bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2024–09–08
six papers selected by
Joanna Zawacka, Karolinska Institutet
  1. Germline RAD51C and RAD51D Mutations in High-Risk Chinese Breast and/or Ovarian Cancer Patients and Families.
  2. A dual biomarker in non-small cell lung cancer that predicts Li Fraumeni syndrome : Lung cancer and Li Fraumeni.
  3. Germline mutation rate predicts cancer mortality across 37 vertebrate species.
  4. Germline variant profiling of CHEK2 sequencing variants in breast cancer patients.
  5. Germline BRCA pathogenic variants in patients with ovarian cancer and post-poly (ADP-ribose) polymerase inhibitor myeloid neoplasms.
  6. Advances in Molecular Mechanisms of Kidney Disease: Integrating Renal Tumorigenesis of Hereditary Cancer Syndrome.
  1. J Pers Med. 2024 Aug 16. pii: 866. [Epub ahead of print]14(8):
    Germline RAD51C and RAD51D Mutations in High-Risk Chinese Breast and/or Ovarian Cancer Patients and Families.
    Ava Kwong, Cecilia Yuen Sze Ho, Chun Hang Au, Sze Keong Tey, Edmond Shiu Kwan Ma.
       BACKGROUND: RAD51C and RAD51D are crucial in homologous recombination (HR) DNA repair. The prevalence of the RAD51C and RAD51D mutations in breast cancer varies across ethnic groups. Associations of RAD51C and RAD51D germline pathogenic variants (GPVs) with breast and ovarian cancer predisposition have been recently reported and are of interest.
    METHODS: We performed multi-gene panel sequencing to study the prevalence of RAD51C and RAD51D germline mutations among 3728 patients with hereditary breast and/or ovarian cancer (HBOC).
    RESULTS: We identified 18 pathogenic RAD51C and RAD51D mutation carriers, with a mutation frequency of 0.13% (5/3728) and 0.35% (13/3728), respectively. The most common recurrent mutation was RAD51D c.270_271dupTA; p.(Lys91Ilefs*13), with a mutation frequency of 0.30% (11/3728), which was also commonly identified in Asians. Only four out of six cases (66.7%) of this common mutation tested positive for homologous recombination deficiency (HRD).
    CONCLUSIONS: Taking the family studies in our registry and tumor molecular pathology together, we concluded that this relatively common RAD51D variant showed incomplete penetrance in our local Chinese community. Personalized genetic counseling emphasizing family history for families with this variant, as suggested at the UK Cancer Genetics Group (UKCGG) Consensus meeting, would also be appropriate in Chinese families.
    Keywords:  Chinese; RAD51C; RAD51D; germline mutation; hereditary breast and ovarian cancers
    DOI:  https://doi.org/10.3390/jpm14080866
  2. Fam Cancer. 2024 Sep 05.
    A dual biomarker in non-small cell lung cancer that predicts Li Fraumeni syndrome : Lung cancer and Li Fraumeni.
    Steven Sorscher.
      Non-small cell lung cancer is the most common cause of cancer death globally. When apparent incidental pathogenic germline variants (PGVs) are uncovered with routine next generation sequencing (NGS) of NSCLCs, germline testing (GT) is recommended to confirm that PGV. Because it is far more common that an uncovered tumor TP53 variant is related to a somatic event than an incidental PGV, however, GT for Li Fraumeni syndrome (LFS) is not recommended based solely on uncovering a NSCLC TP53 variant. Because nearly all tumor EGFR variants are also somatic in origin, GT is not recommended based solely on uncovering a tumor EGFR variant.However, there is evidence that patients with coexisting NSCLC variants in both EGFR and TP53 have significant likelihoods of having LFS. For patients with LFS, there are recommended measures for prevention and early detection of LFS-associated cancers and cascade GT of relatives for LFS. Although co-existing genetic variants in NSCLC are not currently used as a biomarker for GT to identify patients with PGVs, given the evidence reviewed here, select patients with NSCLCs that harbor this dual biomarker (i.e., co-existing TP53/EGFR variants) might reasonably be considered for GT for LFS.
    Keywords:   EGFR ; TP53 ; Co-existing biomarkers; Dual biomarkers; Li Fraumeni syndrome; Pathogenic germline variants
    DOI:  https://doi.org/10.1007/s10689-024-00418-8
  3. Evol Med Public Health. 2024 ;12(1): 122-128
    Germline mutation rate predicts cancer mortality across 37 vertebrate species.
    Stefania E Kapsetaki, Zachary T Compton, Walker Mellon, Orsolya Vincze, Mathieu Giraudeau, Tara M Harrison, Lisa M Abegglen, Amy M Boddy, Carlo C Maley, Joshua D Schiffman.
       Background and objectives: Cancer develops across nearly every species. However, cancer occurs at unexpected and widely different rates throughout the animal kingdom. The reason for this variation in cancer susceptibility remains an area of intense investigation. Cancer evolves in part through the accumulation of mutations, and therefore, we hypothesized that germline mutation rates would be associated with cancer prevalence and mortality across species.
    Methodology: We collected previously published data on germline mutation rate and cancer mortality data for 37 vertebrate species.
    Results: Germline mutation rate was positively correlated with cancer mortality (P-value = 0.0008; R2 = 0.13). Controlling for species' average parental age, maximum longevity, adult body mass or domestication did not improve the model fit (the change (Δ) in Akaike Information Criterion (AIC) was less than 2). However, this model fit was better than a model controlling for species trophic level (ΔAIC > 2).
    Conclusions and implications: The increased death rate from cancer in animals with increased germline mutation rates may suggest underlying hereditary cancer predisposition syndromes similar to those diagnosed in human patients. Species with higher germline mutation rates may benefit from close monitoring for tumors due to increased genetic risk for cancer development. Early diagnoses of cancer in these species may increase their chances of overall survival, especially for threatened and endangered species.
    Keywords:  animals; germ cell mutations; malignancy; tumor
    DOI:  https://doi.org/10.1093/emph/eoae016
  4. Cancer Genet. 2024 Aug 23. pii: S2210-7762(24)00119-4. [Epub ahead of print]288-289 10-19
    Germline variant profiling of CHEK2 sequencing variants in breast cancer patients.
    Claire McCarthy-Leo, Scott Baughan, Hunter Dlugas, Prisca Abraham, Janice Gibbons, Carolyn Baldwin, Sarah Chung, Gerald L Feldman, Gregory Dyson, Russell L Finley, Michael A Tainsky.
      The cell cycle checkpoint kinase 2 (CHEK2) is a tumor suppressor gene coding for a protein kinase with a role in the cell cycle and DNA repair pathways. Variants within CHEK2 are associated with an increased risk of developing breast, colorectal, prostate and several other types of cancer. Comprehensive genetic risk assessment leads to early detection of hereditary cancer and provides an opportunity for better survival. Multigene panel screening can identify the presence of pathogenic variants in hereditary cancer predisposition genes (HCPG), including CHEK2. Multigene panels, however, also result in large quantities of genetic data some of which cannot be interpreted and are classified as variants of uncertain significance (VUS). A VUS provides no information for use in medical management and leads to ambiguity in genetic counseling. In the absence of variant segregation data, in vitro functional analyses can be used to clarify variant annotations, aiding in accurate clinical management of patient risk and treatment plans. In this study, we performed whole exome sequencing (WES) to investigate the prevalence of germline variants in 210 breast cancer (BC) patients and conspicuously among the many variants in HCPGs that we found, we identified 16 individuals with non-synonymous or frameshift CHEK2 variants, sometimes along with additional variants within other BC susceptibility genes. Using this data, we investigated the prevalence of these CHEK2 variants in African American (AA) and Caucasian (CA) populations identifying the presence of two novel frameshift variants, c.1350delA (p.Val451Serfs*18) and c.1528delC (p.Gln510Argfs*3) and a novel missense variant, c262C>T (p.Pro88Ser). Along with the current clinical classifications, we assembled available experimental data and computational predictions of function for these CHEK2 variants, as well as explored the role these variants may play in polygenic risk assessment.
    Keywords:  Breast cancer; CHEK2; Cancer genetics; Cancer risk assessment; Variant of unknown significance
    DOI:  https://doi.org/10.1016/j.cancergen.2024.08.081
  5. ESMO Open. 2024 Aug 29. pii: S2059-7029(24)01454-6. [Epub ahead of print]9(9): 103685
    Germline BRCA pathogenic variants in patients with ovarian cancer and post-poly (ADP-ribose) polymerase inhibitor myeloid neoplasms.
    C Valenza, M Mongillo, F Gigli, D Trapani, J Katrini, E Nicolò, L Boldrini, L Boscolo Bielo, G Castellano, L Guidi, G Pellizzari, S Derio, M Lapresa, G Parma, E Derenzini, G Curigliano, N Colombo.
       BACKGROUND: Among patients with advanced high-grade ovarian carcinoma (aHGOC) treated with poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis), the presence of a germline BRCA pathogenic variant (gBRCA-PV) may increase the risk of bone marrow mutagenesis resulting in postcytotoxic therapy myelodysplastic neoplasms (MDS-pCT) or acute myeloid leukemia (AML-pCT), as it is expressed in heterozygosity also by hematopoietic progenitors. We aimed to investigate the occurrence of post-PARPi MDSs/AMLs-pCTs according to gBRCA-PV status.
    PATIENTS AND METHODS: We conducted a retrospective single-center study to evaluate MDS/AML-pCT in patients with aHGOC and a known gBRCA-PV status receiving at least 8 weeks of maintenance PARPi, in any line of therapy, from February 2017 to December 2022. The endpoint was the proportion of patients who experienced MDSs-pCT and AMLs-pCT during and after treatment with PARPi, in gBRCA-PV carriers and non-carriers.
    RESULTS: A total of 166 patients were included: 95 (57%) had a gBRCA-PV and 72% received PARPi for recurrent disease. The number of lines of chemotherapies before and after PARPi, median overall survival, and median follow-up were comparable between gBRCA-PV carriers and non-carriers. After a median follow-up of 40.0 (95% confidence interval: 35.7-44.3) months, 10 (6%) patients were diagnosed with an MDS-pCT and 4 (2%) with an AML-pCT. A higher proportion of MDSs/AMLs-pCT (10% versus 2%; P = 0.16) and, in particular, of MDSs-pCT (9% versus 1%; P = 0.04) was observed among gBRCA-PV carriers.
    CONCLUSIONS: The presence of a gBRCA-PV is associated with a higher risk of MDS-pCT and possibly of myeloid neoplasms after PARPi in patients with aHGOC who received PARPi, especially in the setting of recurrent disease.
    Keywords:  PARP inhibitors; advanced high-grade ovarian carcinoma; germline BRCA pathogenic variant; myelodysplastic neoplasms
    DOI:  https://doi.org/10.1016/j.esmoop.2024.103685
  6. Int J Mol Sci. 2024 Aug 21. pii: 9060. [Epub ahead of print]25(16):
    Advances in Molecular Mechanisms of Kidney Disease: Integrating Renal Tumorigenesis of Hereditary Cancer Syndrome.
    Rossella Cicchetti, Martina Basconi, Giulio Litterio, Marco Mascitti, Flavia Tamborino, Angelo Orsini, Alessio Digiacomo, Matteo Ferro, Luigi Schips, Michele Marchioni.
      Renal cell carcinoma (RCC) comprises various histologically distinct subtypes, each characterized by specific genetic alterations, necessitating individualized management and treatment strategies for each subtype. An exhaustive search of the PubMed database was conducted without any filters or restrictions. Inclusion criteria encompassed original English articles focusing on molecular mechanisms of kidney cancer. On the other hand, all non-original articles and articles published in any language other than English were excluded. Hereditary kidney cancer represents 5-8% of all kidney cancer cases and is associated with syndromes such as von Hippel-Lindau syndrome, Birt-Hogg-Dubè syndrome, succinate dehydrogenase-deficient renal cell cancer syndrome, tuberous sclerosis complex, hereditary papillary renal cell carcinoma, fumarate hydratase deficiency syndrome, BAP1 tumor predisposition syndrome, and other uncommon hereditary cancer syndromes. These conditions are characterized by distinct genetic mutations and related extra-renal symptoms. The majority of renal cell carcinoma predispositions stem from loss-of-function mutations in tumor suppressor genes. These mutations promote malignant advancement through the somatic inactivation of the remaining allele. This review aims to elucidate the main molecular mechanisms underlying the pathophysiology of major syndromes associated with renal cell carcinoma. By providing a comprehensive overview, it aims to facilitate early diagnosis and to highlight the principal therapeutic options available.
    Keywords:  BAP1 tumor predisposition syndrome; Birt–Hogg–Dubè syndrome; fumarate hydratase deficiency; hereditary cancer syndromes; hereditary papillary renal cell carcinoma; kidney cancer; succinate dehydrogenase-B mutation; tuberous sclerosis complex; von Hippel–Lindau disease
    DOI:  https://doi.org/10.3390/ijms25169060
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