibility genes including homologous recombination repair (HRR) genes.
    RESULTS: A total of 885 breast cancer patients underwent the detection of germline mutations. 107 P/LP germline mutations of 17 genes were identified in 116 breast cancer patients including 79 (8.9%) in BRCA1/2 and 40 (4.5%) in 15 non-BRCA1/2 genes. PALB2 was the most frequently mutated gene other than BRCA1/2 but still relatively rare (1.1%). There were 38 novel P/LP germline variants detected. P/LP germline mutations in BRCA1/2 were significantly associated with onset age(P<0.001), the family history of breast/ovarian cancer(P=0.010), and molecular subtype(P<0.001), while correlated with onset age (P<0.001), site of breast tumor (P=0.028) and molecular subtype (P< 0.001) in HRR genes.
    CONCLUSIONS: The multiple-gene panel prominently increased the detection rate of P/LP germline mutations in 32 cancer susceptibility genes compared to BRCA1/2 alone. Onset younger than or equal to 45 years of age, bilateral and triple-negative breast cancer (TNBC) patients may be more likely to be recommended for detecting P/LP germline mutations in HRR genes.
    DOI:  https://doi.org/10.1159/000532095
  3. J Med Genet. 2023 Aug 04. pii: jmg-2022-109105. [Epub ahead of print]
    Germline HPF1 retrogene insertion in RB1 gene involved in cancer predisposition.
    Jessica Le Gall, Catherine Dehainault, Matteo Boutte, Ambre Petitalot, Sandrine M Caputo, Laura Courtois, Sophie Vacher, Ivan Bieche, François Radvanyi, Hélène Pacquement, François Doz, Livia Lumbroso-Le Rouic, Marion Gauthier Villars, Dominique Stoppa-Lyonnet, François Lallemand, Claude Houdayer, Lisa Golmard.
      About half of the human genome is composed of repeated sequences derived from mobile elements, mainly retrotransposons, generally without pathogenic effect. Familial forms of retinoblastoma are caused by germline pathogenic variants in RB1 gene. Here, we describe a family with retinoblastoma affecting a father and his son. No pathogenic variant was identified after DNA analysis of RB1 gene coding sequence and exon-intron junctions. However, RB1 mRNA analysis showed a chimeric transcript with insertion of 114 nucleotides from HPF1 gene inside RB1 gene. This chimeric transcript led to an insertion of 38 amino acids in functional domain of retinoblastoma protein. Subsequent DNA analysis in RB1 intron 17 revealed the presence of a full-length HPF1 retrogene insertion in opposite orientation. Functional assay shows that this insertion has a deleterious impact on retinoblastoma protein function. This is the first report of a full-length retrogene insertion involved in human Mendelian disease leading to a chimeric transcript and a non-functional chimeric protein. Some retrogene insertions may be missed by standard diagnostic genetic testing, so contribution of retrogene insertions to human disease may be underestimated. The increasing use of whole genome sequencing in diagnostic settings will help to get a more comprehensive view of retrogenes.
    Keywords:  genetic phenomena; genetic predisposition to disease; genetic variation; sequence analysis
    DOI:  https://doi.org/10.1136/jmg-2022-109105
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