bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2023‒03‒26
four papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet
  1. Germline pathogenic variants in patients with early onset neuroendocrine neoplasms.
  2. New pathogenic germline variants identified in mesothelioma.
  3. The Clinical Picture of the ERCC6L2 Disease - from Bone Marrow Failure to Acute Leukemia.
  4. Genetic modifiers of p53: opportunities for breast cancer therapies.
  1. Endocr Relat Cancer. 2023 Mar 01. pii: ERC-22-0258. [Epub ahead of print]
    Germline pathogenic variants in patients with early onset neuroendocrine neoplasms.
    Rachel Pimenta Riechelmann, Mauro D Donadio, Victor Hugo F de Jesus, Nathalia de Angelis de Carvalho, Karina Miranda Santiago, Milton J Barros, Laura Lopes, Gabriel Oliveira Dos Santos, Maria Nirvana Formiga, Dirce Maria Carraro, Giovana Tardin Torrezan.
      Neuroendocrine neoplasms (NEN) are a rare group of cancers with heterogeneous behavior and mostly of unknown aetiology. Excluding some infrequent hereditary cancer syndromes, the extent and clinical significance of mutations in other cancer predisposing genes (CPG) are not known. We aimed to investigate the frequency of pathogenic and likely pathogenic germline variants (GPV) in known CPGs in young adults with NEN and the clinical and molecular characteristics of these patients. We recruited 108 patients with lung or digestive NEN diagnosed between 18 to 50 years and performed targeted sequencing of 113 CPGs on germline DNA. For some patients, tumor features as loss of heterozygosity (LOH), tumor mutation burden and microsatellite instability were evaluated. GPVs were detected in 17 patients (15.7%). Median age, sex, stage at diagnosis, family history of NEN or any personal history of neoplasm were similar between patients with or without GPVs. GPVs carriers had more gastric (p = 0.084), functioning NEN (p = 0.041), positive family history of cancer (p = 0.015), and exclusively well-differentiated histology. Genes affected were mostly involved in DNA repair (CHEK2, ERCC2, ERCC3, XPC, MSH6, POLE, SLX4), with most GPV found in MUTYH (4 cases). LOH was performed in 8 tumors and detected only in a SLX4 positive case. Overall, our findings indicate a role of inherited genetic alterations, particularly in DNA repair genes, in NENs carcinogenesis in young adults. These patients more often had a family history of cancer and functioning NEN.
    DOI:  https://doi.org/10.1530/ERC-22-0258
  2. Lung Cancer. 2023 Mar 15. pii: S0169-5002(23)00095-8. [Epub ahead of print]179 107172
    New pathogenic germline variants identified in mesothelioma.
    Laila Belcaid, Birgitte Bertelsen, Karin Wadt, Ida Tuxen, Iben Spanggaard, Martin Højgaard, Jens Benn Sørensen, Jesper Ravn, Ulrik Lassen, Finn Cilius Nielsen, Kristoffer Rohrberg, Christina Westmose Yde.
      BACKGROUND: Mesothelioma (MM) is associated with asbestos exposure, tumor heterogeneity and aggressive clinical behavior. Identification of germline pathogenic variants (PVs) in mesothelioma is relevant for identifying potential actionable targets and genetic counseling.METHODS: 44 patients underwent whole exome sequencing (WES) or whole genome sequencing (WGS). Germline variants were selected according to association with inherited cancer using a 168-gene in silico panel, and variants classified according to ACMG/AMP classification as pathogenic (class 5) or likely pathogenic (class 4).
    RESULTS: In total, 16 patients (36%) were found to carry pathogenic or likely pathogenic variants in 13 cancer associated genes (ATM, BAP1, BRCA2, CDKN2A, FANCA, FANCC, FANCD2, FANCM, MUTYH, NBN, RAD51B, SDHA and XPC). The germline PVs occurred in DNA repair pathways, including homologous recombination repair (HRR) (75%), nucleotide excision repair (6%), cell cycle regulatory (7%), base excision repair (6%), and hypoxic pathway (6%). Five (31%) patients with a germline PV had a first or second degree relative with mesothelioma compared to none for patients without a germline PV. Previously undiagnosed BRCA2 germline PVs were identified in two patients. Potential actionable targets based on the germline PVs were found in four patients (9%).
    CONCLUSION: This study revealed a high frequency of germline PVs in patients with mesothelioma. Furthermore, we identified germline PVs in two genes (NBN & RAD51B) not previously associated with mesothelioma. The data support germline testing in mesothelioma and provide a rationale for additional investigation of the HRR pathway as a potential actionable target.
    Keywords:  Cancer genetics; Germline variants; Homologous recombination pathway; Mesothelioma; Precision oncology
    DOI:  https://doi.org/10.1016/j.lungcan.2023.03.008
  3. Blood. 2023 Mar 23. pii: blood.2022019425. [Epub ahead of print]
    The Clinical Picture of the ERCC6L2 Disease - from Bone Marrow Failure to Acute Leukemia.
    Marja Hakkarainen, Ilse Kaaja, Suvi P M Douglas, Thomas J Vulliamy, Inderjeet Dokal, Jean Soulier, Lise Larcher, Régis Peffault de Latour, Thierry M Leblanc, Flore Sicre de Fontbrune, Timo Siitonen, Olli Lohi, Eva Hellström-Lindberg, Gisela Barbany, Bianca Tesi, Akiko Shimamura, Fabian Beier, Sharon Rosalie Jackson, Amir Kuperman, Tzipora C Falik Zaccai, Hannah Tamary, Cristina Mecucci, Ilaria Capolsini, Kirsi Jahnukainen, Urpu Salmenniemi, Riitta Niinimäki, Teppo Varilo, Outi Kilpivaara, Ulla Wartiovaara-Kautto.
      Biallelic germline ERCC6L2 variants strongly predispose to bone marrow failure (BMF) and myeloid malignancies characterized by somatic TP53-mutated clones and erythroid predominance. We present a series of 52 subjects (35 families) with ERCC6L2 biallelic germline variants collected retrospectively in 11 centers globally, including follow-up of 1165 person-years. At initial investigations, 32 individuals were diagnosed with BMF and 15 with a hematological malignancy (HM). Subjects presented with 19 different variants across ERCC6L2, and we identified a founder mutation c.1424delT in the Finnish patients. The median age of subjects at baseline was 18 years (range 2-65). Changes in complete blood count (CBC) were mild despite severe bone marrow hypoplasia and somatic TP53 mutations, with no significant difference between subjects with or without (HM). Signs of a progressive disease were increasing TP53 variant allele frequency, dysplasia in megakaryocytes and/or erythroid lineage, and erythroid predominance in bone marrow morphology. The median age at onset of HM was 37.0 years (95% CI: 31.5-42.5; range 12-65). Overall survival (OS) at 3 years was 95% (95% CI: 85-100) and 19% (95% CI: 0-39) for patients with BMF and HM, respectively. Patients with myelodysplastic syndrome or acute myeloid leukemia with mutated TP53 undergoing hematopoietic stem cell transplantation had a poor outcome: 3-year OS is 28% (95% CI: 0-61). Our results demonstrate the importance of early recognition and active surveillance of patients with biallelic germline ERCC6L2 variants.
    DOI:  https://doi.org/10.1182/blood.2022019425
  4. Oncotarget. 2023 Mar 24. 14 236-241
    Genetic modifiers of p53: opportunities for breast cancer therapies.
    Prabin Dhangada Majhi, Aman Sharma, D Joseph Jerry.
      
    Keywords:  DNA repair; Li-Fraumeni syndrome; breast cancer; genetic modifiers; p53
    DOI:  https://doi.org/10.18632/oncotarget.28387
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