bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2023‒08‒13
seven papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet
  1. Factors affecting adherence to a high-risk surveillance protocol among patients with Li-Fraumeni syndrome.
  2. Clinical Features of Li-Fraumeni Syndrome in Korea.
  3. Germline Variants Incidentally Detected via Tumor-Only Genomic Profiling of Patients With Mesothelioma.
  4. Potential pathogenic germline variant reporting from tumor comprehensive genomic profiling complements classic approaches to germline testing.
  5. Associations Between Cancer Predisposition Mutations and Clonal Hematopoiesis in Patients With Solid Tumors.
  6. Constitutional balanced translocations involving SMARCB1: A rare cause of rhabdoid tumor predisposition syndrome.
  7. Secondary leiomyosarcoma of the nasal cavity in a treated patient with possible hereditary retinoblastoma with germline reciprocal translocation of RB1 and DMXL1 and somatic TP53 mutation: A case report.
  1. Hered Cancer Clin Pract. 2023 Aug 11. 21(1): 15
    Factors affecting adherence to a high-risk surveillance protocol among patients with Li-Fraumeni syndrome.
    Kaylee A Underkofler, Martha H Thomas, Christina J Taylor, Christa L Mazur, Sarah H Erickson, Kari L Ring.
      BACKGROUND: High-risk surveillance for patients with Li-Fraumeni syndrome (LFS) has shown a stage shift and improved overall survival, but is demanding. Our objective was to evaluate surveillance adherence in a population of patients with LFS presenting for high-risk care.METHODS: A retrospective analysis of surveillance adherence of adult patients with LFS at a single institution was performed. Adherence was defined by the duration from initial University of Virginia (UVA) LFS clinic visit to the time of first missed surveillance test. Two-sample t-tests and ANOVA tests were used to identify factors associated with duration of adherence.
    RESULTS: A total of 42 patients were evaluated in the UVA LFS clinic between 2017 and 2021. Of these, 21 patients met inclusion criteria. At the time of review, 6 patients (29%) were up to date with high-risk surveillance recommendations. The mean duration of adherence was 17 months. Female sex was found to be associated with longer duration of adherence (mean 21 mo vs. 3.5 mo for males, p = 0.02). A personal history or active diagnosis of cancer was also associated with increased adherence (p = 0.02). However, neither age (p = 0.89), geography (p = 0.84), or known family history of LFS (p = 0.08) were associated with duration of adherence.
    CONCLUSION: Female sex as well as a personal history of cancer were associated with longer duration of adherence to recommended high-risk surveillance among patients with LFS. Identification of barriers to surveillance will be essential moving forward to increase adherence and promote early detection of cancer, thereby reducing the morbidity and mortality of LFS.
    Keywords:  Cancer; Genetics; Health behavior; Li-Fraumeni syndrome; Risk management
    DOI:  https://doi.org/10.1186/s13053-023-00259-z
  2. Cancer Res Treat. 2023 Aug 09.
    Clinical Features of Li-Fraumeni Syndrome in Korea.
    Ran Song, Sun-Young Kong, Wonyoung Choi, Eun-Gyeong Lee, Jaeyeon Woo, Jai Hong Han, Seeyoun Lee, Han-Sung Kang, So-Youn Jung.
      Purpose: Li-Fraumeni syndrome (LFS) is a hereditary disorder caused by germline mutation in TP53. Owing to the rarity of LFS, data on its clinical features are limited. This study aimed to evaluate the clinical characteristics and prognosis of Korean patients with LFS.Materials and Methods: Patients who underwent genetic counseling and confirmed with germline TP53 mutation in the National Cancer Center in Korea between 2011 and 2022 were retrospectively reviewed. Data on family history with pedigree, types of mutation, clinical features, and prognosis were collected.
    Results: Fourteen patients with LFS were included in this study. The median age at diagnosis of the first tumor was 32 years. Missense and nonsense mutations were observed in 13 and 1 patients, respectively. The repeated mutations were p.Arg273His, p.Ala138Val, and pPro190Leu. The sister with breast cancer harbored the same mutation of p.Ala138Val. Seven patients had multiple primary cancers. Breast cancer was most frequently observed, and other types of tumor included sarcoma, thyroid cancer, pancreatic cancer, brain tumor, adrenocortical carcinoma, ovarian cancer, endometrial cancer, colon cancer, vaginal cancer, skin cancer, and leukemia. The median follow-up period was 51.5 months. Two and four patients showed local recurrence and distant metastasis, respectively. Two patients died of leukemia and pancreatic cancer 3 and 23 months after diagnosis, respectively.
    Conclusion: This study provides information on different characteristics of patients with LFS, including types of mutation, types of cancer, and prognostic outcomes. For more appropriate management of these patients, proper genetic screening and multidisciplinary discussion are required.
    Keywords:  Germ-line mutation; Hereditary disease; Li–Fraumeni syndrome; TP53
    DOI:  https://doi.org/10.4143/crt.2023.794
  3. JAMA Netw Open. 2023 08 01. 6(8): e2327351
    Germline Variants Incidentally Detected via Tumor-Only Genomic Profiling of Patients With Mesothelioma.
    Owen D Mitchell, Katie Gilliam, Daniela Del Gaudio, Kelsey E McNeely, Shaili Smith, Maria Acevedo, Meghana Gaduraju, Rachel Hodge, Aubrianna S S Ramsland, Jeremy Segal, Soma Das, Feighanne Hathaway, Darren S Bryan, Sanjukta Tawde, Shelly Galasinski, Peng Wang, Melissa Y Tjota, Aliya N Husain, Samuel G Armato, Jessica Donington, Mark K Ferguson, Kiran Turaga, Jane E Churpek, Hedy L Kindler, Michael W Drazer.
      Importance: Patients with mesothelioma often have next-generation sequencing (NGS) of their tumor performed; tumor-only NGS may incidentally identify germline pathogenic or likely pathogenic (P/LP) variants despite not being designed for this purpose. It is unknown how frequently patients with mesothelioma have germline P/LP variants incidentally detected via tumor-only NGS.Objective: To determine the prevalence of incidental germline P/LP variants detected via tumor-only NGS of mesothelioma.
    Design, Setting, and Participants: A series of 161 unrelated patients with mesothelioma from a high-volume mesothelioma program had tumor-only and germline NGS performed during April 2016 to October 2021. Follow-up ranged from 18 months to 7 years. Tumor and germline assays were compared to determine which P/LP variants identified via tumor-only NGS were of germline origin. Data were analyzed from January to March 2023.
    Main Outcomes and Measures: The proportion of patients with mesothelioma who had P/LP germline variants incidentally detected via tumor-only NGS.
    Results: Of 161 patients with mesothelioma, 105 were male (65%), the mean (SD) age was 64.7 (11.2) years, and 156 patients (97%) self-identified as non-Hispanic White. Most (126 patients [78%]) had at least 1 potentially incidental P/LP germline variant. The positive predictive value of a potentially incidental germline P/LP variant on tumor-only NGS was 20%. Overall, 26 patients (16%) carried a P/LP germline variant. Germline P/LP variants were identified in ATM, ATR, BAP1, CHEK2, DDX41, FANCM, HAX1, MRE11A, MSH6, MUTYH, NF1, SAMD9L, and TMEM127.
    Conclusions and Relevance: In this case series of 161 patients with mesothelioma, 16% had confirmed germline P/LP variants. Given the implications of a hereditary cancer syndrome diagnosis for preventive care and familial counseling, clinical approaches for addressing incidental P/LP germline variants in tumor-only NGS are needed. Tumor-only sequencing should not replace dedicated germline testing. Universal germline testing is likely needed for patients with mesothelioma.
    DOI:  https://doi.org/10.1001/jamanetworkopen.2023.27351
  4. NPJ Precis Oncol. 2023 Aug 11. 7(1): 76
    Potential pathogenic germline variant reporting from tumor comprehensive genomic profiling complements classic approaches to germline testing.
    Nadine Tung, Kali Chatham Dougherty, Emily Stern Gatof, Kim DeLeonardis, Lauren Hogan, Hanna Tukachinsky, Erica Gornstein, Geoffrey R Oxnard, Kimberly McGregor, Rachel B Keller.
      Existing guidance regarding clinically informed germline testing for patients with cancer is effective for evaluation of classic hereditary cancer syndromes and established gene/cancer type associations. However, current screening methods may miss patients with rare, reduced penetrance, or otherwise occult hereditary risk. Secondary finding of suspected germline variants that may confer inherited cancer risk via tumor comprehensive genomic profiling (CGP) has the potential to help address these limitations. However, reporting practices for secondary finding of germline variants are inconsistent, necessitating solutions for transparent and coherent communication of these potentially important findings. A workflow for improved confidence detection and clear reporting of potential pathogenic germline variants (PPGV) in select cancer susceptibility genes (CSG) was applied to a research dataset from real-world clinical tumor CGP of > 125,000 patients with advanced cancer. The presence and patterns of PPGVs identified across tumor types was assessed with a focus on scenarios in which traditional clinical germline evaluation may have been insufficient to capture genetic risk. PPGVs were identified in 9.7% of tumor CGP cases using tissue- and liquid-based assays across a broad range of cancer types, including in a number of "off-tumor" contexts. Overall, PPGVs were identified in a similar proportion of cancers with National Comprehensive Cancer Network (NCCN) recommendations for germline testing regardless of family history (11%) as in all other cancer types (9%). These findings suggest that tumor CGP can serve as a tool that is complementary to traditional germline genetic evaluation in helping to ascertain inherited susceptibility in patients with advanced cancer.
    DOI:  https://doi.org/10.1038/s41698-023-00429-1
  5. JCO Precis Oncol. 2023 Aug;7 e2300070
    Associations Between Cancer Predisposition Mutations and Clonal Hematopoiesis in Patients With Solid Tumors.
    Sebastià Franch-Expósito, Miika Mehine, Ryan N Ptashkin, Kelly L Bolton, Chaitanya Bandlamudi, Preethi Srinivasan, Linda Zhang, Margaret A Goodell, Erika Gedvilaite, Kamal Menghrajani, Pablo Sánchez-Vela, Diana Mandelker, Elizabeth Comen, Larry Norton, Ryma Benayed, Teng Gao, Elli Papaemmanuil, Barry Taylor, Ross Levine, Kenneth Offit, Zsofia Stadler, Michael F Berger, Ahmet Zehir.
      PURPOSE: Clonal hematopoiesis (CH), the expansion of clones in the hematopoietic system, has been linked to different internal and external features such as aging, genetic ancestry, smoking, and oncologic treatment. However, the interplay between mutations in known cancer predisposition genes and CH has not been thoroughly examined in patients with solid tumors.METHODS: We used prospective tumor-blood paired sequencing data from 46,906 patients who underwent Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) testing to interrogate the associations between CH and rare pathogenic or likely pathogenic (P/LP) germline variants.
    RESULTS: We observed an enrichment of CH-positive patients among those carrying P/LP germline mutations and identified a significant association between P/LP germline variants in ATM and CH. Germline and CH comutation patterns in ATM, TP53, and CHEK2 suggested biallelic inactivation as a potential mediator of clonal expansion. Moreover, we observed that CH-PPM1D mutations, similar to somatic tumor-associated PPM1D mutations, were depleted in patients with P/LP germline mutations in the DNA damage response (DDR) genes ATM, CHEK2, and TP53. Patients with solid tumors and harboring P/LP germline mutations, CH mutations, and mosaicism chromosomal alterations might be at an increased risk of developing secondary leukemia while germline variants in TP53 were identified as an independent risk factor (hazard ratio, 36; P < .001) for secondary leukemias.
    CONCLUSION: Our results suggest a close relationship between inherited variants and CH mutations within the DDR genes in patients with solid tumors. Associations identified in this study might translate into enhanced clinical surveillance for CH and associated comorbidities in patients with cancer harboring these germline mutations.
    DOI:  https://doi.org/10.1200/PO.23.00070
  6. Genes Chromosomes Cancer. 2023 Aug 07.
    Constitutional balanced translocations involving SMARCB1: A rare cause of rhabdoid tumor predisposition syndrome.
    Patrick R Blackburn, Rose B McGee, Roya Mostafavi, Andrew J Carroll, Fady M Mikhail, Gregory T Armstrong, Larissa V Furtado, Jason Chiang, David A Wheeler, Steven S Carey, Kim E Nichols, Santhosh A Upadhyaya.
      Rhabdoid Tumor Predisposition Syndrome 1 (RTPS1) confers an increased risk of developing rhabdoid tumors and is caused by germline mutations in SMARCB1. RTPS1 should be evaluated in all individuals with rhabdoid tumor and is more likely in those with a young age at presentation (occasionally congenital presentation), multiple primary tumors, or a family history of rhabdoid tumor or RTPS1. Proband genetic testing is the standard method for diagnosing RTPS1. Most known RTPS1-related SMARCB1 gene mutations are copy number variants (CNVs) or single nucleotide variants/indels, but structural variant analysis (SVA) is not usually included in the molecular evaluation. Here, we report two children with RTPS1 presenting with atypical teratoid/rhabdoid tumor (ATRT) who had constitutional testing showing balanced chromosome translocations involving SMARCB1. Patient 1 is a 23-year-old female diagnosed with pineal region ATRT at 7 months who was found to have a de novo, constitutional t(16;22)(p13.3;q11.2). Patient 2 is a 24-month-old male diagnosed with a posterior fossa ATRT at 14 months, with subsequent testing showing a constitutional t(5;22)(q14.1;q11.23). These structural rearrangements have not been previously reported in RTPS1. While rare, these cases suggest that structural variants should be considered in the evaluation of children with rhabdoid tumors to provide more accurate genetic counseling on the risks of developing tumors, the need for surveillance, and the risks of passing the disorder on to future children. Further research is needed to understand the prevalence, clinical features, and tumor risks associated with RTPS1-related constitutional balanced translocations.
    Keywords:  SMARCB1; balanced translocation; rhabdoid tumor predisposition syndrome
    DOI:  https://doi.org/10.1002/gcc.23195
  7. Mol Clin Oncol. 2023 Aug;19(2): 65
    Secondary leiomyosarcoma of the nasal cavity in a treated patient with possible hereditary retinoblastoma with germline reciprocal translocation of RB1 and DMXL1 and somatic TP53 mutation: A case report.
    Toshinari Yagi, Harumi Nakamura, Yoji Kukita, Toru Wakamatsu, Hironari Tamiya, Shou Nakai, Makiyo Watanabe, Shigeki Kakunaga, Haruna Takami, Rie Suzuki, Satoshi Takenaka, Yoshiko Hashii.
      Retinoblastoma is a common primary intraocular malignant tumor that affects infants and young children. Radiation therapy for hereditary retinoblastoma increases the risk of secondary malignancy. The present report discusses the case of a retinoblastoma survivor who developed secondary leiomyosarcoma 42 years after receiving radiation therapy. The retinoblastoma of the patient was unilateral, and the patient had no family history of the disease. RNA and DNA panel sequencing of the leiomyosarcoma tissue was performed to elucidate the molecular mechanism of this secondary malignancy. The RNA panel sequencing detected a germline reciprocal translocation of RB1 and DMXL1, leading to a diagnosis of possible hereditary retinoblastoma. Furthermore, it detected a somatic fusion gene (RAD51-KNL1). The DNA panel sequencing identified various germline or somatic variants, including a somatic splice acceptor site mutation of TP53. We hypothesized that the molecular mechanism of the secondary malignancy of this patient was the combination of a germline reciprocal translocation of RB1 and DMXL1 and the accumulation of various somatic mutations containing the splice acceptor site mutation of TP53, which ultimately led to the development of a secondary leiomyosarcoma. Further prospective investigations are necessary to fully understand the role of reciprocal translocation of RB1 and DMXL1 or other mutations in the tumorigenesis of second malignancies in patients with hereditary retinoblastoma.
    Keywords:  DMXL1; RB1; TP53; leiomyosarcoma; retinoblastoma
    DOI:  https://doi.org/10.3892/mco.2023.2661
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