bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2021‒02‒28
nineteen papers selected by
Joanna Zawacka-Pankau
University of Warsaw
  1. A Novel Germline TP53 Mutation in a Patient With Li-Fraumeni Syndrome: Resolving a Variant of Uncertain Significance.
  2. The Common Germline TP53-R337H Mutation is Hypomorphic and Confers Incomplete Penetrance and Late Tumor Onset in a Mouse Model.
  3. Therapy-related Myeloid Neoplasms in Children: A Single-institute Study.
  4. Characterization of the Platelet Phenotype Caused by a Germline RUNX1 Variant in a CRISPR/Cas9-Generated Murine Model.
  5. A novel RUNX1 exon 3 - 7 deletion causing a familial platelet disorder.
  6. New germline GATA1 variant in females with anemia and thrombocytopenia.
  7. Unique ethnic features of DDX41 mutations in patients with idiopathic cytopenia of undetermined significance, myelodysplastic syndrome, or acute myeloid leukemia.
  8. Inherited predisposition to haematopoietic malignancies: overcoming barriers and exploring opportunities.
  9. Distinct genetic pathways define pre-malignant versus compensatory clonal hematopoiesis in Shwachman-Diamond syndrome.
  10. Case report of adrenocortical carcinoma associated with double germline mutations in MSH2 and RET.
  11. Co-occurrence of germline pathogenic variants for different hereditary cancer syndromes in patients with Lynch syndrome.
  12. Intronic breakpoint signatures enhance detection and characterization of clinically relevant germline structural variants.
  13. CHEK2 mutation in a patient with pancreatic adenocarcinoma-a rare case report.
  14. Generation and characterization of induced pluripotent stem cells from a family carrying the BRCA1 mutation c.3612delA.
  15. Resolving pathogenicity classification for the CDH1 c.[715G>A] (p.Gly239Arg) Variant.
  16. A Genome-First Approach to Characterize DICER1 Pathogenic Variant Prevalence, Penetrance, and Phenotype.
  17. Precision Medicine in Oncology-Toward the Integrated Targeting of Somatic and Germline Genomic Aberrations.
  18. Re: Human Germline and Heritable Genome Editing: The Global Policy Landscape.
  19. Response to Levrier re: Human Germline and Heritable Genome Editing: The Global Policy Landscape.
  1. J Pediatr Hematol Oncol. 2021 Feb 25.
    A Novel Germline TP53 Mutation in a Patient With Li-Fraumeni Syndrome: Resolving a Variant of Uncertain Significance.
    Douglass DP, Stine KC, Farrar JE.
      Increasing availability of genomic testing poses new challenges to clinicians, particularly where variant interpretation from commercial sources may be equivocal. The authors report a patient with recurrent rhabdomyosarcoma and subsequent bilateral breast cancer who was found to harbor a previously undescribed germline TP53 sequence alteration annotated by the commercial laboratory as a variant of uncertain significance. By investigating publicly available databases of aggregated normal germline and malignant somatic genomic sequences, the authors conclude that this missense variant, c.476C>T (p.A159V), is a novel, pathogenic Li-Fraumeni syndrome mutation and demonstrate the utility of these resources in clinical pediatric hematology and oncology practice.
    DOI:  https://doi.org/10.1097/MPH.0000000000002115
  2. Cancer Res. 2021 Feb 26. pii: canres.1750.2020. [Epub ahead of print]
    The Common Germline TP53-R337H Mutation is Hypomorphic and Confers Incomplete Penetrance and Late Tumor Onset in a Mouse Model.
    Jeffers JR, Pinto EM, Rehg JE, Clay MR, Wang J, Neale G, Heath RJ, Lozano G, Lalli E, Figueiredo BC, Pappo AS, Rodriguez-Galindo C, Chen W, Pounds S, Ribeiro RC, Zambetti GP.
      The TP53-R337H founder mutation exists at a high frequency throughout southern Brazil and represents one of the most common germline TP53 mutations reported to date. It was identified in pediatric adrenocortical tumors in families with a low incidence of cancer. The R337H mutation has since been found in association with early-onset breast cancers and Li-Fraumeni syndrome (LFS). To study this variability in tumor susceptibility, we generated a knockin mutant p53 mouse model (R334H). Endogenous murine p53-R334H protein was naturally expressed at high levels in multiple tissues and was functionally compromised in a tissue- and stress-specific manner. Mutant p53-R334H mice developed tumors with long latency and incomplete penetrance, consistent with many human carriers being at a low but elevated risk for cancer. These findings suggest the involvement of additional cooperating genetic alterations when TP53-R337H occurs in the context of LFS, which has important implications for genetic counseling and long-term clinical follow up.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-1750
  3. J Pediatr Hematol Oncol. 2021 Feb 22.
    Therapy-related Myeloid Neoplasms in Children: A Single-institute Study.
    Li G, Holly T, Kelly DR, Reddy V, Mikhail FM, Carroll AJ, Kutny MA.
      Therapy-related myeloid neoplasm (t-MN) in the pediatric population is not well characterized. We studied 12 pediatric patients diagnosed with t-MN in our institution since 2006. The median age at the t-MN diagnoses was 14.8 years (range, 9 to 20 y). The primary malignancies included 9 solid tumors and 3 hematopoietic malignancies. Rhabdomyosarcoma (n=4) was the most common primary malignancy. Five of the 9 patients with solid tumors and all 3 patients with hematopoietic malignancies had primary neoplasms involving bone marrow. The median latency period was 5.2 years (range, 1.8 to 13.8 y). Thrombocytopenia was present in all patients at the t-MN diagnoses. Complete or partial monosomy of chromosome 5 or 7 were the 2 most common cytogenetic abnormalities. A quarter of patients demonstrated a genetic predisposition to t-MN: 1 with Li-Fraumeni syndrome with a germline TP53 R248Q mutation, 1 with Noonan syndrome with a somatic mutation (PTPN11 S502T), and 1 with a constitutive chromosomal translocation [t(X;9)(p22;q34)] and a germline TP53 L130V mutation. Outcomes remain poor. Two patients survived 3 and 5.1 years after hematopoietic stem cell transplantation.
    DOI:  https://doi.org/10.1097/MPH.0000000000002097
  4. Thromb Haemost. 2021 Feb 18.
    Characterization of the Platelet Phenotype Caused by a Germline RUNX1 Variant in a CRISPR/Cas9-Generated Murine Model.
    Marín-Quílez A, García-Tuñón I, Fernández-Infante C, Hernández-Cano L, Palma-Barqueros V, Vuelta E, Sánchez-Martín M, González-Porras JR, Guerrero C, Benito R, Rivera J, Hernández-Rivas JM, Bastida JM.
      RUNX1-related disorder (RUNX1-RD) is caused by germline variants affecting the RUNX1 gene. This rare, heterogeneous disorder has no specific clinical or laboratory phenotype, making genetic diagnosis necessary. Although international recommendations have been established to classify the pathogenicity of variants, identifying the causative alteration remains a challenge in RUNX1-RD. Murine models may be useful not only for definitively settling the controversy about the pathogenicity of certain RUNX1 variants, but also for elucidating the mechanisms of molecular pathogenesis. Therefore, we developed a knock-in murine model, using the CRISPR/Cas9 system, carrying the RUNX1 p.Leu43Ser variant (mimicking human p.Leu56Ser) to study its pathogenic potential and mechanisms of platelet dysfunction. A total number of 75 mice were generated; 25 per genotype (RUNX1WT/WT, RUNX1WT/L43S, and RUNX1L43S/L43S). Platelet phenotype was assessed by flow cytometry and confocal microscopy. On average, RUNX1L43S/L43S and RUNX1WT/L43S mice had a significantly longer tail-bleeding time than RUNX1WT/WT mice, indicating the variant's involvement in hemostasis. However, only homozygous mice displayed mild thrombocytopenia. RUNX1L43S/L43S and RUNX1WT/L43S displayed impaired agonist-induced spreading and α-granule release, with no differences in δ-granule secretion. Levels of integrin αIIbβ3 activation, fibrinogen binding, and aggregation were significantly lower in platelets from RUNX1L43S/L43S and RUNX1WT/L43S using phorbol 12-myristate 13-acetate (PMA), adenosine diphosphate (ADP), and high thrombin doses. Lower levels of PKC phosphorylation in RUNX1L43S/L43S and RUNX1WT/L43S suggested that the PKC-signaling pathway was impaired. Overall, we demonstrated the deleterious effect of the RUNX1 p.Leu56Ser variant in mice via the impairment of integrin αIIbβ3 activation, aggregation, α-granule secretion, and platelet spreading, mimicking the phenotype associated with RUNX1 variants in the clinical setting.
    DOI:  https://doi.org/10.1055/s-0041-1723987
  5. Platelets. 2021 Feb 22. 1-4
    A novel RUNX1 exon 3 - 7 deletion causing a familial platelet disorder.
    Almazni I, Chudakou P, Dawson-Meadows A, Downes K, Freson K, Mason J, Page P, Reay K, Myers B, Morgan NV.
      Familial Platelet Disorder with associated Myeloid Malignancy (FPDMM) is a rare inherited disorder confirmed with the presence of a pathogenic germline RUNX1 variant and is thought to be heavily underdiagnosed. RUNX1 has also been found to be mutated in up to 10% of adult AML cases and other cell malignancies. We performed targeted next-generation sequencing and subsequent MLPA analysis in a kindred with multiple affected individuals with low platelet counts and a bleeding history. We detected a novel heterozygous exon 3-7 large deletion in the RUNX1 gene in all affected family members which is predicted to remove all of the Runt-homology DNA-binding domain and a portion of the Activation domain. Our results show that the combination of targeted NGS and MLPA analysis is an effective way to detect copy number variants (CNVs) which would be missed by conventional sequencing methods. This precise diagnosis offers the possibility of accurate counseling and clinical management in such patients who could go onto develop other cell malignancies.
    Keywords:  Bleeding; CNV; NGS; RUNX1; platelet disorder; thrombocytopenia
    DOI:  https://doi.org/10.1080/09537104.2021.1887470
  6. Blood Cells Mol Dis. 2021 Feb 03. pii: S1079-9796(21)00011-5. [Epub ahead of print]88 102545
    New germline GATA1 variant in females with anemia and thrombocytopenia.
    Svidnicki MCCM, Filho MAF, Brandão MM, Dos Santos M, de Oliveira Dias R, Tavares RS, Assis-Mendonça GR, Traina F, Saad STO.
      Familial forms of bone marrow defects are rare disorders and description of new cases are valuable opportunities to clarify the molecular machinery that triggers hematopoiesis and blood formation, as well as risk to malignant transformation. We investigated the genetic scenario and possible patterns of transmission in a rare case of familial myeloid disorder with a history of exposure to pesticides. Blood counts of two proband sisters, age 41 and 42, revealed mild anemia, neutrophilia and thrombocytopenia with bone marrow finding mimicking primary myelofibrosis in the cellular phase. We analyzed the coding regions of 78 myeloid neoplasms-related genes and 16 encoding xenobiotic metabolizing genes using Next-Generation Sequencing. The GATA1 variant c.788C > T, p.T263M, located in the C-terminal zinc finger domain of GATA1, was detected in the DNA of the two sisters. The screening of the other kindreds also revealed the p.T263M variant in the mother and two daughters with the same bone marrow disorder. This is the first report of an alteration in the GATA1 CF domain causing anemia, thrombocytopenia and megakaryocyte proliferation with mild myelofibrosis, correlating a new GATA1 germline variant with myeloid disorder.
    Keywords:  Fibrosis; GATA1; MDS/MPN; Mutation; Myeloid disorder
    DOI:  https://doi.org/10.1016/j.bcmd.2021.102545
  7. Haematologica. 2021 Feb 25.
    Unique ethnic features of DDX41 mutations in patients with idiopathic cytopenia of undetermined significance, myelodysplastic syndrome, or acute myeloid leukemia.
    Choi EJ, Cho YU, Hur EH, Jang S, Kim N, Park HS, Lee JH, Lee KH, Kim SH, Hwang SH, Seo EJ, Park CJ, Lee JH.
      DDX41 mutations are associated with hematologic malignancies including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but the incidence in idiopathic cytopenia of undetermined significance (ICUS) is unknown. We investigated the incidence, genetic characteristics, and clinical features of DDX41 mutations in Korean patients with ICUS, MDS, or AML. We performed targeted deep sequencing of 61 genes including DDX41 in 457 patients with ICUS (n=75), MDS (n=210), or AML (n=172). The germline DDX41 mutations with causality were identified in 28 (6.1%) patients, of whom 27 (96.4%) had somatic mutations in the other position of DDX41. Germline origins of the DDX41 mutations were confirmed in all of the 11 patients who performed germline-based testing. Of the germline DDX41 mutations, p.V152G (n=10) was most common, followed by p.Y259C (n=8), p.A500fs (n=6), and p.E7* (n=3). Compared with non-mutated patients, DDX41-mutated patients showed male predominance, old age, normal karyotype, low leukocyte count, and hypocellular marrow at diagnosis. Three of the 4 ICUS patients with germline DDX41 mutations progressed to MDS. DDX41 mutations in Korean patients showed a high incidence and distinct mutation patterns, in that p.V152G was a unique germline variant. ICUS harboring germline DDX41 mutations may be regarded as a hereditary myeloid neoplasm. Germline DDX41 mutations are not uncommon and should be explored when treating the patients with myeloid malignancies.
    DOI:  https://doi.org/10.3324/haematol.2020.270553
  8. Br J Haematol. 2020 Dec 05.
    Inherited predisposition to haematopoietic malignancies: overcoming barriers and exploring opportunities.
    Trottier AM, Godley LA.
      Inherited predisposition to haematopoietic malignancies, due to deleterious germline variants in a variety of genes, is an important clinical entity with implications for the health and management of patients and their family members. Unfortunately, there remain several common misconceptions in this field that can result in patients going unrecognised and/or having incomplete or improper testing including: the impression that inherited haematological malignancy syndromes are rare, that myeloid and lymphoid malignancy predisposition syndromes are mutually exclusive, and that solid tumour predisposition syndromes are unique and distinct from haematopoietic malignancy predisposition syndromes. In the present review, we challenge these ideas with our insights into germline genetic testing for these conditions with the hope that increased awareness and knowledge will overcome barriers and lead to improved diagnosis and management.
    Keywords:  barriers; germline; haematopoietic malignancy
    DOI:  https://doi.org/10.1111/bjh.17247
  9. Nat Commun. 2021 Feb 26. 12(1): 1334
    Distinct genetic pathways define pre-malignant versus compensatory clonal hematopoiesis in Shwachman-Diamond syndrome.
    Kennedy AL, Myers KC, Bowman J, Gibson CJ, Camarda ND, Furutani E, Muscato GM, Klein RH, Ballotti K, Liu S, Harris CE, Galvin A, Malsch M, Dale D, Gansner JM, Nakano TA, Bertuch A, Vlachos A, Lipton JM, Castillo P, Connelly J, Churpek J, Edwards JR, Hijiya N, Ho RH, Hofmann I, Huang JN, Keel S, Lamble A, Lau BW, Norkin M, Stieglitz E, Stock W, Walkovich K, Boettcher S, Brendel C, Fleming MD, Davies SM, Weller EA, Bahl C, Carter SL, Shimamura A, Lindsley RC.
      To understand the mechanisms that mediate germline genetic leukemia predisposition, we studied the inherited ribosomopathy Shwachman-Diamond syndrome (SDS), a bone marrow failure disorder with high risk of myeloid malignancies at an early age. To define the mechanistic basis of clonal hematopoiesis in SDS, we investigate somatic mutations acquired by patients with SDS followed longitudinally. Here we report that multiple independent somatic hematopoietic clones arise early in life, most commonly harboring heterozygous mutations in EIF6 or TP53. We show that germline SBDS deficiency establishes a fitness constraint that drives selection of somatic clones via two distinct mechanisms with different clinical consequences. EIF6 inactivation mediates a compensatory pathway with limited leukemic potential by ameliorating the underlying SDS ribosome defect and enhancing clone fitness. TP53 mutations define a maladaptive pathway with enhanced leukemic potential by inactivating tumor suppressor checkpoints without correcting the ribosome defect. Subsequent development of leukemia was associated with acquisition of biallelic TP53 alterations. These results mechanistically link leukemia predisposition to germline genetic constraints on cellular fitness, and provide a rational framework for clinical surveillance strategies.
    DOI:  https://doi.org/10.1038/s41467-021-21588-4
  10. Am J Med Genet A. 2021 Feb 21.
    Case report of adrenocortical carcinoma associated with double germline mutations in MSH2 and RET.
    Raygada M, Raffeld M, Bernstein A, Miettinen M, Glod J, Hughes MS, Reilly K, Widemann B, DelRivero J.
      Adrenocortical carcinoma (ACC) is a rare aggressive malignancy that originates in the outer layer of the adrenal gland. Most ACCs are sporadic, but a small percentage of cases are due to hereditary cancer syndromes such as Li-Fraumeni syndrome (LFS), Lynch syndrome (LS), and familial adenomatous polyposis (FAP). Multiple endocrine neoplasia type 2A (MEN2A) is an inherited disorder that predisposes to medullary thyroid cancer, pheochromocytoma, and parathyroid hyperplasia. We present here a case of ACC with both LS and MEN2A; the family and medical history were consistent with Lynch. This is, to our knowledge, the first report of a patient with ACC associated with germline mutations in RET and MSH2, and no phenotypical characteristics of MEN2A.
    Keywords:  Lynch syndrome; adrenocortical cancer; multiple endocrine neoplasia type 2A
    DOI:  https://doi.org/10.1002/ajmg.a.62099
  11. Cancer Commun (Lond). 2021 Feb 25.
    Co-occurrence of germline pathogenic variants for different hereditary cancer syndromes in patients with Lynch syndrome.
    Ferrer-Avargues R, Castillejo MI, Dámaso E, Díez-Obrero V, Garrigos N, Molina T, Codoñer-Alejos A, Segura Á, Sánchez-Heras AB, Castillejo A, Soto JL.
      BACKGROUND: Lynch syndrome (LS) is a hereditary condition characterized by a high risk of colorectal cancer, endometrial cancer, and other neoplasia associated with germline alterations in DNA mismatch repair genes. The classical genetic diagnostic strategy for LS consists of the Sanger sequencing of genes associated with the suspected syndrome. Next-generation sequencing (NGS) enables the simultaneous sequencing of a large number of hereditary cancer genes. Here, we aimed to study whether other germline pathogenic variants of hereditary cancer genes are present in patients with LS.METHODS: A cohort of 84 probands with a previous genetic diagnosis of LS by Sanger sequencing was reanalyzed using NGS via a commercial panel of 94 hereditary cancer genes by hybrid capture. The American College of Medical Genetics and Genomics criteria were used to classify the clinical significance of the variants. The findings of NGS were confirmed by Sanger sequencing. When possible, genetic analyses of the new findings in the proband's relatives were also performed by Sanger sequencing.
    RESULTS: We identified five families (6%), out of 84, with at least two germline pathogenic variants conferring to high or moderate risk in different dominant cancer-predisposing genes: [MLH1-BRCA2-NBN], [MLH1-BRCA1], [MSH2-ATM], [MSH6-NF1], and [MLH1-FANCA]. Interestingly, only one out of these five families exhibited a clinical phenotype associated with the new pathogenic variants. The family with three pathogenic variants of the [MLH1-BRCA2-NBN] genes showed a high aggregation of tumors associated with LS and breast and ovarian cancer syndrome.
    CONCLUSIONS: Our results showed that the co-occurrence of more than one pathogenic variant in cancer-predisposing genes was remarkable among cases of LS. In most cases, no clinicial manifestations were associated with the secondary pathogenic variants. Further studies are needed to confirm these findings and elucidate their clinical impact. Reanalysis of LS families should be considered only in families with mixed clinical phenotypes.
    Keywords:  cancer panel; hereditary cancer; lynch syndrome; moderate penetrance genes; multilocus inherited neoplasia alleles syndrome; next-generation sequencing; secondary findings
    DOI:  https://doi.org/10.1002/cac2.12134
  12. J Mol Diagn. 2021 Feb 20. pii: S1525-1578(21)00044-1. [Epub ahead of print]
    Intronic breakpoint signatures enhance detection and characterization of clinically relevant germline structural variants.
    van den Akker J, Hon L, Ondov A, Mahkovec Z, O'Connor R, Chan RC, Lock J, Zimmer AD, Rostamianfar A, Ginsberg J, Leon A, Topper S.
      The relevance of large copy number variants (CNVs) to hereditary disorders has been long recognized, and population sequencing efforts have chronicled many common structural variants (SVs). However, limited data are available on the clinical contribution of rare germline SVs. We performed a detailed characterization of SVs identified using targeted next generation sequencing. Across 50 genes associated with hereditary cancer and cardiovascular disorders, a minimum of 828 unique SVs were reported, including 584 fully characterized SVs. Almost 40% of CNVs were <5kb, with one in three deletions impacting a single exon. Additionally, 36 mid-range deletions/duplications (50-250bp), 21 mobile element insertions, six inversions, and 27 complex rearrangements were detected. This dataset was used to model SV detection in a bioinformatics pipeline solely relying on read depth, which revealed that genome sequencing (30X) allows detection of 71%, a 500X panel only targeting coding regions 53%, and exome sequencing (100X) less than 20% of characterized SVs. SVs accounted for 14.1% of all unique pathogenic variants, supporting the importance of SVs in hereditary disorders. Robust SV detection requires an ensemble of variant calling algorithms that utilize sequencing of intronic regions. These algorithms should use distinct data features representative of each class of mutational mechanism, including recombination between two sequences sharing high similarity, co-variants inserted between CNV breakpoints, and complex rearrangements containing inverted sequences.
    DOI:  https://doi.org/10.1016/j.jmoldx.2021.01.015
  13. AME Case Rep. 2021 ;5 5
    CHEK2 mutation in a patient with pancreatic adenocarcinoma-a rare case report.
    Vittal A, Saha D, Samanta I, Kasi A.
      Pancreatic cancer (PaCa) is very aggressive malignancy with poor prognosis. Individuals with a family history of PaCa have a higher risk of developing cancer which points to a hereditary component. Here, we report a unique case of CHEK2 mutant PaCa in a patient with no medical but significant family history. A 59-year old female presented with 3-month history of worsening epigastric pain and jaundice. CT abdomen/pelvis with contrast showed pancreatic head mass which was confirmed by endoscopic ultrasound guided biopsy. She was diagnosed with pancreatic adenocarcinoma harboring CHEK2 mutation. She had extensive surgery followed by adjuvant chemotherapy. Follow up imaging in 3 months obtained after surgery and adjuvant chemotherapy showed extensive liver metastasis and patient decided to pursue hospice. Germline testing in all PaCa patients has become essential as mutations in CHEK2 and other DNA repair genes constitute a unique subset of PaCas. Not only does it help in assessment of cancer risk in the individual and family members but also guide anticancer therapy selection. PaCa patients harboring CHEK2 mutations do not usually respond to chemotherapeutic agents such as gemcitabine. However, new treatment strategies such as PARP inhibitors targeting defective DNA repair mechanism are currently being investigated and showed some promise in treating CHEK2 mutant PaCa patients.
    Keywords:  CHEK 2; PARP inhibitor; Pancreatic cancer (PaCa)
    DOI:  https://doi.org/10.21037/acr-20-83
  14. Stem Cell Res. 2021 Feb 11. pii: S1873-5061(21)00088-X. [Epub ahead of print]52 102242
    Generation and characterization of induced pluripotent stem cells from a family carrying the BRCA1 mutation c.3612delA.
    Silva TP, Pereira CA, Oliveira AR, Raposo AC, Arez M, Cabral JMS, Milagre I, Carmo-Fonseca M, da Rocha ST.
      How BRCA1 germline mutations predispose to cancer remains poorly understood. Induced pluripotent stem cells (iPSCs) represent an emerging model to investigate the molecular mechanisms underlying malignant transformation in primary cells from individuals who are carriers of deleterious mutations in the BRCA1 gene. Here we report the generation and characterization of iPSC lines from a female donor harboring a germline c.3612delA mutation in the BRCA1 gene and her daughter who does not carry the mutation. Skin fibroblasts were reprogrammed using non-integrative Sendai virus and characterized for their pluripotent properties. These iPSCs are a valuable cellular model for personalized pre-clinical research in the context of BRCA1 mutant hereditary cancers.
    DOI:  https://doi.org/10.1016/j.scr.2021.102242
  15. Eur J Hum Genet. 2021 Feb 22.
    Resolving pathogenicity classification for the CDH1 c.[715G>A] (p.Gly239Arg) Variant.
    Yelskaya Z, Arnold AG, Marcell VJ, Tang LH, Salo-Mullen EE, Strong V, Stadler ZK, Zhang L.
      Hereditary Diffuse Gastric Cancer (HDGC) syndrome is associated with CDH1 germline likely pathogenic/pathogenic variants. Carriers of CDH1 germline likely pathogenic/pathogenic variants are predisposed to diffuse gastric cancer and lobular breast cancer. This study aims to classify the CDH1 c.[715G>A] missense variant identified in a diffuse gastric cancer prone family by performing splicing studies. RT-PCR and subsequent cloning experiments were performed to investigate whether this variant completely disrupts normal splicing. This variant preferentially abolishes normal splicing through activation of a cryptic 3' acceptor splice site within exon 6 of CDH1, presumably leading to a premature protein truncation within first extracellular domain repeat of E-cadherin protein. Our results contributed to evidence necessary to resolve pathogenicity classification of this variant, indicating that this variant is to be classified as pathogenic.
    DOI:  https://doi.org/10.1038/s41431-021-00825-w
  16. JAMA Netw Open. 2021 Feb 01. 4(2): e210112
    A Genome-First Approach to Characterize DICER1 Pathogenic Variant Prevalence, Penetrance, and Phenotype.
    Mirshahi UL, Kim J, Best AF, Chen ZE, Hu Y, Haley JS, Golden A, Stahl R, Manickam K, Carr AG, Harney LA, Field A, Hatton J, Schultz KAP, Bauer AJ, Hill DA, Rosenberg PS, Murray MF, Carey DJ, Stewart DR.
      Importance: Genetic disorders are historically defined through phenotype-first approaches. However, risk estimates derived from phenotype-linked ascertainment may overestimate severity and penetrance. Pathogenic variants in DICER1 are associated with increased risks of rare and common neoplasms and thyroid disease in adults and children. This study explored how effectively a genome-first approach could characterize the clinical traits associated with germline DICER1 putative loss-of-function (pLOF) variants in an unselected clinical cohort.Objective: To examine the prevalence, penetrance, and phenotypic characteristics of carriers of germline DICER1 pLOF variants via genome-first ascertainment.
    Design, Setting, and Participants: This cohort study classifies DICER1 variants in germline exome sequence data from 92 296 participants of the Geisinger MyCode Community Health Initiative. Data for each MyCode participant were used from the start of the Geisinger electronic health record to February 1, 2018.
    Main Outcomes and Measures: Prevalence of germline DICER1 variation; penetrance of malignant tumors and thyroid disease in carriers of germline DICER1 variation; structured, manual review of electronic health records; and DICER1 sequencing of available tumors from an associated cancer registry.
    Results: A total of 92 296 adults (mean [SD] age, 59 [18] years; 98% white; 60% female) participated in the study. Germline DICER1 pLOF variants were observed in 1 in 3700 to 1 in 4600 participants, more than double the expected prevalence. Malignant tumors (primarily thyroid carcinoma) were observed in 4 of 25 participants (16%) with DICER1 pLOF variants, which is comparable (by 50 years of age) to the frequency of neoplasms in the largest registry- and clinic-based (phenotype-first) DICER1 studies published to date. DICER1 pLOF variants were significantly associated with risks of thyroidectomy (odds ratio [OR], 6.0; 95% CI, 2.2-16.3; P = .007) and thyroid cancer (OR, 9.2; 95% CI, 2.1-34.7; P = .02) compared with controls, but there was not a significant increase in the risk of goiter (OR, 1.8; 95% CI, 0.7-4.9). A female patient in her 80s who was a carrier of a germline DICER1 hotspot variant was apparently healthy on electronic health record review. The term DICER1 did not appear in any of the medical records of the 25 participants with a pLOF DICER1 variant, even in those affected with a known DICER1-associated tumor or thyroid phenotype.
    Conclusions and Relevance: This cohort study was able to ascertain individuals with germline DICER1 variants based on a genome-first approach rather than through a previously established DICER1-related phenotype. Use of the genome-first approach may complement more traditional approaches to syndrome delineation and may be an efficient approach for risk estimation.
    DOI:  https://doi.org/10.1001/jamanetworkopen.2021.0112
  17. JAMA Oncol. 2021 Feb 25.
    Precision Medicine in Oncology-Toward the Integrated Targeting of Somatic and Germline Genomic Aberrations.
    Yap TA, Johnson A, Meric-Bernstam F.
      
    DOI:  https://doi.org/10.1001/jamaoncol.2020.7988
  18. CRISPR J. 2021 Feb;4(1): 3-4
    Re: Human Germline and Heritable Genome Editing: The Global Policy Landscape.
    Levrier G.
      
    DOI:  https://doi.org/10.1089/crispr.2021.29121.gle
  19. CRISPR J. 2021 Feb;4(1): 4-5
    Response to Levrier re: Human Germline and Heritable Genome Editing: The Global Policy Landscape.
    Darnovsky M, Hasson K, Krahn TM.
      
    DOI:  https://doi.org/10.1089/crispr.2021.29122.are
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