bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2022–05–15
fourteen papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet
  1. Lung cancer as a predominant feature in a patient with Peutz-Jeghers syndrome: Case report.
  2. Identification of heritable rare variants associated with early-stage lung adenocarcinoma risk.
  3. The genetics of tumor suppression by p53.
  4. Complex Germline K757N Mutation in Non-Small-Cell Lung Cancer: A Case Report.
  5. The genetics of hereditary cancer risk syndromes in Brazil: a comprehensive analysis of 1682 patients.
  6. Clonal hematopoiesis in patients with ANKRD26 or ETV6 germline mutations.
  7. Whole exome sequencing identifies novel germline variants of SLC15A4 gene as potentially cancer predisposing in familial colorectal cancer.
  8. Familial platelet disorder due to germline exonic deletions in RUNX1: a diagnostic challenge with distinct alterations of the transcript isoform equilibrium.
  9. Beyond BRCA: The Emerging Significance of DNA Damage Response and Personalized Treatment in Pancreatic and Prostate Cancer Patients.
  10. Simultaneous Detection of 2 Types of Malignancies in a Pediatric Patient on FDG PET/CT Led to Diagnosis of Li-Fraumeni Syndrome.
  11. Recurrent Germline Variant in RAD21 Predisposes Children to Lymphoblastic Leukemia or Lymphoma.
  12. Germline mutations in mitochondrial complex I reveal genetic and targetable vulnerability in IDH1-mutant acute myeloid leukaemia.
  13. Germline sequencing for presumed germline pathogenic variants via tumor-only comprehensive genomic profiling.
  14. Germline MUTYH mutations and high-grade gliomas: novel evidence for a potential association.
  1. Thorac Cancer. 2022 May 11.
    Lung cancer as a predominant feature in a patient with Peutz-Jeghers syndrome: Case report.
    Florentia Fostira, Elena Fountzilas, Kyriaki Papadopoulou, Theodoros Karaiskos, Ourania Mpatsi, Nikoleta Pastelli, Giannis Mountzios, Irene Konstantopoulou, George Fountzilas.
      Peutz-Jeghers syndrome (PJS) is characterized by mucocutaneous pigmentation and gastrointestinal hamartomatous polyposis, which can lead to intussusception. PJS patients face high lifetime risks for various cancer types, with the majority of patients being diagnosed with tumors along the gastrointestinal tract. Herein, we present the case of a 34-year-old man who carried a germline STK11 pathogenic variant, while lacking the cardinal features of PJS syndrome. Interestingly, he was diagnosed with lung adenocarcinoma despite being a never-smoker. Tumor testing revealed clinically relevant molecular alterations, including the known germline pathogenic variant STK11, a KRAS somatic pathogenic variant, and FGFR3 gene amplification. Treatment with standard chemotherapy and immunotherapy did not have a clinical benefit. Due to clinical deterioration, the patient deceased 18 months after his initial diagnosis prior to having the chance for targeted therapy. Identification of rare hereditary cancer syndromes and the respective presence of tumor biomarkers can provide important alternatives to targeted treatments, including immunotherapy in patients with tumors unresponsive to conventional treatment protocols. This case highlights that although only a small proportion of lung cancer diagnoses will be due to hereditary predisposition, STK11 germline carriers should be under close surveillance for early detection of lung cancer.
    Keywords:  Peutz-Jeghers syndrome; STK11; case report; immunotherapy; lung cancer
    DOI:  https://doi.org/10.1111/1759-7714.14447
  2. Transl Lung Cancer Res. 2022 Apr;11(4): 509-522
    Identification of heritable rare variants associated with early-stage lung adenocarcinoma risk.
    Rui Fu, Jia-Tao Zhang, Rong-Rong Chen, Hong Li, Zai-Xian Tai, Hao-Xiang Lin, Jian Su, Xiang-Peng Chu, Chao Zhang, Zhen-Bin Qiu, Zi-Hao Chen, Wen-Fang Tang, Song Dong, Xue-Ning Yang, Guo-Qing Zhang, Guo-Ping Zhao, Yi-Long Wu, Wen-Zhao Zhong.
       Background: In East Asia, the number of patients with adenocarcinoma, especially those presenting with ground-glass nodules (GGNs), is gradually increasing. Family aggregation of pulmonary GGNs is not uncommon; however, genetic predisposition in these patients remains poorly understood and identification of genes involved in the cause of these early-stage lung cancers might contribute to understanding of the underlying mechanisms and potential prevention strategies.
    Methods: Fifty patients with early-stage lung adenocarcinoma (LUAD) presenting as GGNs and a first-degree family history of lung cancer (FHLC) from 34 independent families were enrolled into this study. Germline mutations of these patients were analyzed with whole exome sequencing (WES) and compared with age- and sex-matched 39 patients with sporadic lung cancer and 689 local healthy people. We used a stepwise variant filtering strategy, gene-based burden testing, and enrichment analysis to investigate rare but potentially pathogenic heritable mutations. Somatic tumor mutations were analyzed to consolidate germline findings.
    Results: In total, 1,571 single nucleotide variants (SNVs) and 238 frameshifts with a minor allele frequency (MAF) <0.01, which were rare, recurrent, and potentially damaging candidates, were finally identified through the filtering in the GGN cohort. Pathway analysis showed the extracellular matrix to be the top dysregulated pathway. Gene-based burden testing of these highly disruptive risk-conferring heritable variants showed that MSH5 [odds ratio (OR), 9.28, 95% confidence interval (CI): 2.49-35.87], MMP9 (OR, 8.11, 95% CI: 2.22-28.43), and CYP2D6 (OR, 8.09, 95% CI: 2.68-24.92) were significantly enriched in our cohort (P<0.05). The number of rare damaging germline variants in non-smoking patients was significantly higher than that of smoking-affected patients (Spearman's ρ=-0.39, P=0.02).
    Conclusions: Heritable, potentially deleterious, and rare candidate variants of MSH5, MMP9 and CYP2D6 were significantly associated with early-stage LUAD presenting with GGNs. Nonsmoking patients likely have a higher genetic predisposition to this type of cancer than smoking-affected patients. These results have extended our understanding of the underlying mechanisms of early-stage LUAD.
    Keywords:  Lung cancer; adenocarcinoma; genetic predisposition; germline mutation; ground-glass nodule (GGN)
    DOI:  https://doi.org/10.21037/tlcr-21-789
  3. FASEB J. 2022 May;36 Suppl 1
    The genetics of tumor suppression by p53.
    Maureen Murphy, Jessica Leung, Julia Leu, Alexandra Indeglia, Nicole Clarke, Toshitha Kannan, Nicole Kirven, Thibaut Barnoud, Andrew Kossenkov, Donna L George.
      Mutational inactivation of TP53 occurs commonly in cancer. In addition to mutation, there are over two hundred germline genetic variants in the TP53 coding region; some of these produce partially functional (hypomorphic) protein. Presently the impact of hypomorphic p53 variants on cancer risk is unknown. Also missing is a test to distinguish hypomorphs from benign variants and/or wild type p53. We report that two African-centric hypomorphs of TP53, Pro47Ser and Tyr107His, share common activities. Specifically, these variants share an increased propensity to misfold into a conformation specific for mutant, misfolded p53, and to activate NF-kB. These hypomorphs also increase migration and invasion, and share common impact on metabolism and drug resistance. RNA sequencing data reveals a gene signature that is predictive of hypomorphic p53 from wild type or benign variants. These data support a role for misfolding of hypomorphic p53 on cancer risk and the efficacy of cancer therapy. They also suggest that a predictive gene signature could have profound impact on the over 4 million individuals in the United States with germline coding region variants of p53.
    DOI:  https://doi.org/10.1096/fasebj.2022.36.S1.0I212
  4. Case Rep Oncol. 2022 Jan-Apr;15(1):15(1): 285-290
    Complex Germline K757N Mutation in Non-Small-Cell Lung Cancer: A Case Report.
    Boaz Wong, Sara Moore, Paul Wheatley-Price.
      Epidermal growth factor receptor (EGFR) mutations are usually oncogenic drivers of lung tumor development and progression. While common sensitizing mutations respond well to targeted therapy, the relevance of germline EGFR mutations is less clear. We describe a 65-year-old, previously healthy, male diagnosed with non-small-cell lung cancer. Familial history for lung cancer is negative. Targeted next-generation sequencing on the tumor biopsy sample revealed an atypical EGFR K757N mutation at 50% allele frequency and genetic review of a previously acquired gastric sample confirms the mutation as a germline change. He received standard first-line chemoimmunotherapy with carboplatin, pemetrexed, and pembrolizumab, and after 8 months therapy continues, with stable disease, to receive maintenance pemetrexed and pembrolizumab. To our knowledge, this is the first report of an atypical, germline K757N EGFR mutation. While the clinical relevance of this mutation is unclear, standard reporting of the allelic frequency of novel, atypical mutations can detect potential germline changes.
    Keywords:  Atypical mutation; Case report; Epidermal growth factor receptor; Germline mutation; Non-small-cell lung cancer
    DOI:  https://doi.org/10.1159/000523734
  5. Eur J Hum Genet. 2022 May 09.
    The genetics of hereditary cancer risk syndromes in Brazil: a comprehensive analysis of 1682 patients.
    Jarbas Maciel de Oliveira, Nuria Bengala Zurro, Antonio Victor Campos Coelho, Marcel Pinheiro Caraciolo, Rodrigo Bertollo de Alexandre, Murilo Castro Cervato, Renata Moldenhauer Minillo, George de Vasconcelos Carvalho Neto, Ivana Grivicich, João Bosco Oliveira.
      Hereditary cancer risk syndromes are caused by germline variants, commonly in tumor suppressor genes. Most studies on hereditary cancer have been conducted in white populations. We report the largest study in Brazilian individuals with multiple ethnicities. We genotyped 1682 individuals from all country regions with Next-generation sequencing (NGS) panels. Most were women with a personal/family history of cancer, mostly breast and ovarian. We identified 321 pathogenic/likely pathogenic (P/LP) variants in 305 people (18.1%) distributed among 32 genes. Most were on BRCA1 and BRCA2 (129 patients, 26.2% and 14.3% of all P/LP, respectively), MUTYH (42 monoallelic patients, 13.1%), PALB2 (25, 7.8%), Lynch syndrome genes (17, 5.3%), and TP53 (17, 5.3%). Transheterozygosity prevalence in our sample was 0.89% (15/1682). BRCA1/BRCA2 double heterozygosity rate was 0.78% (1/129) for BRCA variants carriers and 0.06% (1/1682) overall. We evaluated the performance of the genetic testing criteria by NCCN and the Brazilian National Health Agency (ANS). The inclusion criteria currently used in Brazil fail to identify 17%-25% of carriers of P/LP variants in hereditary cancer genes. Our results add knowledge on the Brazilian spectrum of cancer risk germline variants, demonstrate that large multigene panels have high positivity rates, and indicate that Brazilian inclusion criteria for genetic testing should be improved.
    DOI:  https://doi.org/10.1038/s41431-022-01098-7
  6. Blood Adv. 2022 May 10. pii: bloodadvances.2022007211. [Epub ahead of print]
    Clonal hematopoiesis in patients with ANKRD26 or ETV6 germline mutations.
    Michael W Drazer, Claire Christine Homan, Kai Yu, Marcela Cavalcante de Andrade Silva, Kelsey E McNeely, Matthew J Pozsgai, Maria Acevedo-Mendez, Jeremy P Segal, Peng Wang, Jinghua Feng, Sarah King, Erika Mijin Kwon Kim, Sophia Claire Korotev, David Michael Lawrence, Andreas W Schreiber, Christopher N Hahn, Hamish S Scott, Raman Sood, Nisc Nisc Comparative Sequencing Program, Elvira D R P Velloso, Anna L Brown, Paul P Liu, Lucy A Godley.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2022007211
  7. Mol Genet Genomics. 2022 May 13.
    Whole exome sequencing identifies novel germline variants of SLC15A4 gene as potentially cancer predisposing in familial colorectal cancer.
    Diamanto Skopelitou, Aayushi Srivastava, Beiping Miao, Abhishek Kumar, Dagmara Dymerska, Nagarajan Paramasivam, Matthias Schlesner, Jan Lubinski, Kari Hemminki, Asta Försti, Obul Reddy Bandapalli.
      About 15% of colorectal cancer (CRC) patients have first-degree relatives affected by the same malignancy. However, for most families the cause of familial aggregation of CRC is unknown. To identify novel high-to-moderate-penetrance germline variants underlying CRC susceptibility, we performed whole exome sequencing (WES) on four CRC cases and two unaffected members of a Polish family without any mutation in known CRC predisposition genes. After WES, we used our in-house developed Familial Cancer Variant Prioritization Pipeline and identified two novel variants in the solute carrier family 15 member 4 (SLC15A4) gene. The heterozygous missense variant, p. Y444C, was predicted to affect the phylogenetically conserved PTR2/POT domain and to have a deleterious effect on the function of the encoded peptide/histidine transporter. The other variant was located in the upstream region of the same gene (GRCh37.p13, 12_129308531_C_T; 43 bp upstream of transcription start site, ENST00000266771.5) and it was annotated to affect the promoter region of SLC15A4 as well as binding sites of 17 different transcription factors. Our findings of two distinct variants in the same gene may indicate a synergistic up-regulation of SLC15A4 as the underlying genetic cause and implicate this gene for the first time in genetic inheritance of familial CRC.
    Keywords:  Familial colorectal cancer; Germline variant; SLC15A4; Whole exome sequencing
    DOI:  https://doi.org/10.1007/s00438-022-01896-0
  8. Leuk Lymphoma. 2022 May 09. 1-10
    Familial platelet disorder due to germline exonic deletions in RUNX1: a diagnostic challenge with distinct alterations of the transcript isoform equilibrium.
    Marie Engvall, Ylva Karlsson, Ekaterina Kuchinskaya, Åsa Jörnegren, Lucy Mathot, Tatjana Pandzic, Josefine Palle, Viktor Ljungström, Lucia Cavelier, Eva Hellström Lindberg, Jörg Cammenga, Panagiotis Baliakas.
      Germline pathogenic variants in RUNX1 are associated with familial platelet disorder with predisposition to myeloid malignancies (FPD/MM) with intragenic deletions in RUNX1 accounting for almost 7% of all reported variants. We present two new pedigrees with FPD/MM carrying two different germline RUNX1 intragenic deletions. The aforementioned deletions encompass exons 1-2 and 9-10 respectively, with the exon 9-10 deletion being previously unreported. RNA sequencing of patients carrying the exon 9-10 deletion revealed a fusion with LINC00160 resulting in a change in the 3' sequence of RUNX1. Expression analysis of the transcript isoform demonstrated altered RUNX1a/b/c ratios in carriers from both families compared to controls. Our data provide evidence on the impact of intragenic RUNX1 deletions on transcript isoform expression and highlight the importance of routinely performing copy number variant analysis in patients with suspected MM with germline predisposition.
    Keywords:  FPD/MM; RUNX1 deletions; leukemia; thrombocytopenia
    DOI:  https://doi.org/10.1080/10428194.2022.2067997
  9. Int J Mol Sci. 2022 Apr 24. pii: 4709. [Epub ahead of print]23(9):
    Beyond BRCA: The Emerging Significance of DNA Damage Response and Personalized Treatment in Pancreatic and Prostate Cancer Patients.
    Bruna Dalmasso, Alberto Puccini, Fabio Catalano, Roberto Borea, Maria Laura Iaia, William Bruno, Giuseppe Fornarini, Stefania Sciallero, Sara Elena Rebuzzi, Paola Ghiorzo.
      The BRCA1/2 germline and/or somatic pathogenic variants (PVs) are key players in the hereditary predisposition and therapeutic response for breast, ovarian and, more recently, pancreatic and prostate cancers. Aberrations in other genes involved in homologous recombination and DNA damage response (DDR) pathways are being investigated as promising targets in ongoing clinical trials. However, DDR genes are not routinely tested worldwide. Due to heterogeneity in cohort selection and dissimilar sequencing approaches across studies, neither the burden of PVs in DDR genes nor the prevalence of PVs in genes in common among pancreatic and prostate cancer can be easily quantified. We aim to contextualize these genes, altered in both pancreatic and prostate cancers, in the DDR process, to summarize their hereditary and somatic burden in different studies and harness their deficiency for cancer treatments in the context of currently ongoing clinical trials. We conclude that the inclusion of DDR genes, other than BRCA1/2, shared by both cancers considerably increases the detection rate of potentially actionable variants, which are triplicated in pancreatic and almost doubled in prostate cancer. Thus, DDR alterations are suitable targets for drug development and to improve the outcome in both pancreatic and prostate cancer patients. Importantly, this will increase the detection of germline pathogenic variants, thereby patient referral to genetic counseling.
    Keywords:  BRCA; DNA damage response; PARP inhibitors; genetics; homologous recombination; mismatch repair; pancreatic cancer; prostate cancer
    DOI:  https://doi.org/10.3390/ijms23094709
  10. Clin Nucl Med. 2022 May 11.
    Simultaneous Detection of 2 Types of Malignancies in a Pediatric Patient on FDG PET/CT Led to Diagnosis of Li-Fraumeni Syndrome.
    Ying Kan, Yukun Si, Wei Wang, Jigang Yang.
       ABSTRACT: A 17-month-old girl underwent FDG PET/CT to evaluate a right adrenal lesion, which showed abnormal 18F-FDG avidity. In addition, an unexpected lesion with mild 18F-FDG uptake was noted in the right anterior thoracic wall. Pathology demonstrated adrenocortical carcinoma in the right adrenal and rhabdosarcoma in both the left forearm and right anterior thoracic wall. Gene analysis confirmed the diagnosis of Li-Fraumeni syndrome. The present case emphasized FDG PET/CT value of showing simultaneously multiple lesions in Li-Fraumeni syndrome, especially in the early stage without the gene analysis result.
    DOI:  https://doi.org/10.1097/RLU.0000000000004266
  11. Int J Mol Sci. 2022 May 05. pii: 5174. [Epub ahead of print]23(9):
    Recurrent Germline Variant in RAD21 Predisposes Children to Lymphoblastic Leukemia or Lymphoma.
    Anne Schedel, Ulrike Anne Friedrich, Mina N F Morcos, Rabea Wagener, Juha Mehtonen, Titus Watrin, Claudia Saitta, Triantafyllia Brozou, Pia Michler, Carolin Walter, Asta Försti, Arka Baksi, Maria Menzel, Peter Horak, Nagarajan Paramasivam, Grazia Fazio, Robert J Autry, Stefan Fröhling, Meinolf Suttorp, Christoph Gertzen, Holger Gohlke, Sanil Bhatia, Karin Wadt, Kjeld Schmiegelow, Martin Dugas, Daniela Richter, Hanno Glimm, Merja Heinäniemi, Rolf Jessberger, Gianni Cazzaniga, Arndt Borkhardt, Julia Hauer, Franziska Auer.
      Somatic loss of function mutations in cohesin genes are frequently associated with various cancer types, while cohesin disruption in the germline causes cohesinopathies such as Cornelia-de-Lange syndrome (CdLS). Here, we present the discovery of a recurrent heterozygous RAD21 germline aberration at amino acid position 298 (p.P298S/A) identified in three children with lymphoblastic leukemia or lymphoma in a total dataset of 482 pediatric cancer patients. While RAD21 p.P298S/A did not disrupt the formation of the cohesin complex, it altered RAD21 gene expression, DNA damage response and primary patient fibroblasts showed increased G2/M arrest after irradiation and Mitomycin-C treatment. Subsequent single-cell RNA-sequencing analysis of healthy human bone marrow confirmed the upregulation of distinct cohesin gene patterns during hematopoiesis, highlighting the importance of RAD21 expression within proliferating B- and T-cells. Our clinical and functional data therefore suggest that RAD21 germline variants can predispose to childhood lymphoblastic leukemia or lymphoma without displaying a CdLS phenotype.
    Keywords:  RAD21; acute lymphoblastic leukemia; cohesin complex; germline cancer predisposition; trio sequencing
    DOI:  https://doi.org/10.3390/ijms23095174
  12. Nat Commun. 2022 May 12. 13(1): 2614
    Germline mutations in mitochondrial complex I reveal genetic and targetable vulnerability in IDH1-mutant acute myeloid leukaemia.
    Mahmoud A Bassal, Saumya E Samaraweera, Kelly Lim, Brooks A Bernard, Sheree Bailey, Satinder Kaur, Paul Leo, John Toubia, Chloe Thompson-Peach, Tran Nguyen, Kyaw Ze Ya Maung, Debora A Casolari, Diana G Iarossi, Ilaria S Pagani, Jason Powell, Stuart Pitson, Siria Natera, Ute Roessner, Ian D Lewis, Anna L Brown, Daniel G Tenen, Nirmal Robinson, David M Ross, Ravindra Majeti, Thomas J Gonda, Daniel Thomas, Richard J D'Andrea.
      The interaction of germline variation and somatic cancer driver mutations is under-investigated. Here we describe the genomic mitochondrial landscape in adult acute myeloid leukaemia (AML) and show that rare variants affecting the nuclear- and mitochondrially-encoded complex I genes show near-mutual exclusivity with somatic driver mutations affecting isocitrate dehydrogenase 1 (IDH1), but not IDH2 suggesting a unique epistatic relationship. Whereas AML cells with rare complex I variants or mutations in IDH1 or IDH2 all display attenuated mitochondrial respiration, heightened sensitivity to complex I inhibitors including the clinical-grade inhibitor, IACS-010759, is observed only for IDH1-mutant AML. Furthermore, IDH1 mutant blasts that are resistant to the IDH1-mutant inhibitor, ivosidenib, retain sensitivity to complex I inhibition. We propose that the IDH1 mutation limits the flexibility for citrate utilization in the presence of impaired complex I activity to a degree that is not apparent in IDH2 mutant cells, exposing a mutation-specific metabolic vulnerability. This reduced metabolic plasticity explains the epistatic relationship between the germline complex I variants and oncogenic IDH1 mutation underscoring the utility of genomic data in revealing metabolic vulnerabilities with implications for therapy.
    DOI:  https://doi.org/10.1038/s41467-022-30223-9
  13. Int J Clin Oncol. 2022 May 14.
    Germline sequencing for presumed germline pathogenic variants via tumor-only comprehensive genomic profiling.
    Tomohiro Kondo, Yoshihiro Yamamoto, Keita Fukuyama, Masashi Kanai, Atsushi Yamada, Junichi Matsubara, Pham Nguyen Quy, Masahiro Yoshioka, Takahiro Yamada, Sachiko Minamiguchi, Shigemi Matsumoto, Shinji Kosugi, Manabu Muto.
       BACKGROUND: The European Society for Medical Oncology Precision Medicine Working Group (ESMO-PMWG) published recommendations regarding confirmatory germline testing for presumed germline pathogenic variants (PGPVs) in tumor-only comprehensive genomic profiling (CGP). However, the clinical validity of these recommendations has not been investigated in a real-world practice.
    METHODS: Medical records of 180 consecutive patients who obtained the results of a tumor-only CGP (FoundationOne® CDx, Foundation Medicine, Inc, Cambridge, MA, USA) between October 2018 and March 2020, were retrospectively reviewed. After excluding patients with no reported variants in 45 actionable genes (n = 6), or no archived germline DNA samples (n = 31), 143 patients were investigated. The PGPVs were selected from the CGP report and germline sequencing were performed using DNA samples archived in Clinical Bioresource Center in Kyoto University Hospital (Kyoto, Japan).
    RESULTS: A total of 195 variants were classified as PGPV based on the conventional criteria. Germline sequencing disclosed that 12 variants (6.2%) were of germline origin. In contrast, after filtering these 195 variants through the ESMO-PMWG recommendation criteria for confirmatory germline testing, following seven PGPVs, BRCA2 (n = 2), BRIP1 (n = 1), BAP1 (n = 1), PMS2 (n = 1), MSH2 (n = 1), and SDHB (n = 1) remained and six variants (85.7%) were confirmed to be of germline origin.
    CONCLUSION: Our current data suggested that the application of ESMO-PMWG criteria is helpful in selecting PGPVs with a high likelihood of germline origin in a tumor-only CGP in daily clinical practice.
    Keywords:  Comprehensive genomic profiling; Confirmatory germline testing; Presumed germline pathogenic variants; Secondary findings; Tumor-only testing
    DOI:  https://doi.org/10.1007/s10147-022-02176-y
  14. Genes Chromosomes Cancer. 2022 May 11.
    Germline MUTYH mutations and high-grade gliomas: novel evidence for a potential association.
    Gábor Bedics, Lili Kotmayer, Erik Zajta, Lajos László Hegyi, Edit Ágota Brückner, Hajnalka Rajnai, Lilla Reiniger, Csaba Bödör, Miklós Garami, Bálint Scheich.
      There is growing body of evidence supporting the role of germline mutations in the pathogenesis of pediatric central nervous system (CNS) tumors, and the widespread use of next-generation sequencing (NGS) panels facilitates their detection. Variants of the MUTYH gene are increasingly recognized as suspected germline background of various extraintestinal malignancies, besides their well-characterized role in the polyposis syndrome associated with biallelic mutations. Using a multigene NGS panel (Illumina TruSight Oncology 500), we detected one H3 G34V- and one H3 K27M-mutant pediatric high-grade diffuse glioma, in association with c.1178G>A (p.G393D) and c.916C>T (p.R306C) MUTYH variants, respectively. Both MUTYH mutations were germline, heterozygous and inherited, according to the subsequent genetic testing of the patients and their first-degree relatives. In the H3 K27M-mutant glioma, amplifications affecting the 4q12 region were also detected, in association with KDR-PDGFRA, KIT-PDGFRA and KDR-CHIC2 fusions, previously unreported in this entity. Among 47 other CNS tumors of various histological types tested with the same NGS panel in our institution, only one adult glioblastoma harbored MUTYH mutation. Together with a single previous report, our data raises the possibility of an association between germline MUTYH mutations and CNS malignancies, particularly in pediatric histone H3-mutant gliomas. This article is protected by copyright. All rights reserved.
    Keywords:  Germline mutation; Histone H3-mutant glioma; MUTYH; Next-generation sequencing; PDGFRA fusion; Pediatric glioma
    DOI:  https://doi.org/10.1002/gcc.23054
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