bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2021‒08‒15
nine papers selected by
Joanna Zawacka-Pankau
Karolinska Institutet
  1. Spontaneous and inherited TP53 genetic alterations.
  2. Molecular Characterization and Clinical Treatment of Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS) Patients With TP53 Mutation.
  3. Impact of deleterious variants in other genes beyond BRCA1/2 detected in breast/ovarian and pancreatic cancer patients by NGS-based multi-gene panel testing: looking over the hedge.
  4. GATA2 deficiency syndrome: A decade of discovery.
  5. An Unusual Enteric Yolk Sac Tumor: First Report of an Ovarian Germ Cell Tumor Associated With a Germline Pathogenic Variant in DICER1.
  6. A rare PALB2 germline variant causing G2/M cell cycle arrest is associated with isolated myelosarcoma in infancy.
  7. Spectrum of Hematological Malignancies, Clonal Evolution and Outcomes in 144 Mayo Clinic Patients with Germline Predisposition Syndromes.
  8. Venous thromboembolism incidence in cancer patients with germline BRCA mutations.
  9. A Novel Germline Compound Heterozygous Mutation of BRCA2 Gene Associated With Familial Peripheral Neuroblastic Tumors in Two Siblings.
  1. Oncogene. 2021 Aug 13.
    Spontaneous and inherited TP53 genetic alterations.
    Arnold J Levine.
      The p53 protein is a transcription factor that prevents tumors from developing. In spontaneous and inherited cancers there are many different missense mutations in the DNA binding domain of the TP53 gene that contributes to tumor formation. These mutations produce a wide distribution in the transcriptional capabilities of the mutant p53 proteins with over four logs differences in the efficiencies of forming cancers in many diverse tissue types. These inherited and spontaneous TP53 mutations produce proteins that interact with both genetic and epigenetic cellular modifiers of p53 function and their inherited polymorphisms to produce a large number of diverse phenotypes in individual patients. This manuscript reviews these variables and discusses how the combinations of TP53 genetic alterations interact with genetic polymorphisms, epigenetic alterations, and environmental factors to begin predicting and modifying patient outcomes and provide a better understanding for new therapeutic opportunities.
    DOI:  https://doi.org/10.1038/s41388-021-01991-3
  2. Clin Lymphoma Myeloma Leuk. 2021 Jul 13. pii: S2152-2650(21)00278-0. [Epub ahead of print]
    Molecular Characterization and Clinical Treatment of Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS) Patients With TP53 Mutation.
    Yanfen Li, Hua Wan, Yu Jing.
      BACKGROUND: Mutations in TP53 in myeloid neoplasms patients have been associated with poor prognosis. Effective treatments to these patients remain unclear.PATIENTS AND METHODS: In this study, we retrospectively analyzed diagnostic and outcomes of 31 Acute Myeloid leukemia (AML) and 9 Myelodysplastic syndromes (MDS) patients with TP53 mutation at our hospital from September 2015 to October 2020.
    RESULTS: A total of 42 variants (28 unique variants) in the coding region of TP53 gene were identified, and most were missense mutation (34 of 42, 81%). The median overall survival (OS) was 8 months for the AML patients (1-32 months) and 7 months for the MDS patients (3-27 months). There were 35 and 13 patients underwent frontline chemical therapy and Allo-HSCT, respectively. The overall response rate was 45.3% (16/35) for the frontline treatment. There was no significant difference between intensive and low-intensity regimens on either response to the frontline treatment (P = .255) or overall survival (P = .078). Patients, who achieved complete or partial remission at the frontline treatment, presented a higher survival than patients in non-remission, no matter transplant or not.
    CONCLUSION: This study corroborates that improving the response to the first-line treatment could prolong the survival of myeloid neoplasms patients with TP53 mutation. Allo-HSCT could be a curative option for patients with TP53 mutation, when in complete remission during the first-line treatment.
    Keywords:  Allo-HSCT.; Low-intensity treatment; Myeloid neoplasms; Overall survival; first-line treatment
    DOI:  https://doi.org/10.1016/j.clml.2021.07.007
  3. ESMO Open. 2021 Aug 06. pii: S2059-7029(21)00196-4. [Epub ahead of print]6(4): 100235
    Impact of deleterious variants in other genes beyond BRCA1/2 detected in breast/ovarian and pancreatic cancer patients by NGS-based multi-gene panel testing: looking over the hedge.
    M Bono, D Fanale, L Incorvaia, D Cancelliere, A Fiorino, V Calò, A Dimino, C Filorizzo, L R Corsini, C Brando, G Madonia, A Cucinella, R Scalia, N Barraco, F Guadagni, E Pedone, G Badalamenti, A Russo, V Bazan.
      BACKGROUND: Hereditary breast cancer (BC), ovarian cancer (OC), and pancreatic cancer (PC) are the major BRCA-associated tumours. However, some BRCA1/2-wild-type (wt) patients with a strong personal and/or family history of cancer need a further genetic testing through a multi-gene panel containing other high- and moderate-risk susceptibility genes.PATIENTS AND METHODS: Our study was aimed to assess if some BC, OC, or PC patients should be offered multi-gene panel testing, based on well-defined criteria concerning their personal and/or family history of cancer, such as earliness of cancer onset, occurrence of multiple tumours, or presence of at least two or more affected first-degree relatives. For this purpose, 205 out of 915 BC, OC, or PC patients, resulted negative for BRCA1/2 and with significant personal and/or family history of cancer, were genetically tested for germline pathogenic or likely pathogenic variants (PVs/LPVs) in genes different from BRCA1/2.
    RESULTS: Our investigation revealed that 31 (15.1%) out of 205 patients harboured germline PVs/LPVs in no-BRCA genes, including PALB2, CHEK2, ATM, MUTYH, MSH2, and RAD51C. Interestingly, in the absence of an analysis conducted through multi-gene panel, a considerable percentage (15.1%) of PVs/LPVs would have been lost.
    CONCLUSIONS: Providing a multi-gene panel testing to BRCA1/2-wt BC/OC/PC patients with a strong personal and/or family history of cancer could significantly increase the detection rates of germline PVs/LPVs in other cancer predisposition genes beyond BRCA1/2. The use of a multi-gene panel testing could improve the inherited cancer risk estimation and clinical management of patients and unaffected family members.
    Keywords:  breast cancer; germline pathogenic variants; multi-gene panel testing; ovarian cancer; pancreatic cancer
    DOI:  https://doi.org/10.1016/j.esmoop.2021.100235
  4. Hum Mutat. 2021 Aug 13.
    GATA2 deficiency syndrome: A decade of discovery.
    Claire C Homan, Parvathy Venugopal, Peer Arts, Nur Hezrin Shahrin, Simone Feurstein, Lesley Rawlings, David M Lawrence, James Andrews, Sarah L King-Smith, Natasha L Harvey, Anna L Brown, Hamish S Scott, Christopher N Hahn.
      GATA2 deficiency syndrome (G2DS) is a rare autosomal dominant genetic disease predisposing to a range of symptoms of which myeloid malignancy and immunodeficiency including recurrent infections are most common. In the last decade since it was first reported, there have been over 480 individuals identified carrying a pathogenic or likely pathogenic germline GATA2 variant with symptoms of G2DS, with 240 of these confirmed to be familial and 24 de novo. For those that develop myeloid malignancy (75% of all carriers with G2DS disease symptoms), the median age of onset is 17 years (range 0-78 years) and myelodysplastic syndrome (MDS) is the first diagnosis in 75% of these cases with acute myeloid leukemia (AML) in a further 9%. All variant types appear to predispose to myeloid malignancy and immunodeficiency. Apart from lymphedema in which haploinsufficiency seems necessary, the mutational requirements of the other less common G2DS phenotypes is still unclear. These predominantly loss-of-function variants impact GATA2 expression and function in numerous ways including perturbations to DNA binding, protein structure, protein:protein interactions, and gene transcription, splicing and expression. In this review, we provide the first expert-curated ACMG/AMP classification with codes of published variants compatible for use in clinical or diagnostic settings. This article is protected by copyright. All rights reserved.
    Keywords:  GATA2 deficiency syndrome; Germline variants; Immunodeficiency; Lymphedema; Myeloid malignancy; Predisposition
    DOI:  https://doi.org/10.1002/humu.24271
  5. Int J Gynecol Pathol. 2021 Aug 11.
    An Unusual Enteric Yolk Sac Tumor: First Report of an Ovarian Germ Cell Tumor Associated With a Germline Pathogenic Variant in DICER1.
    W Glenn McCluggage, Lili Fu, Kristen Mohler, Leanne de Kock, Nelly Sabbaghian, Allison Mindlin, Colin J R Stewart, C Blake Gilks, William D Foulkes.
      A variety of unusual tumors are associated with both germline and somatic DICER1 pathogenic variants (PVs), including, in the female genital tract, embryonal rhabdomyosarcoma at various sites and ovarian Sertoli-Leydig cell tumor. There have been occasional reported cases of ovarian germ cell tumors [mainly yolk sac tumor (YST)] harboring DICER1 PVs but, as far as we are aware, none of these has been proven to have a germline provenance. We report an unusual enteric variant of ovarian YST in a 28-yr-old woman associated with a germline PV c.901C>T (p.Gln301Ter) in exon 7 of DICER1, accompanied by a somatic (YST-only) hotspot mutation: c.5437G>A, p.E1813K. To our knowledge, this is the first report of an ovarian germ cell tumor associated with a germline DICER1 PV. We review other reported cases of ovarian germ cell tumor with DICER1 PVs and discuss the differential diagnosis of this unusual variant of YST which was originally diagnosed as a mucinous adenocarcinoma.
    DOI:  https://doi.org/10.1097/PGP.0000000000000818
  6. Mol Genet Genomic Med. 2021 Aug 12. e1746
    A rare PALB2 germline variant causing G2/M cell cycle arrest is associated with isolated myelosarcoma in infancy.
    Angelina Beer, Ricardo Beck, Anne Schedel, Malte von Bonin, Jörn Meinel, Ulrike Anne Friedrich, Maria Menzel, Meinolf Suttorp, Sebastian Brenner, Guido Fitze, Björn Lange, Ralf Knöfler, Julia Hauer, Franziska Auer.
      BACKGROUND: Isolated myelosarcoma of infancy is a rare presentation of acute myelogenous leukaemia (AML). Because of its rarity and early onset in infancy underlying genetic predisposition is potentially relevant in disease initiation.METHODS AND RESULTS: We report an oncologic emergency in an infant with thoracic and intraspinal aleukaemic myeloid sarcoma causing acute myelon compression and lower leg palsy. Whole-exome sequencing of the patient's germline DNA identified a rare PALB2 (OMIM 610355) variant (p.A1079S), which is located in a domain critical for the gene's proper function within the homology-directed repair pathway. In line with potential DNA damage repair defects mediated by the PALB2 deregulation, the patient's fibroblasts showed increased sensitivity towards radiation and DNA intercalating agents.
    CONCLUSION: Therefore, we suggest PALB2 p.A1079S as a pathogenic variant potentially contributing to the here observed patient phenotype.
    Keywords:  PALB2; extramedullary myelogenous leukaemia; myeloid sarcoma; tumour suppressor
    DOI:  https://doi.org/10.1002/mgg3.1746
  7. Am J Hematol. 2021 Aug 14.
    Spectrum of Hematological Malignancies, Clonal Evolution and Outcomes in 144 Mayo Clinic Patients with Germline Predisposition Syndromes.
    Emma St Martin, Alejandro Ferrer, Abhishek A Mangaonkar, Shakila P Khan, Mira A Kohorst, Avni Y Joshi, William J Hogan, Horatiu Olteanu, Ann M Moyer, Aref Al-Kali, Ayalew Tefferi, Dong Chen, Kitsada Wudhikarn, Ronald Go, David Viswanatha, Rong He, Rhett Ketterling, Phuong L Nguyen, Jennifer L Oliveira, Naseema Gangat, Terra Lasho, Mrinal M Patnaik.
      Germline predisposition syndromes (GPS) result from constitutional aberrations in tumor suppressive and homeostatic genes, increasing risk for neoplasia in affected kindred. In this study, we present clinical and genomic data on 144 Mayo Clinic patients with GPS; 59 evaluated prospectively using an algorithm-based diagnostic approach in the setting of a dedicated GPS/ inherited bone marrow failure syndrome (IBMFS) clinic. Seventy-two (50%) patients had IBMFS (telomere biology disorders-32,Fanconi anemia-18, Diamon Blackfan Anemia - 11, congenital neutropenia-5, Schwachman-Diamond Syndrome-5 and Bloom Syndrome-1), 27 (19%) had GPS with antecedent thrombocytopenia (RUNX1-FPD-15, ANKRD26-6, ETV6-2, GATA1-1, MPL-3), 28 (19%) had GPS without antecedent thrombocytopenia (GATA2 haploinsufficiency-16, DDX41-10, CBL-1 and CEBPA-1) and 17 (12%) had general cancer predisposition syndromes (ataxia telangiectasia-7, heterozygous ATM variants-3, CHEK2-2, TP53-2, CDK2NA-1, NF1-1 and Nijmegen Breakage Syndrome-1). Homozygous and heterozygous ATM pathogenic variants were exclusively associated with lymphoproliferative disorders (LPD), while DDX41 GPS was associated with LPD and myeloid neoplasms. The use of somatic NGS-testing identified clonal evolution in GPS patients, with ASXL1, RAS pathway genes, SRSF2 and TET2 being most frequently mutated. Fifty-two (91%) of 59 prospectively identified GPS patients had a change in their management approach, including additional GPS-related screening in 42 (71%), referral for allogenic HSCT workup and screening of related donors in 16 (27%), medication initiation and selection of specific conditioning regimens in 14 (24%), and genetic counseling with specific intent of fertility preservation and preconceptual counselling in 10 (17%) patients; highlighting the importance of dedicated GPS screening, detection and management programs for patients with hematological neoplasms. This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1002/ajh.26321
  8. Clin Transl Oncol. 2021 Aug 09.
    Venous thromboembolism incidence in cancer patients with germline BRCA mutations.
    A J Muñoz, M de Toro, L Ortega, C López, A Gutiérrez, D S Juliao, M Arregui, N Lobato, I Echavarría, I Márquez-Rodas, M Martín.
      BACKGROUND: Germline BRCA (gBRCA) mutations predispose to an increased risk of breast and ovarian cancer among other neoplasms. Recently, several genomic alterations such as ALK and ROS-1 rearrangements have been described as molecular drivers of venous thromboembolism (VTE). The association of gBRCA mutations and VTE is unknown.MATERIALS AND METHODS: We performed an observational, retrospective, single-center study to determine the VTE incidence in consecutive patients with gBRCA mutations and cancer diagnosis attended in the multidisciplinary heredofamiliar cancer unit (HFCU) of Hospital General Universitario Gregorio Marañón, Spain, from 2010 to 2019.
    RESULTS: One-hundred and forty-one patients were included in the analysis. The overall VTE incidence was 12.8%. The highest incidence was reported in ovarian cancer patients (20.0%), followed by patients with both ovarian and breast cancers (16.6%) and the lowest was found in breast cancer (4.9%). No difference in the type of gBRCA mutation (1 or 2) in terms of VTE rate was observed. Sixty one percent of the patients were receiving anti-cancer therapy at the time of VTE diagnosis and the majority of the events (83.3%) were diagnosed in ambulatory setting. Khorana score was of limited value to detect high-risk patients.
    CONCLUSIONS: The VTE incidence observed in our study is consistent with prior data described in general population of breast and ovarian cancer. The risk of VTE in these patients seems to be driven by the type of cancer. We have not observed any significant interaction of gBRCA mutation status and cancer-associated thrombosis.
    Keywords:  BRCA mutation; Breast cancer; Cancer; Ovarian cancer; Venous thromboembolism
    DOI:  https://doi.org/10.1007/s12094-021-02678-7
  9. Front Genet. 2021 ;12 652718
    A Novel Germline Compound Heterozygous Mutation of BRCA2 Gene Associated With Familial Peripheral Neuroblastic Tumors in Two Siblings.
    Yeran Yang, Jiwei Chen, Hong Qin, Yaqiong Jin, Li Zhang, Shen Yang, Huanmin Wang, Libing Fu, Enyu Hong, Yongbo Yu, Jie Lu, Yan Chang, Xin Ni, Min Xu, Tieliu Shi, Yongli Guo.
      Objectives: To investigate the genetic variants that are responsible for peripheral neuroblastic tumors (PNTs) oncogenesis in one family case.Materials and Methods: One family was recruited, including the healthy parents, sister affected by neuroblastoma (NB), and brother who suffered from ganglioneuroma (GN). Whole-genome sequencing (WGS) of germline DNA from all the family members and RNA-seq of tumor RNA from the siblings were performed. Mutants were validated by Sanger sequencing and co-IP was performed to assess the impact of the mutant on chemosensitivity in the SH-SY5Y cell line.
    Results: A novel compound heterozygous mutation of BRCA2 was locked as the cause of carcinogenesis. One allele was BRCA2-S871X (stop-gain) from the siblings' mother, the other was BRCA2-N372H (missense) from their father. This novel compound heterozygous mutations of the BRCA2 gene associated with PNTs by disordering DNA damage and response (DDR) signal pathway. Moreover, chemosensitivity was reduced in the NB cell line due to the BRCA2-N372H mutant.
    Conclusion: In summary, these results revealed a novel germline compound heterozygous mutation of the BRCA2 gene associated with familial PNTs.
    Keywords:  BRCA2; RNA-Seq; cancer predisposition gene; ganglioneuroma; neuroblastoma; peripheral neuroblastic tumors; whole-genome sequencing
    DOI:  https://doi.org/10.3389/fgene.2021.652718
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