bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2023–09–24
seven papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet
  1. Clinical implication of CDH1 mutations in genetic testing for diffuse gastric cancer patients.
  2. Prevalence of pathogenic germline variants in adult-type diffuse glioma.
  3. Interpretation of ambiguous TP53 test results: Mosaicism, clonal hematopoiesis, and variants of uncertain significance.
  4. A Pathogenic Germline BRCA1 Variant in a Patient With Cellular Congenital Mesoblastic Nephroma: A Case Report.
  5. Germline Pathogenic Variants and Genetic Counseling by Ancestry in Patients With Epithelial Ovarian Cancer.
  6. Natural History Study of Patients with Familial Platelet Disorder with Myeloid Malignancy.
  7. Germline BRCA testing in pancreatic cancer: improving awareness, timing, turnaround, and uptake.
  1. Oncology. 2023 Sep 19.
    Clinical implication of CDH1 mutations in genetic testing for diffuse gastric cancer patients.
    Giovanni Corso, Cristina Maria Trovato, Salvatore Petitto, Antonia Girardi, Alessandra Margherita De Scalzi, Beatrice Bianchi, Francesca Magnoni, Antonio Cioffi, Viviana Galimberti, Paolo Veronesi, Giovanni Mazzarol, Patrick Maisonneuve.
       INTRODUCTION: The objective of this study was to re-classify published germline CDH1 variants identified in gastric cancer (GC) in accordance with the latest ClinVar definition and to correlate their pathogenicity with the established international clinical criteria for genetic testing.
    METHODS: The relevant literature dating from 1998 to 2019 was systematically searched for data on CDH1 germline mutations in accord with PRISMA guidelines. The collected variants were classified according to the latest ClinVar definition into the following classes: benign (B), likely benign (LB), pathogenic (P), likely pathogenic (LP), and variant of unknown significance (VUS). The Mc-Nemar test was used to compare the adequacy of current versus previous International GC Linkage Consortium (IGCLC) criteria.
    RESULTS: We re-classified a total of 247 CDH1 variants, and we identified that about 70% of B/LB variant carriers were not fulfilling the defined clinical criteria. Instead, all P/LP variants (100%) were associated with the hereditary diffuse gastric cancer (HDGC) phenotype fulfilling the 2020 ILGCC criteria, with a significant improvement (p=0.025) compared to previous version.
    CONCLUSIONS: We conclude that germline CDH1 genetic testing is indicated only in families meeting the clinical criteria for the HDGC syndrome. This observation suggests that clinical phenotypes that do not clearly fulfill these criteria should not be considered for CDH1 genetic testing.
    DOI:  https://doi.org/10.1159/000533774
  2. Neurooncol Pract. 2023 Oct;10(5): 482-490
    Prevalence of pathogenic germline variants in adult-type diffuse glioma.
    Malcolm F McDonald, Lyndsey L Prather, Cassandra R Helfer, Ethan B Ludmir, Alfredo E Echeverria, Shlomit Yust-Katz, Akash J Patel, Benjamin Deneen, Ganesh Rao, Ali Jalali, Shweta U Dhar, Chris I Amos, Jacob J Mandel.
       Background: No consensus germline testing guidelines currently exist for glioma patients, so the prevalence of germline pathogenic variants remains unknown. This study aims to determine the prevalence and type of pathogenic germline variants in adult glioma.
    Methods: A retrospective review at a single institution with paired tumor/normal sequencing from August 2018-April 2022 was performed and corresponding clinical data were collected.
    Results: We identified 152 glioma patients of which 15 (9.8%) had pathogenic germline variants. Pathogenic germline variants were seen in 11/84 (13.1%) of Glioblastoma, IDH wild type; 3/42 (7.1%) of Astrocytoma, IDH mutant; and 1/26 (3.8%) of Oligodendroglioma, IDH mutant, and 1p/19q co-deleted patients. Pathogenic variants in BRCA2, MUTYH, and CHEK2 were most common (3/15, 20% each). BRCA1 variants occurred in 2/15 (13%) patients, with variants in NF1, ATM, MSH2, and MSH3 occurring in one patient (7%) each. Prior cancer diagnosis was found in 5/15 patients (33%). Second-hit somatic variants were seen in 3/15 patients (20%) in NF1, MUTYH, and MSH2. Referral to genetics was performed in 6/15 (40%) patients with pathogenic germline variants. 14/15 (93%) of patients discovered their pathogenic variant as a result of their paired glioma sequencing.
    Conclusions: These findings suggest a possible overlooked opportunity for determination of hereditary cancer syndromes with impact on surveillance as well as potential broader treatment options. Further studies that can determine the role of variants in gliomagenesis and confirm the occurrence and types of pathogenic germline variants in patients with IDH wild type compared to IDH mutant tumors are necessary.
    Keywords:  diffuse glioma; glioblastoma; pathogenic germline variants
    DOI:  https://doi.org/10.1093/nop/npad033
  3. J Genet Couns. 2023 Sep 16.
    Interpretation of ambiguous TP53 test results: Mosaicism, clonal hematopoiesis, and variants of uncertain significance.
    Darcy K Berry, Nancy Gillis, Eric Padron, Colin Moore, Laura V Barton, Kathleen R Gewandter, Carolyn G Haskins, Todd C Knepper.
      The increased use of next-generation sequencing has led to the detection of pathogenic TP53 variants in the germline setting in patients without a personal or family history consistent with Li-Fraumeni syndrome (LFS). These variants can represent low-penetrance LFS, mosaic LFS, or clonal hematopoiesis of indeterminate potential. Additionally, TP53 variants of uncertain significance can be detected in patients with a history suspicious for LFS. The interpretation of the significance of these variants can be challenging but is crucial for an accurate diagnosis and appropriate medical management. This retrospective case review provides illustrative examples of the interpretation of challenging TP53 results through multidisciplinary expertise and use of a flowchart. The authors describe eight patients with TP53 variants associated with ambiguous diagnoses and, for each case, describe how the results were interpreted and the medical care that was implemented. This report presents illustrative cases to help guide clinicians to reach definitive diagnoses for patients when confronted with TP53 variants that are inconsistent with the clinical picture and to add to the body of literature regarding interpretation and medical management of TP53 variants discovered on germline testing.
    Keywords:   TP53 ; CHIP; Li-Fraumeni syndrome; cancer genetics; clonal hematopoiesis; genetic counseling; hereditary cancer; mosaicism; risk assessment
    DOI:  https://doi.org/10.1002/jgc4.1789
  4. Cureus. 2023 Aug;15(8): e43857
    A Pathogenic Germline BRCA1 Variant in a Patient With Cellular Congenital Mesoblastic Nephroma: A Case Report.
    Gayatri Dholakia, Julia Meade.
      Benign cystic tumors of the kidney are well-described in infants and young children. Here we report an infant diagnosed with a cellular congenital mesoblastic nephroma (CMN) with a germline pathogenic variant in BRCA1. This finding is novel because BRCA1 is an adult-onset cancer predisposition gene causing breast, ovarian, pancreatic, and prostate cancers. However, increasing studies are indicating the presence of germline BRCA1 in both malignant and benign childhood cancers.
    Keywords:  brca1 germline mutation; case report; cystic nephroma; genetic syndromes; pediatric hematology-oncology
    DOI:  https://doi.org/10.7759/cureus.43857
  5. JCO Precis Oncol. 2023 Sep;7 e2300137
    Germline Pathogenic Variants and Genetic Counseling by Ancestry in Patients With Epithelial Ovarian Cancer.
    Tiffany Y Sia, Anna Maio, Yelena M Kemel, Kanika S Arora, Sushmita B Gordhandas, Ryan M Kahn, Erin E Salo-Mullen, Margaret A Sheehan, Prince Rainier Tejada, Chaitanya Bandlamudi, Qin Zhou, Alexia Iasonos, Rachel N Grisham, Roisin E O'Cearbhaill, William P Tew, Kara Long Roche, Oliver Zivanovic, Yukio Sonoda, Ginger J Gardner, Dennis S Chi, Alicia J Latham, Maria I Carlo, Yonina R Murciano-Goroff, Marie Will, Michael F Walsh, Mark E Robson, Diana L Mandelker, Michael F Berger, Nadeem R Abu-Rustum, Carol L Brown, Kenneth Offit, Jada G Hamilton, Carol Aghajanian, Britta Weigelt, Zsofia K Stadler, Ying L Liu.
       PURPOSE: To evaluate rates of germline pathogenic/likely pathogenic variants (PVs) and genetic counseling by ancestry in patients with epithelial ovarian cancer (EOC).
    METHODS: Patients with pathologically confirmed EOC who underwent clinical tumor-normal sequencing from January 1, 2015, to December 31, 2020, inclusive of germline analysis of ≥76 genes were included. Patients with newly identified PVs were referred for Clinical Genetics Service (CGS) counseling. Ancestry groups were defined using self-reported race/ethnicity and Ashkenazi Jewish (AJ) heritage. Genetic ancestry was inferred computationally using validated algorithms. Logistic regression models were built.
    RESULTS: Of 1,266 patients, self-reported ancestry (AJ, 17%; Asian, 10%; Black/African American, 5.4%; Hispanic, 6.2%; non-Hispanic White, 57%; other, 0.16%; unknown, 4.0%) correlated with genetic ancestry (AJ ancestry, 18%; admixed, 10%; African, 4%; East Asian [EAS], 6%; European, 56%; Native American, 0.2%; South Asian [SAS], 4%; unknown, 2%). Germline PVs were observed in 313 (25%) patients, including 195 (15%) with PVs in EOC-associated genes. Those with PVs were younger at diagnosis (59 v 62 years; P < .001) and more likely to have high-grade serous ovarian cancer (83% v 72%; P = .009). PV prevalence varied between ancestry groups (P < .001), with highest rates in the AJ (39.9%) and Asian (26.5%) groups and similar rates (>10%) across other ancestry groups. Use of genetic ancestry demonstrated similar findings and further characterized high rates of PV in EAS/SAS groups. Younger age, high-grade serous histology, and self-reported AJ or Asian ancestry were associated with PV in an EOC-associated gene. Rates of CGS counseling for newly identified PVs were high (80%) across ancestry groups.
    CONCLUSION: Rates of PV, particularly in EOC-associated genes, were high regardless of ancestry, with similar rates of counseling between groups, emphasizing the importance of universal genetic testing in all patients with EOC.
    DOI:  https://doi.org/10.1200/PO.23.00137
  6. Blood. 2023 Sep 22. pii: blood.2023019746. [Epub ahead of print]
    Natural History Study of Patients with Familial Platelet Disorder with Myeloid Malignancy.
    Paul P Liu, Lea Cunningham, Matthew Douglas Merguerian, Katherine R Calvo, Joie Davis, Natalie T Deuitch, Alina E Dulau-Florea, Nisha Patel, Kai Yu, Keith Sacco, Sumona Bhattacharya, Monica Passi, Neval Ozkaya, Seila Vanessa De Leon, Shawn Nathan Chong, Kathleen Marie Craft, Jamie L Diemer, Erica Bresciani, Kevin J O'Brien, Elizabeth J Andrews, Nguyen Park, Londa Hathaway, Edward W Cowen, Theo Heller, Kerry Ryan, Amisha Barochia, Khanh Nghiem, Julie E Niemela, Sergio D Rosenzweig, David J Young, Pamela Frischmeyer-Guerrerio, Raul C Braylan.
      Deleterious germline RUNX1 variants cause the autosomal dominant disease familial platelet disorder with associated myeloid malignancy (FPDMM), characterized by thrombocytopenia, platelet functional defects and predisposition to hematologic malignancies (HMs). We launched a FPDMM natural history study and, from January 2019-December 2021, enrolled 214 participants, including 111 patients with 39 different RUNX1 variants from 45 unrelated families. Of those with available data, 91% (70/77) had thrombocytopenia, 100% (18/18) had abnormal platelet aggregometry, 46% (16/35) had platelets with decreased dense granules, and 51% (28/55) had abnormal bleeding scores. Histologic evaluation of non-malignant bone marrows showed increased number of megakaryocytes in 22% (12/55) patients, dysmegakaryopoiesis in 76% (42/55), and reduced cellularity for age in 55% adult (30/55) and 81% pediatric (17/21) cases. 19 of 111 (17%) enrolled patients were diagnosed with HMs, including myelodysplastic syndrome, acute myeloid leukemia, chronic myelomonocytic leukemia, acute lymphoblastic leukemia and smoldering myeloma. 18 of the 19 patients with HM were relapsed or refractory to upfront therapy and referred for hematopoietic stem cell transplantation. In addition, 62% (28/45) of families have at least one member who has developed HMs. Moreover, 93% (42/45) of patients had allergic and 80% (24/30) had gastrointestinal symptoms. Our results highlight the importance of a multidisciplinary approach, early malignancy detection, and wider awareness of inherited disorders. This actively accruing, longitudinal study will genotype and phenotype more patients with FPDMM, which may lead to better understanding of the disease pathogenesis and clinical course, which may then inform preventative and therapeutic interventions.
    DOI:  https://doi.org/10.1182/blood.2023019746
  7. Ther Adv Med Oncol. 2023 ;15 17588359231189127
    Germline BRCA testing in pancreatic cancer: improving awareness, timing, turnaround, and uptake.
    Talia Golan, Raffaella Casolino, Andrew V Biankin, Pascal Hammel, Kristen D Whitaker, Michael J Hall, Douglas L Riegert-Johnson.
      Prognosis is generally poor for patients with pancreatic ductal adenocarcinoma. However, patients with germline BRCA1 or BRCA2 mutations (gBRCAm) may benefit from first-line platinum-based chemotherapy and maintenance therapy with the poly(adenosine diphosphate-ribose) polymerase inhibitor olaparib following at least 16 weeks of first-line platinum-based chemotherapy without disease progression. Germline breast cancer gene (BRCA) testing is therefore important to ensure that patients receive the most effective treatment. In addition, testing for other DNA damage response gene mutations beyond gBRCAm may also guide treatment decisions. However, clinical pathways for genetic testing are often suboptimal, leading to delays in treatment initiation or missed opportunities for personalized therapy. Barriers to testing include low rates of referral and uptake, delays to referral and slow result turnaround times, cost, and biopsy and assay limitations if somatic testing is performed, leading to the requirement for subsequent dedicated germline testing. Low rates of referral may result from lack of awareness among physicians of the clinical value of testing, coupled with low confidence in interpreting test results and poor availability of genetic counseling services. Among patients, barriers to uptake may include similar lack of awareness of the clinical value of testing, anxiety regarding the implications of test results, lack of insurance coverage, fear of negative insurance implications, and socioeconomic factors. Potential solutions include innovative approaches to testing pathways, including 'mainstreaming' of testing in which BRCA tests are routinely arranged by the treating oncologist, with the involvement of genetic counselors if a patient is found to have a gBRCAm. More recently, the utility of multigene panel analyses has also been explored. Access to genetic counseling may also be improved through initiatives such as having a genetic counseling appointment for all new patient visits and telemedicine approaches, including the use of telephone consultations or DVD-assisted counseling. Educational programs will also be beneficial, and cost effectiveness is likely to improve as the number of targeted treatments increases and when the earlier detection of tumors in family members following cascade testing is considered.
    Keywords:  genetic counseling; genetic testing; germline BRCA mutation; pancreatic ductal adenocarcinoma; referral; targeted therapy
    DOI:  https://doi.org/10.1177/17588359231189127
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