bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2020‒08‒02
five papers selected by
Joanna Zawacka-Pankau
University of Warsaw


  1. J Oncol. 2020 ;2020 6384190
    Piombino C, Cortesi L, Lambertini M, Punie K, Grandi G, Toss A.
      BRCA1- and BRCA2-associated hereditary breast and ovarian cancer syndromes are among the best-known and most extensively studied hereditary cancer syndromes. Nevertheless, many patients who proved negative at BRCA genetic testing bring pathogenic mutations in other suppressor genes and oncogenes associated with hereditary breast and/or ovarian cancers. These genes include TP53 in Li-Fraumeni syndrome, PTEN in Cowden syndrome, mismatch repair (MMR) genes in Lynch syndrome, CDH1 in diffuse gastric cancer syndrome, STK11 in Peutz-Jeghers syndrome, and NF1 in neurofibromatosis type 1 syndrome. To these, several other genes can be added that act jointly with BRCA1 and BRCA2 in the double-strand break repair system, such as PALB2, ATM, CHEK2, NBN, BRIP1, RAD51C, and RAD51D. Management of primary and secondary cancer prevention in these hereditary cancer syndromes is crucial. In particular, secondary prevention by screening aims to discover precancerous lesions or cancers at their initial stages because early detection could allow for effective treatment and a full recovery. The present review aims to summarize the available literature and suggest proper screening strategies for hereditary breast and/or ovarian cancer syndromes other than BRCA.
    DOI:  https://doi.org/10.1155/2020/6384190
  2. J Oncol. 2020 ;2020 8362179
    Abdel-Razeq H, Abujamous L, Jadaan D.
      Purpose: Knowledge of BRCA1 and BRCA2 mutations has a significant clinical impact on the management and prevention of breast cancer. In this study, we evaluate the pattern and prevalence of germline mutations in BRCA1 and BRCA2 among high-risk Jordanian breast cancer patients selected as per international guidelines.Methods: BRCA1 and BRCA2 testing were performed at a reference genetic lab. Mutations were classified as pathogenic/likely pathogenic and variant of uncertain significance (VUS).
    Results: A total of 517 patients, median age: 39 (range: 19-78) years, were enrolled. Among the whole group, 72 (13.9%) patients had pathogenic or likely pathogenic BRCA1 (n = 24, 4.6%) or BRCA2 (n = 48, 9.3%) mutations, while 53 (10.3%) others had VUS. Among 333 younger (≤40 years) patients, mutations were observed in 44 (13.2%). Positive mutations were found in 40 (16.5%) patients with one or more close relatives with breast cancer and in 20 (35.1%) of the 57 patients with triple-negative disease. Multivariate analysis showed that a triple-negative status, history of two or more close relatives with breast cancer, and history of one or more close relatives with invasive ovarian cancer were associated with significant high odds ratios (OR) of carrying a pathogenic variant, with an OR (95% CI) of 5.08 (2.66-9.67), 3.24 (1.78-5.89), and 2.97 (1.04-8.52), respectively.
    Conclusions: BRCA1 and BRCA2 mutations are not uncommon among Jordanian patients. Young age has the weakest association with positive mutations, while patients with triple-negative disease, especially those with an additional positive family history, have the highest mutation rate.
    DOI:  https://doi.org/10.1155/2020/8362179
  3. Int J Genomics. 2020 ;2020 2641370
    Wu J, Mamidi TKK, Zhang L, Hicks C.
      Background: Breast cancer development and progression involve both germline and somatic mutations. High-throughput genotyping and next-generation sequencing technologies have enabled discovery of genetic risk variants and acquired somatic mutations driving the disease. However, the possible oncogenic interactions between germline genetic risk variants and somatic mutations in triple-negative breast cancer (TNBC) and non-triple-negative breast cancer (non-TNBC) have not been characterized. Here, we delineated the possible oncogenic interactions between genes containing germline and somatic mutations in TNBC and non-TNBC and investigated whether there are differences in gene expression and mutation burden between the two types of breast cancer.Methods: We addressed this problem by integrating germline mutation information from genome-wide association studies with somatic mutation information from next-generation sequencing using gene expression data as the intermediated phenotype. We performed network and pathway analyses to discover molecular networks and signalling pathways enriched for germline and somatic mutations.
    Results: The investigation revealed signatures of differentially expressed and differentially somatic mutated genes between TNBC and non-TNBC. Network and pathway analyses revealed functionally related genes interacting in gene regulatory networks and multiple signalling pathways enriched for germline and somatic mutations for each type of breast cancer. Among the signalling pathways discovered included the DNA repair and Androgen and ATM signalling pathways for TNBC and the DNA damage response, molecular mechanisms of cancer, and ATM and GP6 signalling pathways for non-TNBC.
    Conclusions: The results show that integrative genomics is a powerful approach for delineating oncogenic interactions between genes containing germline and genes containing somatic mutations in TNBC and non-TNBC and establishes putative functional bridges between genetic and somatic alterations and the pathways they control in the two types of breast cancer.
    DOI:  https://doi.org/10.1155/2020/2641370
  4. Blood. 2020 Jul 30. pii: blood.2020006158. [Epub ahead of print]
    Sallman DA, McLemore AF, Aldrich AL, Komrokji RS, McGraw KL, Dhawan A, Geyer S, Hou HA, Eksioglu EA, Sullivan A, Warren S, MacBeth KJ, Meggendorfer M, Haferlach T, Boettcher S, Ebert BL, Al-Ali N, Lancet JE, Cleveland JL, Padron E, List AF.
      Somatic gene mutations are key determinants of outcome in patients with myelodysplastic syndromes (MDS) and secondary AML (sAML). In particular, patients with TP53 mutations represent a distinct molecular cohort with uniformly poor prognosis. The precise pathogenetic mechanisms underlying these inferior outcomes have not been delineated. Here we characterize the immunological features of the malignant clone and alterations in the immune microenvironment in TP53 mutant and wild type MDS and sAML patients. Notably, PDL1 expression is significantly increased in hematopoietic stem cells of TP53 mutant patients, which is associated with MYC upregulation and marked down-regulation of MYC's negative regulator miR-34a, a p53 transcription target. Notably, TP53 mutant patients display significantly reduced numbers of bone marrow infiltrating OX40+ cytotoxic T-cells and helper T-cells, as well as decreased ICOS+ and 4-1BB+ NK cells. Further, highly immunosuppressive regulatory T-cells (i.e., ICOSHigh/PD-1neg) and MDSCs (PD-1low) are expanded in TP53 mutant cases. Finally, a higher proportion of bone marrow infiltrating ICOSHigh/PD-1neg Tregs is a highly significant independent predictor of overall survival. We conclude the microenvironment of TP53 mutant MDS and sAML has an immune privileged, evasive phenotype that may be a primary driver of poor outcomes, and submit that immunomodulatory therapeutic strategies may offer a benefit for this molecularly-defined subpopulation.
    DOI:  https://doi.org/10.1182/blood.2020006158
  5. Cancers (Basel). 2020 Jul 24. pii: E2049. [Epub ahead of print]12(8):
    Graziano F, Fischer NW, Bagaloni I, Di Bartolomeo M, Lonardi S, Vincenzi B, Perrone G, Fornaro L, Ongaro E, Aprile G, Bisonni R, Prisciandaro M, Malkin D, Gariépy J, Fassan M, Loupakis F, Sarti D, Del Prete M, Catalano V, Alessandroni P, Magnani M, Ruzzo A.
      Loss of p53 promotes vascular endothelial growth factor (VEGF)-A up-regulation and the angiogenic potential of cancer cells. We investigated TP53 somatic mutations in 110 primary gastric adenocarcinomas of two retrospective metastatic series including 48 patients treated with second-line Ramucirumab/Paclitaxel and 62 patients who received first-line chemotherapy with Cisplatin or Oxaliplatin plus 5-Fluorouracil. Missense mutations were classified by tumor protein p53 (TP53) mutant-specific residual transcriptional activity scores (TP53RTAS) and used to stratify patients into two groups: transcriptionally TP53Active and TP53Inactive. The primary endpoint was overall survival (OS). An additional analysis was addressed to measure VEGF/VEGF receptor 2 (VEGFR2) expression levels in relation to the TP53RTAS. In the Ramucirumab/Paclitaxel group, 29/48 (60.4%) patients had TP53 mutations. Ten patients with TP53Inactive mutations showed better OS than carriers of other TP53 mutations. This effect was retained in the multivariate model analysis (Hazard Ratio = 0.29, 95% confidence interval = 0.17-0.85, p = 0.02). In the chemotherapy group, 41/62 (66%) patients had TP53 mutations, and the 11 carriers of TP53Inactive mutations showed the worst OS (Hazard Ratio = 2.64, 95% confidence interval = 1.17-5.95, p = 0.02). VEGF-A mRNA expression levels were significantly increased in TP53Inactive cases. Further studies are warranted to explore the effect of TP53Inactive mutations in different anti-cancer regimens. This information would lead to new tailored therapy strategies for this lethal disease.
    Keywords:  Paclitaxel; Ramucirumab; TP53; angiogenesis; gastric cancer
    DOI:  https://doi.org/10.3390/cancers12082049