bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2023‒05‒21
seven papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet
  1. TP53 germline pathogenic variant frequency in anaplastic rhabdomyosarcoma: A Children's Oncology Group report.
  2. Treatment and Response Evaluation Challenges in a Pregnant Woman With B-Cell Lymphoblastic Leukemia and Li-Fraumeni Syndrome.
  3. Risk of Syndrome-Associated Cancers Among First-Degree Relatives of Patients With Pancreatic Ductal Adenocarcinoma With Pathogenic or Likely Pathogenic Germline Variants.
  4. Effect on Germline Mutation Rate in a High-Risk Chinese Breast Cancer Cohort after Compliance with The National Comprehensive Cancer Network (NCCN) 2023 v.1 Testing Criteria.
  5. Clinical and molecular correlates of somatic and germline DDX41 variants in patients and families with myeloid neoplasms.
  6. Germline Predisposition to Myelodysplastic Syndromes.
  7. Incidence and Prognostic Impact of Deleterious Germline Mutations in Primary Advanced Ovarian Carcinoma Patients.
  1. Pediatr Blood Cancer. 2023 May 17. e30413
    TP53 germline pathogenic variant frequency in anaplastic rhabdomyosarcoma: A Children's Oncology Group report.
    Douglas Fair, Luke Maese, Yueh-Yun Chi, Minjie Li, Douglas S Hawkins, Rajkumar Venkatramani, Erin Rudzinski, David Parham, Lisa Teot, David Malkin, Sharon E Plon, He Li, Aniko Sabo, Philip J Lupo, Joshua D Schiffman.
      Rhabdomyosarcoma (RMS) is a well-described cancer in Li-Fraumeni syndrome, resulting from germline TP53 pathogenic variants (PVs). RMS exhibiting anaplasia (anRMS) are associated with a high rate of germline TP53 PVs. This study provides updated estimates of the prevalence of TP53 germline PVs in RMS (3%) and anRMS (11%) from a large cohort (n = 239) enrolled in five Children's Oncology Group (COG) clinical trials. Although the prevalence of germline TP53 PVs in patients with anRMS in this series is much lower than previously reported, this prevalence remains elevated. Germline evaluation for TP53 PVs should be strongly considered in patients with anRMS.
    Keywords:  Li-Fraumeni syndrome; TP53; anaplasia; germline; predisposition; rhabdomyosarcoma
    DOI:  https://doi.org/10.1002/pbc.30413
  2. J Hematol. 2023 Apr;12(2): 92-99
    Treatment and Response Evaluation Challenges in a Pregnant Woman With B-Cell Lymphoblastic Leukemia and Li-Fraumeni Syndrome.
    Bjarte Skoe Erikstein, Aymen Bushra Ahmed, Rakel Brendsdal Forthun, Friedemann Leh, Bjørn Tore Gjertsen, Håkon Reikvam.
      Li-Fraumeni syndrome (LFS) is a cancer predisposing syndrome caused by pathogenic germline TP53 gene mutations with important therapeutic and prognostic implications for many types of cancer. A small proportion of LFS patients develop B-cell lymphoblastic leukemia (B-ALL) in adult years. Standard treatment often proves inadequate, but immunotherapy has provided new treatment options. The current case report presents a pregnant woman with LFS and newly diagnosed B-ALL with hypodiploidy developed after treatment for early-onset breast cancer. We describe the treatment course, treatment-related complications and provide laboratory data crucial for evaluating and modifying treatment for this difficult clinical case. Our findings support the need for close collaboration between clinicians and experts on immunophenotyping. Through our report, we show that immunotherapy is feasible in patients with LFS and B-ALL, despite a poor initial response to induction therapy.
    Keywords:  Anti-CD20; Anti-CD22; B-cell lymphoblastic leukemia; Bispecific anti-CD19/anti-CD3; Heritable TP53-related cancer; Immunotherapy; Li-Fraumeni syndrome; Pregnancy
    DOI:  https://doi.org/10.14740/jh1107
  3. JAMA Oncol. 2023 May 18.
    Risk of Syndrome-Associated Cancers Among First-Degree Relatives of Patients With Pancreatic Ductal Adenocarcinoma With Pathogenic or Likely Pathogenic Germline Variants.
    Xuan Chen, Margaret A Meyer, Jennifer L Kemppainen, Masayasu Horibe, Shruti Chandra, Shounak Majumder, Gloria M Petersen, Kari G Rabe.
      Importance: Increased cancer risk in first-degree relatives of probands with pancreatic ductal adenocarcinoma (PDAC probands) who carry pathogenic or likely pathogenic germline variants (PGVs) in cancer syndrome-associated genes encourages cascade genetic testing. To date, unbiased risk estimates for the development of cancers on a gene-specific basis have not been assessed.Objective: To quantify the risk of development of PDAC and extra-PDAC among first-degree relatives of PDAC probands who carry a PGV in 1 of 9 cancer syndrome-associated genes-ATM, BRCA1, BRCA2, PALB2, MLH1, MSH2, MSH6, PMS2, and CDKN2A.
    Design, Setting, and Participants: This case series focused on first-degree relatives of PDAC probands carrying PGVs in specific cancer syndrome-associated genes. The cohort comprised clinic-ascertained patients enrolled in the Mayo Clinic Biospecimen Resource for Pancreas Research registry with germline genetic testing. In total, 234 PDAC probands carrying PGVs were drawn from the prospective research registry of 4562 participants who had undergone genetic testing of cancer syndrome-associated genes. Demographic and cancer-related family histories were obtained by questionnaire. The data were collected from October 1, 2000, to December 31, 2021.
    Main Outcomes and Measures: For the PDAC probands, the genetic test results of the presence of PGVs in 9 cancer syndrome-associated genes were obtained by clinical testing. Cancers (ovary, breast, uterus or endometrial, colon, malignant melanoma, and pancreas) among first-degree relatives were reported by the probands. Standardized incidence ratios (SIRs) were used to estimate cancer risks among first-degree relatives of PDAC probands carrying a PGV.
    Results: In total, 1670 first-degree relatives (mean [SD] age, 58.1 [17.8] years; 853 male [51.1%]) of 234 PDAC probands (mean [SD] age, 62.5 [10.1] years; 124 male [53.0%]; 219 [94.4%] White; 225 [98.7%] non-Hispanic or non-Latino]) were included in the study. There was a significantly increased risk of ovarian cancer in female first-degree relatives of probands who had variants in BRCA1 (SIR, 9.49; 95% CI, 3.06-22.14) and BRCA2 (SIR, 3.72; 95% CI, 1.36-8.11). Breast cancer risks were higher with BRCA2 variants (SIR, 2.62; 95% CI, 1.89-3.54). The risks of uterine or endometrial cancer (SIR, 6.53; 95% CI, 2.81-12.86) and colon cancer (SIR, 5.83; 95% CI, 3.70-8.75) were increased in first-degree relatives of probands who carried Lynch syndrome mismatch repair variants. Risk of PDAC was also increased for variants in ATM (SIR, 4.53; 95% CI, 2.69-7.16), BRCA2 (SIR, 3.45; 95% CI, 1.72-6.17), CDKN2A (SIR, 7.38; 95% CI, 3.18-14.54), and PALB2 (SIR, 5.39; 95% CI, 1.45-13.79). Melanoma risk was elevated for first-degree relatives of probands with CDKN2A variants (SIR, 7.47; 95% CI, 3.97-12.77).
    Conclusions and Relevance: In this case series, the presence of PGVs in 9 cancer syndrome-associated genes in PDAC probands was found to be associated with increased risk of 6 types of cancers in first-degree relatives. These gene-specific PDAC and extra-PDAC cancer risks may provide justification for clinicians to counsel first-degree relatives about the relevance and importance of genetic cascade testing, with the goal of higher uptake of testing.
    DOI:  https://doi.org/10.1001/jamaoncol.2023.0806
  4. Cancers (Basel). 2023 May 06. pii: 2635. [Epub ahead of print]15(9):
    Effect on Germline Mutation Rate in a High-Risk Chinese Breast Cancer Cohort after Compliance with The National Comprehensive Cancer Network (NCCN) 2023 v.1 Testing Criteria.
    Ava Kwong, Cecilia Y S Ho, Wing-Pan Luk, Ling-Hiu Fung, Chun-Hang Au, Edmond S K Ma.
      BACKGROUND: The National Comprehensive Cancer Network (NCCN) testing criteria for the high-penetrance breast cancer susceptibility genes, specifically BRCA1, BRCA2, CDH1, PALB2, PTEN, and TP53, have been recently modified in 2023 to 2023 v.1. The following criteria have been changed: (1) from a person diagnosed with breast cancer at ≤45 to ≤50; (2) from aged 45-50 of personal breast diagnosis to any age of diagnosis with multiple breast cancers; and (3) from aged ≥51 of personal breast diagnosis to any age of diagnosis with family history listed in NCCN 2022 v.2.METHODS: High-risk breast cancer patients (n = 3797) were recruited from the Hong Kong Hereditary Breast Cancer Family Registry between 2007 and 2022. Patients were grouped according to NCCN testing criteria 2023 v.1 and 2022 v.2. A 30-gene panel for hereditary breast cancer was performed. The mutation rates on high-penetrance breast cancer susceptibility genes were compared.
    RESULTS: About 91.2% of the patients met the 2022 v.2 criteria, while 97.5% of the patients met the 2023 v.1 criteria. An extra 6.4% of the patients were included after the revision of the criteria, and 2.5% of the patients did not meet both testing criteria. The germline BRCA1/2 mutation rates for patients meeting the 2022 v.2 and 2023 v.1 criteria were 10.1% and 9.6%, respectively. The germline mutation rates of all 6 high-penetrance genes in these two groups were 12.2% and 11.6%, respectively. Among the additional 242 patients who were included using the new selection criteria, the mutation rates were 2.1% and 2.5% for BRCA1/2 and all 6 high-penetrance genes, respectively. Patients who did not meet both testing criteria were those with multiple personal cancers, a strong family history of cancers not listed in the NCCN, unclear pathology information, or the patient's voluntary intention to be tested. The mutation rates of BRCA1/2 and the 6 high-penetrance genes in these patients were 5.3% and 6.4%, respectively.
    CONCLUSION: This study provided a real-world application of the revision of NCCN guidelines and its effect on the germline mutation rate in the Chinese population. Applying the updated criteria for further genetic investigation would increase the positive detection rate, and potentially more patients would benefit. The balance between the resource and outcome requires careful consideration.
    Keywords:  Chinese; NCCN; germline mutation; hereditary breast cancers
    DOI:  https://doi.org/10.3390/cancers15092635
  5. Haematologica. 2023 May 18.
    Clinical and molecular correlates of somatic and germline DDX41 variants in patients and families with myeloid neoplasms.
    Talha Badar, Ahmad Nanaa, James M Foran, David Viswanatha, Aref Al-Kali, Terra Lasho, Christy Finke, Hassan B Alkhateeb, Rong He, Naseema Gangat, Mithun Shah, Ayalew Tefferi, Abhishek A Mangaonkar, Mark R Litzow, Laura J Ongie, Timothy Chlon, Alejandro Ferrer, Mrinal M Patnaik.
      The diagnosis of germline predisposition to myeloid neoplasms (MN) secondary to DDX41 variants is currently hindered by the long latency period, variable family histories and the frequent occurrence of DDX41 variants of uncertain significance (VUS). We reviewed 4,524 consecutive patients who underwent targeted sequencing for suspected or known MN and analyzed the clinical impact and relevance of DDX41VUS in comparison to DDX41path variants. Among 107 patients (44 [0.9%] DDX41path and 63 DDX41VUS [1.4%; 11 patients with both DDX41path and DDX41VUS]), we identified 17 unique DDX41path and 45 DDX41VUS variants: 24 (23%) and 77 (72%) patients had proven and presumed germline DDX41 variants, respectively. The median ages were similar between DDX41path and DDX41VUS (66 vs 62, p= 0.41). The median VAF (47% vs 48%, p= 0.62), frequency of somatic myeloid co-mutations (34% vs 25%, p= 0.28), cytogenetic abnormalities (16% vs 12%, p= >0.99) and family history of hematological malignancies (20% vs 33%, p= 0.59) were comparable between the two groups. Time to treatment in months (1.53 vs 0.3, p= 0.16) and proportion of patients progressing to acute myeloid leukemia (AML) (14% vs 11%, p= 0.68), were similar. The median overall survival in patients with high-risk myelodysplastic syndrome (MDS)/AML was 63.4 and 55.7 months in the context of DDX41path and DDX41VUS, respectively (p= 0.93). Comparable molecular profiles and clinical outcomes among DDX41path and DDX41VUS patients highlights the need for a comprehensive DDX41 variant interrogation/classification system, to improve surveillance and management strategies in patients and families with germline DDX41 predisposition syndromes.
    DOI:  https://doi.org/10.3324/haematol.2023.282867
  6. Cancer J. 2023 May-Jun 01;29(3):29(3): 143-151
    Germline Predisposition to Myelodysplastic Syndromes.
    Georgina Gener-Ricos, Yoheved S Gerstein, Danielle Hammond, Courtney D DiNardo.
      ABSTRACT: While germline predisposition to myelodysplastic syndromes is well-established, knowledge has advanced rapidly resulting in more cases of inherited hematologic malignancies being identified. Understanding the biological features and main clinical manifestations of hereditary hematologic malignancies is essential to recognizing and referring patients with myelodysplastic syndrome, who may underlie inherited predisposition, for appropriate genetic evaluation. Importance lies in individualized genetic counseling along with informed treatment decisions, especially with regard to hematopoietic stem cell transplant-related donor selection. Future studies will improve comprehension of these disorders, enabling better management of affected patients and their families.
    DOI:  https://doi.org/10.1097/PPO.0000000000000660
  7. Cancers (Basel). 2023 Apr 28. pii: 2534. [Epub ahead of print]15(9):
    Incidence and Prognostic Impact of Deleterious Germline Mutations in Primary Advanced Ovarian Carcinoma Patients.
    Majdi Imterat, Philipp Harter, Kerstin Rhiem, Florian Heitz, Stephanie Schneider, Nicole Concin, Malak Moubarak, Julia Welz, Vasileios Vrentas, Alexander Traut, Eric Hahnen, Rita Schmutzler, Andreas du Bois, Beyhan Ataseven.
      Data on deleterious variants in genes other than BRCA1/2 remain limited. A retrospective cohort study was performed, including primary OC cases with TruRisk® germline gene panel testing between 2011 and 2020. Patients with testing after relapse were excluded. The cohort was divided into three groups: (A) no mutations, (B) deleterious BRCA1/2 mutations, and (C) deleterious mutations in other genes. A total of 702 patients met the inclusion criteria. Of these 17.4% (n = 122) showed BRCA1/2 mutations and a further 6.0% (n = 42) in other genes. Three-year overall survival (OS) of the entire cohort was significantly longer in patients with germline mutations (85%/82.8% for cohort B/C vs. 70.2% for cohort A, p < 0.001) and 3-year progression-free survival (PFS) only for cohort B (58.1% vs. 36.9%/41.6% in cohort A/C, p = 0.002). In multivariate analysis for the subgroup of advanced-stages of high-grade serous OC, both cohorts B/C were found to be independent factors for significantly better outcome, cohort C for OS (HR 0.46; 95% CI 0.25-0.84), and cohort B for both OS and PFS (HR 0.40; 95% CI 0.27-0.61 and HR 0.49; 95% CI 0.37-0.66, respectively). Germline mutations were detected in a quarter of OC patients, and a quarter of those in genes other than BRCA1/2. Germline mutations demonstrate in our cohort a prognostic factor and predict better prognosis for OC patients.
    Keywords:  BRCA1/2; BRIP1; PALB2; RAD51C/D; ovarian cancer; survival
    DOI:  https://doi.org/10.3390/cancers15092534
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