bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2022–10–30
twelve papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet
  1. Health Behavior and Cancer Prevention among Adults with Li-Fraumeni Syndrome and Relatives in Germany-A Cohort Description.
  2. Approach Toward Germline Predisposition Syndromes in Patients with Hematologic Malignancies.
  3. Increased Risk of Hereditary Prostate Cancer in Italian Families with Hereditary Breast and Ovarian Cancer Syndrome Harboring Mutations in BRCA and in Other Susceptibility Genes.
  4. Application of Multigene Panels Testing for Hereditary Cancer Syndromes.
  5. Contribution of Inherited Variants to Hereditary Cancer Syndrome Predisposition.
  6. Common germline risk variants impact somatic alterations and clinical features across cancers.
  7. An MSH6 germline pathogenic variant p.Gly162Ter associated with Lynch syndrome.
  8. What is the most effective way to ensure that patients successfully undergo germline testing for prostate cancer?
  9. Comparison of Germline Genetic Testing Before and After a Medical Policy Covering Universal Testing Among Patients With Colorectal Cancer.
  10. Germline mutations in 5' to c.7914 of BRCA2 significantly increase risk of prostate cancer.
  11. Evaluation of family history in individuals with heterozygous BRCA pathogenic variants diagnosed with breast or ovarian cancer in a single center in Italy.
  12. Late Presentation of Dyskeratosis Congenita: Germline Predisposition to Adult-Onset Secondary Acute Myeloid Leukemia.
  1. Curr Oncol. 2022 Oct 15. 29(10): 7768-7778
    Health Behavior and Cancer Prevention among Adults with Li-Fraumeni Syndrome and Relatives in Germany-A Cohort Description.
    Juliane Nees, Senta Kiermeier, Farina Struewe, Myriam Keymling, Imad Maatouk, Christian P Kratz, Sarah Schott.
      Li-Fraumeni-syndrome (LFS) is a rare, highly penetrant cancer predisposition syndrome (CPS) caused by pathogenic variants (PVs) in TP53. Physical activity (PA) and a Mediterranean diet lead to cancer reduction or survival benefits and increased quality of life (QoL), but this is yet unstudied among LFS. TP53 PV carriers (PVC) and their relatives were questioned on dietary patterns (Mediterranean Diet Adherence Screener), PA (Freiburg Questionnaire), QoL (Short-form-Health-Survey-12), smoking, alcohol consumption and perception of cancer risk in a German bi-centric study from March 2020-June 2021. The study enrolled 70 PVC and 43 relatives. Women compared to men (6.49 vs. 5.38, p = 0.005) and PVC to relatives (6.59 vs. 5.51; p = 0.006) showed a healthier diet, associated with participation in surveillance (p = 0.04) and education (diet p = 0.02 smoking p = 0.0003). Women smoked less (2.91 vs. 5.91 packyears; p = 0.03), psychological well-being was higher among men (SF-12: males 48.06 vs. females 41.94; p = 0.004). PVC rated their own cancer risk statistically higher than relatives (72% vs. 38%, p < 0.001) however, cancer risk of the general population was rated lower (38% vs. 70%, p < 0.001). A relative's cancer-related death increased the estimated personal cancer risk (p = 0.01). The possibilities of reducing cancer through self-determined health behavior among PVC and relatives has not yet been exhausted. Educating families with a CPS on cancer-preventive behavior requires further investigation with regard to acceptance and real-life implementation.
    Keywords:  Li-Fraumeni syndrome; MEDAS; SF-12; cancer predisposition; cancer prevention; pathogenic TP53 germline variant; physical activity
    DOI:  https://doi.org/10.3390/curroncol29100614
  2. Curr Hematol Malig Rep. 2022 Oct 24.
    Approach Toward Germline Predisposition Syndromes in Patients with Hematologic Malignancies.
    Himachandana Atluri, Yoheved S Gerstein, Courtney D DiNardo.
       PURPOSE OF REVIEW: Hematologic malignancies were previously thought to be primarily sporadic cancers without germline predispositions. However, over the last two decades, with the widespread use of next generation sequencing (NGS), there have been several genes have been identified that carry a risk of inheriting hematologic malignancies. Identification of individuals with hereditary hematologic malignancies (HHM) involves a high index of suspicion and careful attention to family history, clinical features, and variant allele frequency on somatic NGS panels.
    RECENT FINDINGS: Over the last several years, many genetic predisposition syndromes have been recognized to have unique features with both hematologic and non-hematologic co-morbidities. Multidisciplinary evaluation, including genetic counseling, is critical to optimizing diagnostic testing of individuals and at-risk family members. Prompt recognition of affected patients is imperative not only for personalized surveillance strategies but also for proper donor selection for those undergoing stem cell transplantation to avoid familial donors who also may share the same germline mutation. Herein, we describe our approach to recognizing patients suspected to carry a germline predisposition to hematologic malignancies and evaluation within a hereditary hematologic malignancies clinic (HHMC).
    Keywords:  Acute myeloid leukemia; Germline predisposition; Hematologic malignancies; Next generation sequencing
    DOI:  https://doi.org/10.1007/s11899-022-00684-2
  3. Genes (Basel). 2022 Sep 21. pii: 1692. [Epub ahead of print]13(10):
    Increased Risk of Hereditary Prostate Cancer in Italian Families with Hereditary Breast and Ovarian Cancer Syndrome Harboring Mutations in BRCA and in Other Susceptibility Genes.
    Giovanna D'Elia, Gemma Caliendo, Maria-Myrsini Tzioni, Luisa Albanese, Luana Passariello, Anna Maria Molinari, Maria Teresa Vietri.
      Hereditary prostate cancer (HPCa) has the highest heritability of any cancer in men. Interestingly, it occurs in several hereditary syndromes, including breast and ovarian cancer (HBOC) and Lynch syndrome (LS). Several gene mutations related to these syndromes have been identified as biomarkers in HPCa. The goal of this study was to screen for germline mutations in susceptibility genes by using a multigene panel, and to subsequently correlate the results with clinical and laboratory parameters. This was undertaken in 180 HBOC families, which included 217 males with prostate cancer (PCa). Mutational analysis was further extended to 104 family members of mutated patients. Screening of HBOC families revealed that 30.5% harbored germline mutations in susceptibility genes, with 21.6% harboring pathogenic variants (PVs) and 8.9% having variants of uncertain significance (VUS). We found PVs at similar frequency in BRCA1 and BRCA2 genes (8.8% and 9.4%, respectively), while 0.56% of PVs were present in well-established susceptibility genes PALB2, TP53 and RAD51C. Moreover, 0.56% of monoallelic PVs were present in MUTYH, a gene whose function in tumorigenesis in the context of PCa is still unclear. Finally, we reported double heterozygosity (DH) in BRCA1/2 genes in a single family, and found double mutation (DM) present in BRCA2 in a separate family. There was no significant difference between the mean age of onset of PCa in HBOC families with or without germline mutations in susceptibility genes, while the mean survival was highest in mutated patients compared to wild type. Furthermore, PCa is the second most recurrent cancer in our cohort, resulting in 18% of cases in both mutated and non-mutated families. Our investigation shows that PVs were located mostly in the 3' of BRCA1 and BRCA2 genes, and in BRCA2, most PVs fell in exon 11, suggesting a mutation cluster region relating to risk of HPCa. A total of 65 family members inherited the proband's mutation; of these, 24 developed cancer, with 41 remaining unaffected.
    Keywords:  BRCA genes; hereditary breast and ovarian cancer syndrome; hereditary prostate cancer; susceptibility genes
    DOI:  https://doi.org/10.3390/genes13101692
  4. Biology (Basel). 2022 Oct 05. pii: 1461. [Epub ahead of print]11(10):
    Application of Multigene Panels Testing for Hereditary Cancer Syndromes.
    Airat Bilyalov, Sergey Nikolaev, Leila Shigapova, Igor Khatkov, Anastasia Danishevich, Ludmila Zhukova, Sergei Smolin, Marina Titova, Tatyana Lisica, Natalia Bodunova, Elena Shagimardanova, Oleg Gusev.
       BACKGROUND: Approximately 5-10% of all cancers are associated with hereditary cancer predisposition syndromes (HCPS). Early identification of HCPS is facilitated by widespread use of next-generation sequencing (NGS) and brings significant benefits to both the patient and their relatives. This study aims to evaluate the landscape of genetic variants in patients with personal and/or family history of cancer using NGS-based multigene panel testing.
    MATERIALS AND METHODS: The study cohort included 1117 probands from Russia: 1060 (94.9%) patients with clinical signs of HCPS and 57 (5.1%) healthy individuals with family history of cancer. NGS analysis of 76 HCPS genes was performed using a custom Roche NimbleGen enrichment panel.
    RESULTS: Pathogenic/likely pathogenic variants were identified in 378 of 1117 individuals (33.8%). The predominant number (59.8%) of genetic variants was identified in BRCA1/BRCA2 genes. CHEK2 was the second most commonly altered gene with a total of 28 (7.4%) variants, and 124 (32.8%) genetic variants were found in other 35 cancer-associated genes with variable penetrance.
    CONCLUSIONS: Multigene panel testing allows for a differential diagnosis and identification of high-risk group for oncological diseases. Our results demonstrate that inclusion of non-coding gene regions into HCPS gene panels is highly important for the identification of rare spliceogenic variants with high penetrance.
    Keywords:  NGS; hereditary cancer; multigene panels
    DOI:  https://doi.org/10.3390/biology11101461
  5. Tohoku J Exp Med. 2022 Oct 27.
    Contribution of Inherited Variants to Hereditary Cancer Syndrome Predisposition.
    Gülay Güleç Ceylan, S Betül Arslan Satılmış, Büşranur Çavdarlı, C Nur Semerci Gündüz.
      
    DOI:  https://doi.org/10.1620/tjem.2022.J087
  6. Cancer Res. 2022 Oct 26. pii: CAN-22-1492. [Epub ahead of print]
    Common germline risk variants impact somatic alterations and clinical features across cancers.
    Shinichi Namba, Yuki Saito, Yasunori Kogure, Tatsuo Masuda, Melissa L Bondy, Puya Gharahkhani, Ines Gockel, Dominik Heider, Axel Hillmer, Janusz Jankowski, Stuart MacGregor, Carlo Maj, Beatrice Melin, Quinn T Ostrom, Claire Palles, Johannes Schumacher, Ian Tomlinson, David C Whiteman, Yukinori Okada, Keisuke Kataoka.
      Aggregation of genome-wide common risk variants, such as polygenic risk score (PRS), can measure genetic susceptibility to cancer. A better understanding of how common germline variants associate with somatic alterations and clinical features could facilitate personalized cancer prevention and early detection. We constructed PRSs from 14 genome-wide association studies (GWASs) (median n = 64,905) for 12 cancer types by multiple methods and calibrated them using the UK Biobank (UKB) resources (n = 335,048). Meta-analyses across cancer types in The Cancer Genome Atlas (TCGA) (n = 7,965) revealed that higher PRS values were associated with earlier cancer onset and lower burden of somatic alterations, including total mutations, chromosome/arm somatic copy number alterations (SCNAs), and focal SCNAs. This contrasts with rare germline pathogenic variants (e.g., BRCA1/2 variants), showing heterogeneous associations with somatic alterations. Our results suggest that common germline cancer risk variants allow early tumor development before the accumulation of many somatic alterations characteristic of later stages of carcinogenesis.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-1492
  7. Hum Genome Var. 2022 Oct 26. 9(1): 37
    An MSH6 germline pathogenic variant p.Gly162Ter associated with Lynch syndrome.
    Olga A Vostrukhina, Elena D Mirlina, Darya N Khmelkova, Galina M Butrovich, Alexandra D Shakhmatova, Yury V Kil, Yliya L Polyatskin, Anna S Artemyeva, Alexey V Gulyaev, Valery N Verbenko.
      We identified a three-generation Russian family with Lynch syndrome with a novel germline variant of the MSH6 gene. An 84-year-old female was diagnosed with endometrial adenocarcinoma at the age of 49 years. Her son was diagnosed with colorectal tubular adenoma at the age of 32 years. A germline nonsense variant (c.484 G > T:p.Gly162Ter) in exon 3 of the MSH6 gene was revealed by whole-exome sequencing. Sanger sequencing confirmed the cosegregation of the MSH6 nonsense variant in family members.
    DOI:  https://doi.org/10.1038/s41439-022-00216-7
  8. Urol Oncol. 2022 Oct 22. pii: S1078-1439(22)00309-X. [Epub ahead of print]
    What is the most effective way to ensure that patients successfully undergo germline testing for prostate cancer?
    David Ahlborn, Ilene Staff, Tara McLaughlin, Joseph Tortora, Joseph Wagner.
       INTRODUCTION: We sought to identify the most effective way to refer patients with prostate cancer to germline testing.
    METHODS: After IRB approval, we queried the electronic medical records (EMR) to identify patients (ages 18-89) with prostate cancer who were referred for or offered germline testing for prostate cancer from May 1, 2019 to February 24, 2021 through either telephone referral, EMR referral or in-office testing. The 3 cohorts were compared on receipt of testing and time to testing. Multivariate logistic regression and Cox regression evaluated the influence of referral cohort and reason for testing on receipt of testing and time to testing, respectively.
    RESULTS: A total of 184 patients met study inclusion criteria; 47 were referred for germline testing via telephone, 70 were referred through the EMR and 67 were offered testing in the office. No significant demographic or clinical differences were observed. Telephone referral yielded the lowest response (17%; P < 0.001) with the longest time interval between referral and testing (103 days; P < 0.001); in-office testing yielded the highest response (66%). More patients were referred because of both family history and high risk characteristics in the EMR and in-office testing cohorts (21.4% and 25.4% respectively). Referral method was significantly (P < 0.001) associated with receipt of test, while reason for testing was not. Referral method was also independently related to time to testing (P < 0.001) while reason for referral was not.
    CONCLUSIONS: Urologists should offer germline testing in the office for the most effective and expedient results.
    Keywords:  Genetic testing; Prostatic neoplasms; Referral
    DOI:  https://doi.org/10.1016/j.urolonc.2022.09.002
  9. JAMA Netw Open. 2022 Oct 03. 5(10): e2238167
    Comparison of Germline Genetic Testing Before and After a Medical Policy Covering Universal Testing Among Patients With Colorectal Cancer.
    Chad Moretz, Stacey DaCosta Byfield, Kathryn E Hatchell, Joline Dalton, Peter Nicholas Onglao, Lillian Hang, Pamela Hansen, Cristi Radford, Sarah M Nielsen, Brandie Heald, Sandra B Munro, Robert L Nussbaum, Edward D Esplin.
       Importance: In 2020, some health insurance plans updated their medical policy to cover germline genetic testing for all patients diagnosed with colorectal cancer (CRC). Guidelines for universal tumor screening via microsatellite instability and/or immunohistochemistry (MSI/IHC) for mismatch repair protein expression for patients with CRC have been in place since 2009.
    Objectives: To examine whether uptake of MSI/IHC screening and germline genetic testing in patients with CRC has improved under these policies and to identify actionable findings and management implications for patients referred for germline genetic testing.
    Design, Setting, and Participants: The multicenter, retrospective cohort study comprised 2 analyses of patients 18 years or older who were diagnosed with CRC between January 1, 2017, and December 31, 2020. The first analysis used an insurance claims data set to examine use of MSI/IHC screening and germline genetic testing for patients diagnosed with CRC between 2017 and 2020 and treated with systemic therapy. The second comprised patients with CRC who had germline genetic testing performed in 2020 that was billed under a universal testing policy.
    Main Outcomes and Measures: Patient demographic characteristics, clinical information, and use of MSI/IHC screening and germline genetic testing were analyzed.
    Results: For 9066 patients with newly diagnosed CRC (mean [SD] age, 64.2 [12.7] years; 4964 [54.8%] male), administrative claims data indicated that MSI/IHC was performed in 6645 eligible patients (73.3%) during the study period, with 2288 (25.2%) not receiving MSI/IHC despite being eligible for coverage. Analysis of a second cohort of 55 595 patients with CRC diagnosed in 2020 and covered by insurance found that only 1675 (3.0%) received germline genetic testing. In a subset of patients for whom germline genetic testing results were available, 1 in 6 patients had pathogenic or likely pathogenic variants, with most of these patients having variants with established clinical actionability.
    Conclusions and Relevance: This nationwide cohort study found suboptimal rates of MSI/IHC screening and germline genetic testing uptake, resulting in clinically actionable genetic data being unavailable to patients diagnosed with CRC, despite universal eligibility. Effective strategies are required to address barriers to implementation of evidence-based universal testing policies that support precision treatment and optimal care management for patients with CRC.
    DOI:  https://doi.org/10.1001/jamanetworkopen.2022.38167
  10. Asian J Androl. 2022 Oct 28.
    Germline mutations in 5' to c.7914 of BRCA2 significantly increase risk of prostate cancer.
    Xiao-Hao Ruan, Da Huang, Xiao-Ling Lin, Zu-Jun Fang, Qiang Ding, Yi-Shuo Wu, Rong Na.
      
    DOI:  https://doi.org/10.4103/aja202277
  11. Mol Genet Genomic Med. 2022 Oct 28. e2071
    Evaluation of family history in individuals with heterozygous BRCA pathogenic variants diagnosed with breast or ovarian cancer in a single center in Italy.
    Serena Negri, Elena De Ponti, Federica Paola Sina, Elena Sala, Cristina Dell'Oro, Gaia Roversi, Sara Lazzarin, Martina Delle Marchette, Alesssandra Inzoli, Claudia Toso, Simona Fumagalli, Maria Campanella, Joanne Kotsopoulos, Robert Fruscio.
       BACKGROUND: BRCA1 and BRCA2 gene mutations are responsible for 5% of breast cancer (BC) and 10-15% of ovarian cancer (EOC). The presence of a germline mutation and therefore the identification of subjects at high risk of developing cancer should ideally precede the onset of the disease, so that appropriate surveillance and risk-reducing treatments can be proposed. In this study, we revisited the family history (FH) of women who tested positive for BRCA mutations after being diagnosed with BC or EOC.
    METHODS: The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines®), and the Italian Association of Medical Oncology (AIOM) guidelines were applied to the FH of 157 women who were referred to San Gerardo Hospital for genetic counseling.
    RESULTS: Almost 85% of women had an FH of BRCA-related cancer. 63.7% and 52.2% of women could have undergone genetic testing according to NCCN and AIOM testing criteria (p < .05) before tumor diagnosis. An FH of EOC was the most frequent NCCN criterion, followed by BC diagnosed <45 years old. Sixty-five percent of deceased women could have undergone genetic testing before developing cancer.
    CONCLUSIONS: FH is a powerful tool to identify high-risk individuals eligible for genetic counseling and testing. Testing of healthy individuals should be considered when an appropriately affected family member is unavailable for testing.
    Keywords:  AIOM; BRCA1/2 mutations; NCCN; family history; genetic testing
    DOI:  https://doi.org/10.1002/mgg3.2071
  12. Hematol Rep. 2022 Oct 02. 14(4): 294-299
    Late Presentation of Dyskeratosis Congenita: Germline Predisposition to Adult-Onset Secondary Acute Myeloid Leukemia.
    Harry Ramos, Mai Mostafa Aly, Suresh Kumar Balasubramanian.
      Classic dyskeratosis congenita is a hereditary disease where the majority of patients present with bone marrow failure and mucocutaneous changes: mainly skin pigmentation, nail dystrophy, oral premalignant leukoplakia, in addition to increased risk for malignancies. A 63-year-old man with a long history of untreated chronic pulmonary disease, a smoker in the past, presented initially with pancytopenia and a clinical diagnosis of myelodysplastic syndrome with excess blasts returned a month later with leukocytosis (WBC 215.9 × 106/μL) and diagnosed with acute myeloid leukemia (AML) with deletion of chromosome 7 and FLT3-TKD mutation. The patient's mother and sister died in their 6th decade from rapidly progressing fulminant pulmonary fibrosis. He had abnormal skin pigmentation and oral leukoplakia on presentation. He was induced with 7 + 3 chemotherapy and started on midostaurin but experienced prolonged cytopenias, complicated by hypoxic acute on chronic respiratory failure requiring intubation and mechanical ventilation. D + 28 and D + 36 bone marrow examination showed trilineage hypoplasia but no blasts, though the D + 28 bone marrow biopsy revealed one metaphase with del (7) that was cleared on D + 35. The constellation of clinical features and strong family history along with del 7 and FLT3-TKD AML with preceding MDS highly suggests a germline predisposition state dyskeratosis congenita. Germline predispositions are often underrecognized as delayed onset conditions leading to AML and may have treatment and preventative implications especially genetic counseling for blood-related family members.
    Keywords:  AML; FLT3-TKD; del 7; dyskeratosis congenita; telomere
    DOI:  https://doi.org/10.3390/hematolrep14040042
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