bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2024–07–21
eight papers selected by
Joanna Zawacka, Karolinska Institutet
  1. Case report: TP53 c.848G>A germline mutation as a possible screening target at initial diagnosis for acute lymphoblastic leukemia.
  2. Germline pathogenic variants of cancer predisposition genes in a multicentre Italian cohort of pancreatic cancer patients.
  3. High-risk pathogenic germline variants in blood relatives of BRCA1/2 negative probands.
  4. Exome Sequencing Identifies Carriers of the Autosomal Dominant Cancer Predisposition Disorders Beyond Current Practice Guideline Recommendations.
  5. Case series of Li-Fraumeni syndrome: carcinogenic mechanisms in breast cancer with TP53 pathogenic variant carriers.
  6. Survival benefit associated with screening of patients at elevated risk for pancreatic cancer.
  7. Li-Fraumeni Syndrome: Imaging Features and Guidelines.
  8. A comprehensive analysis of germline predisposition to early-onset ovarian cancer.
  1. Hematology. 2024 Dec;29(1): 2377860
    Case report: TP53 c.848G>A germline mutation as a possible screening target at initial diagnosis for acute lymphoblastic leukemia.
    Fang Hua, Yue Hu, Guang-Cui He, Si-Han Lai, Ying He, Shan Zhang, Yan Deng, Ying Han, Xiao-Dong Liu, Kun Yang, Hui-Xiu Zhong, Jian Xiao, Zhong-Zheng Zheng, Hai Yi.
       BACKGROUD: Li-Fraumeni syndrome is a hereditary tumor syndrome characterized by an elevated risk of malignancy, particularly acute lymphoblastic leukemia (ALL), which can be caused by the heterozygous germline mutation. TP53 gene germline mutation is considered a potential risk factor and crucial prognostic parameter for acute leukemia development and diagnosis, but rarely occurs in adults, and its specific pathogenic significance in acute leukemia is unclear.
    CASE PRESENTATION: We describes a case of a 45-year-old woman diagnosed with ALL. Whole-exome sequencing approach identified one of the TP53 germline mutations from her bone marrow sample with possible pathogenic significance, c.848G>A (p.Arg283His) heterozygous missense mutation located on exon 8, which was further verified in her hair, oral mucous and nail samples. Family pedigree screening revealed that the same TP53 genetic variant was present in the patient's father and non-donor son, whereas not in the donor. Digital PCR observed that this point mutation frequency dropped post-transplantation but remained low during maintenance therapy when the patient was leukemia-free.
    CONCLUSION: This suspected Li-Fraumeni syndrome case report with a likely pathogenic heterozygous TP53 variant expands the cancer genetic spectrum. Screening her family members for mutations facilitates identifying the optimal relative donor and avoids unnecessary treatment by monitoring TP53 germline mutations for minimal residual disease following hematopoietic stem cell transplantation. Its potential roles in hematological malignant tumor development and clinical pathogenic implications necessitate further probing.
    Keywords:  Li-Fraumeni syndrome; TP53 gene; acute leukemia; case report; digital PCR; germline mutation; haploidentical allogeneic hematopoietic stem cell transplantation
    DOI:  https://doi.org/10.1080/16078454.2024.2377860
  2. Eur J Cancer. 2024 Jul 16. pii: S0959-8049(24)00882-7. [Epub ahead of print]208 114226
    Germline pathogenic variants of cancer predisposition genes in a multicentre Italian cohort of pancreatic cancer patients.
    Giulia Orsi, Catia Carconi, Paola Ghiorzo, Paola Carrera, Lorenza Pastorino, Silvia Presi, Marta Chiaravalli, Elena Barbieri, Guido Giordano, Stefania Sciallero, Alberto Puccini, Lisa Salvatore, Laura Cortesi, Marina Macchini, Maria Iole Natalicchio, Eleonora Allavena, Chiara Pirrone, Livia Archibugi, Bruna Dalmasso, William Bruno, Giampaolo Tortora, Matteo Landriscina, Gabriele Capurso, Stefano Cascinu, Massimo Falconi, Michele Reni.
       BACKGROUND AND AIM: Germline BRCA1-2 test is routinely recommended in Pancreatic Cancer (PC) patients, due to its clinical-epidemiological relevance. Data on the prevalence of germline pathogenic variants (gPV) in other cancer predisposition and DNA Damage Repair (DDR) system-related genes in unselected PC cases are sparce in Italy. We assessed this prevalence in a multicentre cohort, to derive recommendations for PC patients.
    METHODS: Clinical data of 1200 consecutive PC patients, of any age and stage, tested with a multigene germline panel were collected. A descriptive analysis of gPV frequency and clinical variables was performed both in 1092 patients tested for an 18 genes core-panel (CP-18 cohort) and in 869 patients screened only for CDKN2A.
    RESULTS: 11.5 % (126/1092) of CP-18 cohort patients harbored a gPV in ≥ 1 gene. Highest gPV frequencies were detected in ATM (3.1 %), BRCA2 (2.9 %), BRCA1 (1.6 %), CHEK2 (1.1 %). Patients harboring any CP-18 gene and BRCA1-2 gPV were younger and with a higher rate of personal (PH) or family history (FH) of cancer when compared to no gPV patients. The risk of having a gPV was ≥ 7 % in all subgroups of patients, including those aged > 73, with tumor stage I-III and negative FH/PH. CDKN2A gPV were detected in 2.6 % (23/869) of patients.
    CONCLUSIONS: A remarkable prevalence of gPV in cancer predisposition and DDR genes is reported in this large multicentre cohort of consecutive and unselected PC patients. Therefore, we recommend multigene germline testing (at least including BRCA1-2, ATM, CDKN2A, PALB2) for all PC patients, irrespective of age, stage, PH/FH.
    Keywords:  ATM; BRCA; Cancer predisposition genes; DNA damage repair; Germline pathogenic variant; Pancreatic cancer
    DOI:  https://doi.org/10.1016/j.ejca.2024.114226
  3. Breast Cancer. 2024 Jul 13.
    High-risk pathogenic germline variants in blood relatives of BRCA1/2 negative probands.
    Reiko Yoshida, Tomoko Kaneyasu, Arisa Ueki, Hideko Yamauchi, Shozo Ohsumi, Shinji Ohno, Daisuke Aoki, Shinichi Baba, Junko Kawano, Naomichi Matsumoto, Masao Nagasaki, Takayuki Ueno, Hitoshi Inari, Yusuke Kobayashi, Junko Takei, Osamu Gotoh, Mitsuyo Nishi, Miki Okamura, Keika Kaneko, Megumi Okawa, Misato Suzuki, Sayuri Amino, Mayuko Inuzuka, Tetsuo Noda, Seiichi Mori, Seigo Nakamura.
       BACKGROUND: Tailored, preventive cancer care requires the identification of pathogenic germline variants (PGVs) among potentially at-risk blood relatives (BRs). Cascade testing is carried out for BRs of probands who are positive for PGVs of an inherited cancer but not for negative probands. This study was conducted to examine the prevalence of PGVs for BRs of PGV-negative probands.
    METHODS: PGV prevalence was assessed for 682 BRs of 281 probands with BRCA1/BRCA2 wild-type hereditary breast and ovarian cancer (HBOC) syndrome.
    RESULTS: PGVs were discovered in 22 (45.8%) of the 48 BRs of the PGV-positive probands and in 14 (2.2%) of 634 BRs of the PGV-negative probands. Eleven PGVs on high-risk BRCA1, BRCA2, and TP53 genes were present only in BRs and not in the probands (probands vs BRs in Fisher exact test; p = 0.0104; odds ratio [OR] = 0.000 [0.000-0.5489 of 95% confidence interval]), partly due to the nature of the selection criteria. The enrichment of high-risk PGVs among BRs was also significant as compared with a non-cancer East Asian population (p = 0.0016; OR = 3.0791 [1.5521-5.6694]). PGV prevalence, risk class of gene, and genotype concordance were unaffected by the cancer history among BRs.
    CONCLUSION: These findings imply the necessity to construct a novel testing scheme to complement cascade testing.
    Keywords:  Blood relative analysis; Cascade testing; Genetic testing; Hereditary breast and ovarian cancer syndrome; Pathogenic germline variant
    DOI:  https://doi.org/10.1007/s12282-024-01615-0
  4. JCO Precis Oncol. 2024 Jul;8 e2400106
    Exome Sequencing Identifies Carriers of the Autosomal Dominant Cancer Predisposition Disorders Beyond Current Practice Guideline Recommendations.
    N Jewel Samadder, Emily Gay, Vanda Lindpere, Michelle L Bublitz, Lorelei A Bandel, Sebastian M Armasu, Robert A Vierkant, Matthew J Ferber, Eric W Klee, Nicholas B Larson, Teresa M Kruisselbrink, Jan B Egan, Jennifer L Kemppainen, Jessa S Bidwell, Jennifer L Anderson, Tammy M McAllister, T'Nita S Walker, Katie L Kunze, Michael A Golafshar, Margaret A Klint, Richard J Presutti, William V Bobo, Aleksander Sekulic, Jolene M Summer-Bolster, Cheryl L Willman, Konstantinos N Lazaridis.
       PURPOSE: The autosomal dominant cancer predisposition disorders hereditary breast and ovarian cancer (HBOC) and Lynch syndrome (LS) are genetic conditions for which early identification and intervention have a positive effect on the individual and public health. The goals of this study were to determine whether germline genetic screening using exome sequencing could be used to efficiently identify carriers of HBOC and LS.
    METHODS: Participants were recruited from three geographically and racially diverse sites in the United States (Rochester, MN; Phoenix, AZ; Jacksonville, FL). Participants underwent Exome+ sequencing (Helix Inc, San Mateo, CA) and return of results for specific genetic findings: HBOC (BRCA1 and BRCA1) and LS (MLH1, MSH2, MSH6, PMS2, and EPCAM). Chart review was performed to collect demographics and personal and family cancer history.
    RESULTS: To date, 44,306 participants have enrolled in Tapestry. Annotation and interpretation of all variants in genes for HBOC and LS resulted in the identification of 550 carriers (prevalence, 1.24%), which included 387 with HBOC (27.2% BRCA1, 42.8% BRCA2) and 163 with LS (12.3% MSH6, 8.8% PMS2, 4.5% MLH1, 3.8% MSH2, and 0.2% EPCAM). More than half of these participants (52.1%) were newly diagnosed carriers with HBOC and LS. In all, 39.2% of HBOC/LS carriers did not satisfy National Comprehensive Cancer Network (NCCN) criteria for genetic evaluation. NCCN criteria were less commonly met in underrepresented minority populations versus self-reported White race (51.5% v 37.5%, P = .028).
    CONCLUSION: Our results emphasize the need for wider utilization of germline genetic sequencing for enhanced screening and detection of individuals who have LS and HBOC cancer predisposition syndromes.
    DOI:  https://doi.org/10.1200/PO.24.00106
  5. Breast Cancer. 2024 Jul 17.
    Case series of Li-Fraumeni syndrome: carcinogenic mechanisms in breast cancer with TP53 pathogenic variant carriers.
    Mari Hosonaga, Eri Habano, Hiromi Arakawa, Keika Kaneko, Takeshi Nakajima, Naomi Hayashi, Ippei Fukada, Akira Nakamura, Yurie Haruyama, Tetsuyo Maeda, Hitoshi Inari, Takayuki Kobayashi, Eri Nakashima, Takayuki Ueno, Toshimi Takano, Shunji Takahashi, Shinji Ohno, Arisa Ueki.
       BACKGROUND: Li-Fraumeni syndrome (LFS), a hereditary condition attributed to TP53 pathogenic variants,(PV), is associated with high risks for various malignant tumors, including breast cancer. Notably, individuals harboring TP53 PVs are more likely (67-83%) to develop HER2 + breast cancer than noncarriers (16-25%). In this retrospective study, we evaluated the associations between TP53 variants and breast cancer phenotype.
    METHODS: We conducted a retrospective review of the medical records of patients with LFS treated at a single institution and reviewed the literature on TP53 functions and the mechanisms underlying HER2 + breast cancer development in LFS.
    RESULTS: We analyzed data for 10 patients with LFS from 8 families. The median age at the onset of the first tumor was 35.5 years. Only case 2 met the classic criteria; this patient harbored a nonsense variant, whereas the other patients carried missense variants. We observed that 9 of 10 patients developed breast cancer. Immunohistochemical analyses revealed that 40% of breast cancers in patients with LFS were HR - /HER2 + . The median age at the onset of breast cancer was slightly younger in HR - /HER2 + tumors than in HR + /HER2 -  tumors (31 years and 35.5 years, respectively).
    CONCLUSIONS: The occurrence of HER2 + breast cancer subtype was 40% in our LFS case series, which is greater than that in the general population (16-25%). Some TP53 PVs may facilitate HER2-derived oncogenesis in breast cancer. However, further studies with larger sample sizes are warranted to clarify the oncogenic mechanisms underlying each subtype of breast cancer in TP53 PV carriers.
    Keywords:   TP53 ; Breast cancer; Hormone receptor; Human epidermal growth factor receptor 2; Li-Fraumeni syndrome
    DOI:  https://doi.org/10.1007/s12282-024-01612-3
  6. J Surg Oncol. 2024 Jul 17.
    Survival benefit associated with screening of patients at elevated risk for pancreatic cancer.
    William J Kane, Kathleen R Haden, Elizabeth N Martin, Vanessa M Shami, Andrew Y Wang, Daniel S Strand, Sara J Adair, Sarbajeet Nagdas, Allan Tsung, Victor M Zaydfudim, Reid B Adams, Todd W Bauer.
      BACKGROUND & OBJECTIVES: Screening for pancreatic cancer is recommended for individuals with a strong family history, certain genetic syndromes, or a neoplastic cyst of the pancreas. However, limited data supports a survival benefit attributable to screening these higher-risk individuals.
    METHODS: All patients enrolled in screening at a High-Risk Pancreatic Cancer Clinic (HRC) from July 2013 to June 2020 were identified from a prospectively maintained institutional database and compared to patients evaluated at a Surgical Oncology Clinic (SOC) at the same institution during the same period. Clinical outcomes of patients selected for surgical resection, particularly clinicopathologic stage and overall survival, were compared.
    RESULTS: Among 826 HRC patients followed for a median (IQR) of 2.3 (0.8-4.2) years, 128 were selected for surgical resection and compared to 402 SOC patients selected for resection. Overall survival was significantly longer among HRC patients (median survival: not reached vs. 2.6 years, p < 0.001). Among 31 HRC and 217 SOC patients with a diagnosis of pancreatic ductal adenocarcinoma (PDAC), the majority of HRC patients were diagnosed with stage 0 disease (carcinoma in situ), while the majority of SOC patients were diagnosed with stage II disease (p < 0.001). Overall survival after resection of invasive PDAC was also significantly longer among HRC patients compared to SOC patients (median survival 5.5 vs. 1.6 years, p = 0.002).
    CONCLUSION: Patients at increased risk for PDAC and followed with guideline-based screening exhibited downstaging of disease and improved survival from PDAC in comparison to patients who were not screened.
    Keywords:  cancer screening; pancreatectomy; pancreatic adenocarcinoma; pancreatic cancer; pancreatoduodenectomy; surgical oncology
    DOI:  https://doi.org/10.1002/jso.27784
  7. Radiographics. 2024 Aug;44(8): e230202
    Li-Fraumeni Syndrome: Imaging Features and Guidelines.
    Babina Gosangi, Irene Dixe de Oliveira Santo, Abhishek Keraliya, Yifan Wang, David Irugu, Richard Thomas, Ashish Khandelwal, Ami N Rubinowitz, Anna S Bader.
      Li-Fraumeni syndrome (LFS) is a rare autosomal dominant familial cancer syndrome caused by germline mutations of the tumor protein p53 gene (TP53), which encodes the p53 transcription factor, also known as the "guardian of the genome." The most common types of cancer found in families with LFS include sarcomas, leukemia, breast malignancies, brain tumors, and adrenocortical cancers. Osteosarcoma and rhabdomyosarcoma are the most common sarcomas. Patients with LFS are at increased risk of developing early-onset gastric and colon cancers. They are also at increased risk for several other cancers involving the thyroid, lungs, ovaries, and skin. The lifetime risk of cancer in individuals with LFS is greater than 70% in males and greater than 90% in females. Some patients with LFS develop multiple primary cancers during their lifetime, and guidelines have been established for screening these patients. Whole-body MRI is the preferred modality for annual screening of these patients. The management guidelines for patients with LFS vary, as these individuals are more susceptible to developing radiation-induced cancers-for example, women with LFS and breast cancer are treated with total mastectomy instead of lumpectomy with radiation to the breast. The authors review the role of imaging, imaging guidelines, and imaging features of tumors in the setting of LFS. ©RSNA, 2024 Supplemental material is available for this article.
    DOI:  https://doi.org/10.1148/rg.230202
  8. Sci Rep. 2024 Jul 13. 14(1): 16183
    A comprehensive analysis of germline predisposition to early-onset ovarian cancer.
    Klara Horackova, Petra Zemankova, Petr Nehasil, Michal Vocka, Milena Hovhannisyan, Katerina Matejkova, Marketa Janatova, Marta Cerna, Petra Kleiblova, Sandra Jelinkova, Barbora Stastna, Pavel Just, Tatana Dolezalova, Barbora Nemcova, Marketa Urbanova, Monika Koudova, Jana Hazova, Eva Machackova, Lenka Foretova, Viktor Stranecky, Michal Zikan, Zdenek Kleibl, Jana Soukupova.
      The subset of ovarian cancer (OC) diagnosed ≤ 30yo represents a distinct subgroup exhibiting disparities from late-onset OC in many aspects, including indefinite germline cancer predisposition. We performed DNA/RNA-WES with HLA-typing, PRS assessment and survival analysis in 123 early-onset OC-patients compared to histology/stage-matched late-onset and unselected OC-patients, and population-matched controls. Only 6/123(4.9%) early-onset OC-patients carried a germline pathogenic variant (GPV) in high-penetrance OC-predisposition genes. Nevertheless, our comprehensive germline analysis of early-onset OC-patients revealed two divergent trajectories of potential germline susceptibility. Firstly, overrepresentation analysis highlighted a connection to breast cancer (BC) that was supported by the CHEK2 GPV enrichment in early-onset OC(p = 1.2 × 10-4), and the presumably BC-specific PRS313, which successfully stratified early-onset OC-patients from controls(p = 0.03). The second avenue pointed towards the impaired immune response, indicated by LY75-CD302 GPV(p = 8.3 × 10-4) and diminished HLA diversity compared with controls(p = 3 × 10-7). Furthermore, we found a significantly higher overall GPV burden in early-onset OC-patients compared to controls(p = 3.8 × 10-4). The genetic predisposition to early-onset OC appears to be a heterogeneous and complex process that goes beyond the traditional Mendelian monogenic understanding of hereditary cancer predisposition, with a significant role of the immune system. We speculate that rather a cumulative overall GPV burden than specific GPV may potentially increase OC risk, concomitantly with reduced HLA diversity.
    Keywords:  Early-onset; Germline whole exome sequencing; HLA; Mutation burden; Ovarian cancer; Polygenic risk score
    DOI:  https://doi.org/10.1038/s41598-024-66324-2
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