bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2023–10–08
ten papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet
  1. Genome-First Approach of the Prevalence and Cancer Phenotypes of Pathogenic or Likely Pathogenic Germline TP53 Variants.
  2. Cancer-predisposing germline variants and subsequent cancer risk.
  3. [Myeloid neoplasms with germline predisposition].
  4. Risk of Radiation-Associated Secondary Malignancies among Patients with Breast Cancer Harboring TP53 Germline Variants.
  5. Association of glycated hemoglobin with risk of pancreatic cancer in high-risk individuals based on genetic and family history.
  6. Current and new frontiers in hereditary cancer surveillance: Opportunities for liquid biopsy.
  7. Surgical options for patients with early-stage breast cancer and pathogenic germline variants: an oncologist perspectives.
  8. The evaluation of the possibility of Li-Fraumeni syndrome in cancer patients in East Azarbaijan Province of Iran.
  9. Multiple TP53 p.R337H haplotypes and implications for tumor susceptibility.
  10. TRIM28 inactivation in epithelial nephroblastoma is frequent and often associated with predisposing TRIM28 germline variants.
  1. HGG Adv. 2023 Sep 29. pii: S2666-2477(23)00074-X. [Epub ahead of print] 100242
    Genome-First Approach of the Prevalence and Cancer Phenotypes of Pathogenic or Likely Pathogenic Germline TP53 Variants.
    Kelvin C de Andrade, Natasha T Strande, Jung Kim, Jeremy S Haley, Jessica N Hatton, Megan N Frone, Payal P Khincha, Gretchen M Thone, Uyenlinh L Mirshahi, Cynthia Schneider, Heena Desai, James T Dove, Diane T Smelser, Penn Medicine BioBank, Regeneron Genetics Center, Arnold J Levine, Kara N Maxwell, Douglas R Stewart, David J Carey, Sharon A Savage.
      Pathogenic or likely pathogenic (P/LP) germline TP53 variants are the primary cause of Li-Fraumeni syndrome (LFS), a hereditary cancer predisposition disorder characterized by early-onset cancers. The population prevalence of P/LP germline TP53 variants is estimated to be approximately one in every 3,500-20,000 individuals. However, these estimates are likely impacted by ascertainment biases and lack of clinical and genetic data to account for potential confounding factors, such as clonal hematopoiesis. Genome-first approaches of cohorts linked to phenotype data can further refine these estimates by identifying individuals with variants of interest and then assessing their phenotypes. This study evaluated P/LP germline (variant allele fraction ≥ 30%) TP53 variants in three cohorts: UK Biobank (UKB, n=200,590), Geisinger (n=170,503), and Penn Medicine Biobank (PMBB, n=43,731). A total of 109 individuals were identified with P/LP germline TP53 variants across the three databases. The TP53 p.R181H variant was the most frequently identified (9/109 individuals, 8%). A total of 110 cancers, including 47 hematologic cancers (47/110, 43%), were reported in 71 individuals. The prevalence of P/LP germline TP53 variants were conservatively estimated as 1:10,439 in UKB, 1:3,790 in Geisinger, and 1:2,983 in PMBB after removing related individuals and heterozygotes who had ever developed a hematologic cancer due to the potential confounding impact of clonal hematopoiesis. These varying estimates likely reflect intrinsic selection biases of each database, such as healthcare or population-based contexts. Prospective studies of diverse, young cohorts are required to better understand population prevalence of germline TP53 variants and its associated cancer penetrance.
    DOI:  https://doi.org/10.1016/j.xhgg.2023.100242
  2. Lancet Oncol. 2023 Oct;pii: S1470-2045(23)00461-8. [Epub ahead of print]24(10): 1059-1061
    Cancer-predisposing germline variants and subsequent cancer risk.
    Cécile M Ronckers, Christian P Kratz, Amy Berrington de Gonzalez.
      
    DOI:  https://doi.org/10.1016/S1470-2045(23)00461-8
  3. Rinsho Ketsueki. 2023 ;64(9): 949-954
    [Myeloid neoplasms with germline predisposition].
    Kenichi Yoshida.
      With recent advances in sequencing technologies, novel genes associated with the predisposition to myeloid neoplasms have been discovered, and subsequent studies have shown that the incidence of myeloid neoplasms associated with germline variants is higher than expected. Accordingly, myeloid neoplasms with germline predisposition have represented a unique category in the recent WHO classification and the International Consensus Classification, and DDX41 mutation accounts for 2-5% of myeloid neoplasms. Clonal hematopoiesis commonly occurs in healthy individuals, especially in older people. For patients with germline predisposition, clonal hematopoiesis is frequently observed at a younger age and often associated with disease-specific driver mutations, leading to further understating of the pathogenesis of diseases.
    Keywords:  Clonal hematopoiesis; Germline predisposition; Myeloid neoplasms
    DOI:  https://doi.org/10.11406/rinketsu.64.949
  4. Int J Radiat Oncol Biol Phys. 2023 Oct 01. pii: S0360-3016(23)04757-0. [Epub ahead of print]117(2S): S45-S46
    Risk of Radiation-Associated Secondary Malignancies among Patients with Breast Cancer Harboring TP53 Germline Variants.
    G Cederquist, L Boe, M F Walsh, Z Stadler, A J Xu, B A Mueller, D A Roth O'Brien, M B Bernstein, J Cuaron, S F Bakhoum, S N Powell, A J Khan, M E Robson, K Maxwell, N K Taunk, L Z Braunstein.
       PURPOSE/OBJECTIVE(S): Radiation-associated malignancies are rare and poorly understood. TP53 encodes a multifunctional protein that maintains genome integrity and is the most common somatically mutated gene in cancer. Germline pathogenic variants of TP53 predispose carriers to several cancers comprising the Li-Fraumeni syndrome. It is hypothesized that carriers are also at increased risk of radiotherapy (RT)-associated secondary malignancies; however, reports are mixed. We evaluated the risk of secondary malignancies after breast RT among patients with Li-Fraumeni syndrome.
    MATERIALS/METHODS: This multi-institutional cohort study included carriers of TP53 germline variants who underwent surgical treatment for breast cancer between 1980 and 2020. Patients were stratified based on germline TP53 classification (pathogenic variants [PV] vs variants of uncertain significance [VUS]). The primary outcome of interest was the cumulative incidence risk of developing an in-field secondary cancer after radiotherapy for primary breast carcinoma.
    RESULTS: Ninety-one patients (57 PV and 34 VUS) were evaluated with a median age of 36 years (interquartile range [IQR] 31, 42) and a median follow up of 7.9 years (IQR 4.7, 14.4). Among those with PV who received RT (n = 22), 4 secondary non-breast cancers developed in the radiation field (15-year cumulative incidence 19% [95% CI: 4-43%]), whereas, among those with PV who did not receive RT (n = 35), 0 secondary non-breast cancers were observed in the treated breast (15-year cumulative incidence 0%; p = 0.043). We observed 3 radiation-associated sarcomas among patients with PV who received RT (15-year risk 12% [95% CI 2-33%]) compared with 0 among those who did not receive RT (p = 0.08). No RT-associated sarcomas were observed among 18 patients with TP53 VUS who received RT. RT was not associated with overall survival, despite higher T and N breast cancer stage among those receiving RT (p = 0.33). As expected, patients with PV were more likely than those with VUS to develop any secondary cancer following breast cancer treatment (15-year risk: 54% [95% CI: 33-72%] vs. 14% [95% CI: 3-36%]).
    CONCLUSION: Carriers of pathogenic variants of TP53 are at elevated risk of developing secondary malignancies after breast cancer treatment. This population is at particular risk of developing in-field secondary cancers following RT. This iatrogenic risk must be weighed against the anticipated therapeutic benefit of tumor control. Shared decision making is crucial in the radiotherapeutic management of breast cancer patients harboring the Li-Fraumeni syndrome.
    DOI:  https://doi.org/10.1016/j.ijrobp.2023.06.323
  5. Clin Transl Gastroenterol. 2023 Oct 06.
    Association of glycated hemoglobin with risk of pancreatic cancer in high-risk individuals based on genetic and family history.
    Bechien U Wu, Qiaoling Chen, Becky H Moon, Eva Lustigova, Erin G Nielsen, Monica Alvarado, Syed A Ahmed.
       BACKGROUND: Screening for pancreatic cancer (PC) is suggested for high-risk individuals (HRI). Additional risk factors may enhance early detection in this population.
    METHODS: Retrospective cohort study among patients with germline variants and/or familial pancreatic cancer in an integrated healthcare system between 2003-2019. We calculated incidence rate (IR) by risk category and performed a nested case-control study to evaluate relationship between HbA1C and PC within 3 years prior to diagnosis(cases) or match date(controls). Cases were matched 1:4 by age, sex, and timing of HbA1c. Logistic regression was performed to assess independent association with PC.
    RESULTS: We identified 5,931 HRIs: 1175(19.8%) familial PC, 45(0.8%) high-risk germline variants (STK11, CDKN2A), 4097(69.1%) had other germline variants (ATM, BRCA 1, BRCA 2, CASR, CDKN2A, CFTR, EPCAM, MLH1, MSH2, MSH6, PALB2, PRSS1, STK11, TP53), and 614(10.4%) had both germline variants and family history. 68 (1.1%) patients developed PC; 50% were metastatic at diagnosis. High-risk variant was associated with greatest risk of PC, IR=85.1(95% CI: 36.7-197.6)/10,000 person-years, other germline variants and FDR had IR=33 (18.4, 59.3) while IR among ≥2 FDR alone was 10.7 (6.1, 18.8). HbA1c was significantly higher among cases vs. controls (median=7.0% vs. 6.4%, p=0.02). In multivariable analysis, every 1% increase in HbA1c was associated with 36% increase in odds of PC (OR=1.36, 95% CI: 1.08-1.72). Pancreatitis was independently associated with risk of PC (OR 3.93, 95% CL1.19,12.91).
    CONCLUSION: Risk of PC varies among high-risk individuals. HbA1c and history of pancreatitis may be useful additional markers for early detection in this patient population.
    DOI:  https://doi.org/10.14309/ctg.0000000000000650
  6. Am J Hum Genet. 2023 Oct 05. pii: S0002-9297(23)00290-2. [Epub ahead of print]110(10): 1616-1627
    Current and new frontiers in hereditary cancer surveillance: Opportunities for liquid biopsy.
    CHARM consortium
      At least 5% of cancer diagnoses are attributed to a causal pathogenic or likely pathogenic germline genetic variant (hereditary cancer syndrome-HCS). These individuals are burdened with lifelong surveillance monitoring organs for a wide spectrum of cancers. This is associated with substantial uncertainty and anxiety in the time between screening tests and while the individuals are awaiting results. Cell-free DNA (cfDNA) sequencing has recently shown potential as a non-invasive strategy for monitoring cancer. There is an opportunity for high-yield cancer early detection in HCS. To assess clinical validity of cfDNA in individuals with HCS, representatives from eight genetics centers from across Canada founded the CHARM (cfDNA in Hereditary and High-Risk Malignancies) Consortium in 2017. In this perspective, we discuss operationalization of this consortium and early data emerging from the most common and well-characterized HCSs: hereditary breast and ovarian cancer, Lynch syndrome, Li-Fraumeni syndrome, and Neurofibromatosis type 1. We identify opportunities for the incorporation of cfDNA sequencing into surveillance protocols; these opportunities are backed by examples of earlier cancer detection efficacy in HCSs from the CHARM Consortium. We seek to establish a paradigm shift in early cancer surveillance in individuals with HCSs, away from highly centralized, regimented medical screening visits and toward more accessible, frequent, and proactive care for these high-risk individuals.
    Keywords:  cell-free DNA; genetic predisposition; hereditary cancer syndromes; liquid biopsy; surveillance
    DOI:  https://doi.org/10.1016/j.ajhg.2023.08.014
  7. Front Oncol. 2023 ;13 1265197
    Surgical options for patients with early-stage breast cancer and pathogenic germline variants: an oncologist perspectives.
    Hikmat Abdel-Razeq.
      Breast cancer continues to be the most common cancer diagnosed among women worldwide. Family history of breast cancer is frequently encountered, and 5-15% of patients may carry inherited pathogenic germline variants, identification of which can be helpful for both; patients themselves and their unaffected close relatives. The availability and affordability of molecular diagnostics, like next generation sequencing (NGS), had resulted in wider adoption of such technologies to detect pathogenic variants of cancer-predisposing genes. International guidelines had recently broadened the indications for germline genetic testing to include much more patients, and also expanded the testing to include multi-gene panels, while some professional societies are calling for universal testing of all newly diagnosed patients with breast cancer, regardless of their age, personal or family history. The risk of experiencing a contralateral breast cancer (CBC) or ipsilateral recurrence, is well known. Such risk is highest with variants like BRCA1 and BRCA2, but less well-studied with other less common variants. The optimal local therapy for women with BRCA-associated breast cancer remains controversial, but tends to be aggressive and may involve bilateral mastectomies, which may not have any survival advantage. Additionally, surgical management of unaffected women, known to carry a pathogenic cancer-predisposing gene, may vary from surveillance to bilateral mastectomies, too. The oncological safety, and the higher satisfaction of unaffected women and patients with new surgical techniques, like the skin-sparing (SSM) and nipple-sparing (NSM) mastectomies, eased up the process of counselling. In this review, we address the oncological safety of less aggressive surgical options for both; patients and unaffected carriers.
    Keywords:  ATM; BRCA; CHEK2; PALB2; TP53; hereditary breast cancer; ipsilateral breast tumor recurrence; risk-reducing surgery
    DOI:  https://doi.org/10.3389/fonc.2023.1265197
  8. Nucleosides Nucleotides Nucleic Acids. 2023 Oct 06. 1-10
    The evaluation of the possibility of Li-Fraumeni syndrome in cancer patients in East Azarbaijan Province of Iran.
    Maryam Esmaeilzadeh Aghjeh, Mohammad Ali Hosseinpour Feizi, Reza Safaralizadeh, Abbas Ali Hosseinpour Feizi, Nasser Pouladi.
       INTRODUCTION: In 1969, Li-Fraumeni syndrome (LFS), which is a rare cancer predisposition syndrome, was reported for the first time. The main problem in LFS is the mutation in the TP53 gene, which is a crucial tumor suppressor gene in the cell cycle. A hereditary syndrome is inherited in an autosomal dominant pattern. There is a significant correlation between this syndrome and various cancers such as sarcoma, breast cancer, brain tumors, and different other types of malignancies. This study aimed to identify the possibility of LFS in cancer patients in the East Azarbaijan, Iran.
    METHODS: In this experimental study, 45 children with cancer in the Northwest of Iran were investigated for LFS. DNA was extracted from the whole blood cells using the salting-out method. The region within the exons 5-8 of the TP53 gene has been replicated via Polymerase Chain Reaction (PCR) method. The PCR products were sent for Sanger sequencing, and finally, the data were analyzed by Chromas software.
    RESULTS: In the studied probands, in 12 (26.67%) cases, polymorphisms in Exon 6 and Introns 6 and Intron 7 were identified, and no mutation was observed in exons 5-8 of the TP53 gene.
    CONCLUSION: Our results show that there were no mutations in exons 5-8 of the TP53 gene as an indication of LFS possibility in these families. Further studies are needed to be done in a bigger population, and Next-Generation Sequencing (NGS) needs to be done to evaluate the whole genome of these patients to complete our data.
    Keywords:  Cancer; Li-Fraumeni syndrome; TP53 gene; heredity; mutation
    DOI:  https://doi.org/10.1080/15257770.2023.2264361
  9. HGG Adv. 2023 Oct 03. pii: S2666-2477(23)00076-3. [Epub ahead of print] 100244
    Multiple TP53 p.R337H haplotypes and implications for tumor susceptibility.
    Emilia M Pinto, Cintia Fridman, Bonald C Figueiredo, Hector Salvador, Manuel R Teixeira, Carla Pinto, Manuela Pinheiro, Christian P Kratz, Cinzia Lavarino, Edith A M F Legal, Anh Le, Gregory Kelly, Erika Koeppe, Elena M Stoffel, Kelsey Breen, Stefanie Hahner, Britta Heinze, Piti Techavichit, Amanda Krause, Tsutomu Ogata, Yasuko Fujisawa, Michael F Walsh, Huma Q Rana, Kara N Maxwell, Judy E Garber, Carlos Rodriguez-Galindo, Raul C Ribeiro, Gerard P Zambetti.
      The germline TP53 p.R337H mutation is reported as the most common germline TP53 variant. It exists at a remarkably high frequency in the population of Southeast Brazil as founder mutation in two distinct haplotypes with the most frequent co-segregating with the p.E134* variant of the XAF1 tumor suppressor and an increased cancer risk. Founder mutations demonstrate linkage disequilibrium with neighboring genetic polymorphic markers that can be used to identify the founder variant in different geographic regions and diverse populations. We report here a shared haplotype among Brazilian, Portuguese, and Spanish families and the existence of three additional distinct TP53 p.R337H alleles. Mitochondrial DNA sequencing and Y-STR profiling of Brazilian carriers of the founder TP53 p.R337H allele reveals an excess of native American haplogroups in maternal lineages and exclusively European haplogroups in paternal lineages, consistent with communities established through male European settlers with extensive intermarriage with Indigenous women. The identification of founder and independent TP53 p.R337H alleles underlines the importance for considering the haplotype as a functional unit and the additive effects of constitutive polymorphisms and associated variants in modifier genes that can influence the cancer phenotype.
    Keywords:  Brazil; Iberian Peninsula; R337H; Sephardic Jewish; Y-STR; ancestry; cancer predisposition; founder mutation; haplogroup; haplotype; mitochondrial DNA
    DOI:  https://doi.org/10.1016/j.xhgg.2023.100244
  10. J Pathol. 2023 Oct 04.
    TRIM28 inactivation in epithelial nephroblastoma is frequent and often associated with predisposing TRIM28 germline variants.
    Jenny Wegert, Anne Kristin Fischer, Balazs Palhazi, Taryn D Treger, Cäcilia Hilgers, Barbara Ziegler, Hyunchul Jung, Eva Jüttner, Andreas Waha, Jörg Fuchs, Steven W Warmann, Michael C Frühwald, Jochen Hubertus, Kathy Pritchard-Jones, Norbert Graf, Sam Behjati, Rhoikos Furtwängler, Manfred Gessler, Christian Vokuhl.
      Wilms tumors (WTs) are histologically diverse childhood cancers with variable contributions of blastema, stroma, and epithelia. A variety of cancer genes operate in WTs, including the tripartite-motif-containing-28 gene (TRIM28). Case reports and small case series suggest that TRIM28 mutations are associated with epithelial morphology and WT predisposition. Here, we systematically investigated the prevalence of TRIM28 inactivation and predisposing mutations in a cohort of 126 WTs with >2/3 epithelial cells, spanning 20 years of biobanking in the German SIOP93-01/GPOH and SIOP2001/GPOH studies. Overall, 44.4% (56/126) cases exhibited loss of TRIM28 by immunohistochemical staining. Of these, 48 could be further analyzed molecularly, revealing TRIM28 sequence variants in each case - either homozygous (~2/3) or heterozygous with epigenetic silencing of the second allele (~1/3). The majority (80%) of the mutations resulted in premature stops and frameshifts. In addition, we detected missense mutations and small deletions predicted to destabilize the protein through interference with folding of key structural elements such as the zinc-binding clusters of the RING, B-box-2, and PHD domains or the central coiled-coil region. TRIM28-mutant tumors otherwise lacked WT-typical IGF2 alterations or driver events, except for rare TP53 progression events that occurred with expected frequency. Expression profiling identified TRIM28-mutant tumors as a homogeneous subset of epithelial WTs that mostly present with stage I disease. There was a high prevalence of perilobar nephrogenic rests, putative precursor lesions, that carried the same biallelic TRIM28 alterations in 7/7 cases tested. Importantly, 46% of the TRIM28 mutations were present in blood cells or normal kidney tissue, suggesting germline events or somatic mosaicism, partly supported by family history. Given the high prevalence of predisposing variants in TRIM28-driven WT, we suggest that immunohistochemical testing of TRIM28 be integrated into diagnostic practice as the management of WT in predisposed children differs from that with sporadic tumors. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
    Keywords:  TRIM28; Wilms tumor; epithelial WT; genetic tumor predisposition; transposable elements
    DOI:  https://doi.org/10.1002/path.6206
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