bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2021–09–19
ten papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet
  1. ASXL1 and STAG2 are Common Mutations in GATA2 Deficiency Patients with Bone Marrow Disease and Myelodysplastic Syndrome.
  2. HEREDITARY LEIOMYOMATOSIS AND ACUTE LYMPHOBLASTIC LEUKEMIA: a LINK THROUGH FUMARATE DYSHYDRATASE MUTATION?
  3. Clinical and molecular characterization of patients fulfilling Chompret criteria for Li-Fraumeni syndrome in Southern Brazil.
  4. Risk of Pancreatic Cancer Among Individuals With Pathogenic Variants in the ATM Gene.
  5. Inherited Pancreatic Cancer Syndromes and High-Risk Screening.
  6. Uterine leiomyomatosis in adolescents and young adults (AYAs) may represent a narrow phenotypic variant of FH tumour predisposition syndrome.
  7. Fibroadenoma in vulval ectopic breast tissue in a patient with PTEN Hamartoma Tumour Syndrome.
  8. Association between pathogenic germline mutations in BRCA2 and ATM and tumor-infiltrating lymphocytes in primary prostate cancer.
  9. Efficacy of systemic therapies in men with metastatic castration resistant prostate cancer harboring germline ATM versus BRCA2 mutations.
  10. Childhood Acute Myeloid Leukemia shows a high level of germline predisposition.
  1. Blood Adv. 2021 Sep 16. pii: bloodadvances.2021005065. [Epub ahead of print]
    ASXL1 and STAG2 are Common Mutations in GATA2 Deficiency Patients with Bone Marrow Disease and Myelodysplastic Syndrome.
    Robert R West, Katherine R Calvo, Lisa J Embree, Weixin Wang, Laura M Tuschong, Thomas R Bauer, Desiree Tillo, Justin Lack, Stephenie Droll, Amy P Hsu, Steven M Holland, Dennis D Hickstein.
      GATA2 Deficiency patients harbor de novo or inherited germline mutations in the GATA2 transcription factor gene, predisposing them to myeloid malignancies. There is considerable variation in disease progression, even among family members with the same mutation in GATA2. We investigated somatic mutations in 106 patients with GATA2 Deficiency to identify acquired mutations that are associated with myeloid malignancies. Myelodysplastic Syndrome (MDS) was the most common diagnosis (~44%), followed by GATA2 bone marrow immunodeficiency disorder (G2BMID) (~37%). Thirteen percent of the cohort had GATA2 mutations but displayed no disease manifestations. There were no correlations between patient age or sex with disease progression or survival. Cytogenetic analyses showed a high incidence of abnormalities (~43%)- notably trisomy 8 (~23%) and monosomy 7 (~12%), but these changes did not correlate with lower survival. Somatic mutations in ASXL1 and STAG2 were detected in ~25% of patients, though these mutations were rarely concomitant. Mutations in DNMT3A were found in ~10% of patients. These somatic mutations were found similarly in G2BMID and MDS, suggesting clonal hematopoiesis in early stages of disease, before the onset of MDS. ASXL1 mutations conferred a lower survival probability and were more prevalent in female patients. STAG2 mutations also conferred a lower survival probability, but did not show a statistically significant sex bias. There was a conspicuous absence of many commonly mutated genes associated with myeloid malignancies, including TET2, IDH1/2, and the splicing factor genes. Notably, somatic mutations in chromatin-related genes and cohesin genes characterized disease progression in GATA2 Deficiency.
    DOI:  https://doi.org/10.1182/bloodadvances.2021005065
  2. Acta Clin Belg. 2021 Sep 13. 1-4
    HEREDITARY LEIOMYOMATOSIS AND ACUTE LYMPHOBLASTIC LEUKEMIA: a LINK THROUGH FUMARATE DYSHYDRATASE MUTATION?
    Sophie Bailleux, Joan Somja, Marie Martin, Bernard De Prijck, Arjen F Nikkels.
       BACKGROUND: : Hereditary leiomyomatosis (HL) is an autosomal dominant condition due to a variety of fumarate hydratase (FH) mutations in which individuals tend to develop cutaneous leiomyomas, multiple uterine leiomyomas and are at risk for developing aggressive papillary renal cell carcinoma.
    CASE PRESENTATION: : A 26-year-old man with a past history of acute lymphoblastic leukemia (T-ALL) presented with numerous painful light brown papules and nodules spread all over his body except for the head, appearing since infancy. Similar lesions were present in his mother's family. A cutaneous biopsy revealed a cutaneous leiomyoma. His mother died from metastatic uterine neoplasia and his sister suffered from leiomyoma of the uterus. No renal cancer was reported in his family. A heterozygous pathogenic variant was detected in the FH gene.
    CONCLUSION: : To our knowledge, this is the first case possibly linking HL and T-ALL through FH deficiency.
    Keywords:  Hereditary leiomyomatosis; T-All; T-cell acute lymphoblastic leukemia; fumarate hydratase; mutation
    DOI:  https://doi.org/10.1080/17843286.2021.1980669
  3. PLoS One. 2021 ;16(9): e0251639
    Clinical and molecular characterization of patients fulfilling Chompret criteria for Li-Fraumeni syndrome in Southern Brazil.
    Camila Matzenbacher Bittar, Yasminne Marinho de Araújo Rocha, Igor Araujo Vieira, Clévia Rosset, Tiago Finger Andreis, Ivaine Tais Sauthier Sartor, Osvaldo Artigalás, Cristina B O Netto, Barbara Alemar, Gabriel S Macedo, Patricia Ashton-Prolla.
      Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition syndrome caused by pathogenic germline variants in the TP53 gene, characterized by a predisposition to the development of a broad spectrum of tumors at an early age. The core tumors related to LFS are bone and soft tissue sarcomas, premenopausal breast cancer, brain tumors, adrenocortical carcinomas (ACC), and leukemias. The revised Chompret criteria has been widely used to establish clinical suspicion and support TP53 germline variant testing and LFS diagnosis. Information on TP53 germline pathogenic variant (PV) prevalence when using Chompret criteria in South America and especially in Brazil is scarce. Therefore, the aim of this study was to characterize patients that fulfilled these specific criteria in southern Brazil, a region known for its high population frequency of a founder TP53 variant c.1010G>A (p.Arg337His), as known as R337H. TP53 germline testing of 191 cancer-affected and independent probands with LFS phenotype identified a heterozygous pathogenic/likely pathogenic variant in 26 (13.6%) probands, both in the DNA binding domain (group A) and in the oligomerization domain (group B) of the gene. Of the 26 carriers, 18 (69.23%) were R337H heterozygotes. Median age at diagnosis of the first tumor in groups A and B differed significantly in this cohort: 22 and 2 years, respectively (P = 0.009). The present study shows the clinical heterogeneity of LFS, highlights particularities of the R337H variant and underscores the need for larger collaborative studies to better define LFS prevalence, clinical spectrum and penetrance of different germline TP53 pathogenic variants.
    DOI:  https://doi.org/10.1371/journal.pone.0251639
  4. JAMA Oncol. 2021 Sep 16.
    Risk of Pancreatic Cancer Among Individuals With Pathogenic Variants in the ATM Gene.
    Fang-Chi Hsu, Nicholas J Roberts, Erica Childs, Nancy Porter, Kari G Rabe, Ayelet Borgida, Chinedu Ukaegbu, Michael G Goggins, Ralph H Hruban, George Zogopoulos, Sapna Syngal, Steven Gallinger, Gloria M Petersen, Alison P Klein.
       Importance: Pathogenic germline variants in the ATM gene have been associated with pancreatic cancer risk. Although genetic testing identifies these variants in approximately 1% to 3% of unselected patients with pancreatic cancer, the lifetime risk of pancreatic cancer among individuals with pathogenic ATM variants has not been well estimated.
    Objective: To estimate age-specific penetrance of pancreatic cancer in individuals with a pathogenic variant in the ATM gene.
    Design, Setting, and Participants: This was a multicenter cohort study of pancreatic cancer family registries in the US and Canada using pedigree data from 130 pancreatic cancer kindreds with a pathogenic germline ATM variant. Data analyses were performed from January 2020 to February 2021.
    Main Outcomes and Measures: Observational age-specific risk of pancreatic cancer. Penetrance was estimated using modified segregation analysis.
    Results: The study population of 130 families (123 [95%] White families) comprised 2227 family members (mean age [SD], 58 [22] years; 1096 [49%] women) with complete records (ie, including familial relationships, pancreatic cancer diagnosis, ATM status, proband status, and age), of which 155 individuals had positive results for an ATM pathogenic variant, 16 had a negative result, and the remainder did not have a test result. In these 130 families, 217 individuals had pancreatic cancer: 78 families had 1 such member; 34 families had 2 such members; and 18 families had 3 or more members with pancreatic cancer. The average (range) age at diagnosis was 64 (31-98) years. The cumulative risk of pancreatic cancer among individuals with a germline pathogenic ATM variant was estimated to be 1.1% (95% CI, 0.8%-1.3%) by age 50 years; 6.3% (95% CI, 3.9%-8.7%) by age 70 years; and 9.5% (95% CI, 5.0%-14.0%) by age 80 years. Overall, the relative risk of pancreatic cancer was 6.5 (95% CI, 4.5-9.5) in ATM variant carriers compared with noncarriers.
    Conclusions and Relevance: This multicenter cohort study found that individuals with a germline pathogenic ATM variant were at an increased lifetime risk of pancreatic cancer. These risk estimates can help guide decision-making when evaluating the risks and benefits of enhanced early detection surveillance.
    DOI:  https://doi.org/10.1001/jamaoncol.2021.3701
  5. Surg Oncol Clin N Am. 2021 Oct;pii: S1055-3207(21)00042-9. [Epub ahead of print]30(4): 773-786
    Inherited Pancreatic Cancer Syndromes and High-Risk Screening.
    Leah H Biller, Brian M Wolpin, Michael Goggins.
      Pancreatic cancer is the third leading cause of cancer death in the United States, with a 5-year survival rate of 9%. Individuals with inherited pancreatic cancer syndromes are at an increased risk for developing pancreatic cancer and may benefit from pancreatic cancer surveillance with the goal to detect and intervene on early-stage cancer or high-risk precursor lesions. Given the screening implications for family members and therapeutic implications for probands, all patients diagnosed with pancreatic cancer are recommended to undergo germline genetic testing.
    Keywords:  Cancer risk; Hereditary; Pancreatic cyst; Surveillance
    DOI:  https://doi.org/10.1016/j.soc.2021.06.002
  6. Fam Cancer. 2021 Sep 14.
    Uterine leiomyomatosis in adolescents and young adults (AYAs) may represent a narrow phenotypic variant of FH tumour predisposition syndrome.
    Tiffany Foo, Vivek Nama, Ayoma D Attygalle, Jonathan Williams, Kara Heelan, Samantha Butler, Terri P McVeigh.
      FH Tumour Predisposition Syndrome, also known as Hereditary Leiomyomatosis and renal cell cancer (HLRCC), or Reed Syndrome, is an autosomal dominant condition clinically characterized by multiple cutaneous leiomyomas, multiple early-onset uterine leiomyomas and early-onset renal cell cancer. Here we report a young female with FH Tumour Predisposition Syndrome with no clinical features except early-onset uterine leiomyomas. Whilst there is a significant history of uterine leiomyomas in her family, there is no history of cutaneous leiomyomas or renal cell cancer (RCC). Uterine leiomyomatosis in young adults may represent a narrow phenotypic variant of FH Tumour Predisposition Syndrome. It is important that young women who present with multiple leiomyomata or leiomyomata with atypical features are referred for molecular genetic testing.
    Keywords:  AYA; Cancer; FH tumour predisposition syndrome; Genetics; Hereditary leiomyomatosis and renal cell cancer (HLRCC); Reed syndrome
    DOI:  https://doi.org/10.1007/s10689-021-00272-y
  7. Fam Cancer. 2021 Sep 15.
    Fibroadenoma in vulval ectopic breast tissue in a patient with PTEN Hamartoma Tumour Syndrome.
    Hannah Dawson, Alannah Smrke, Peter M Ellery, Nafisa Wilkinson, Adam N Rosenthal, Terri P McVeigh.
      PTEN is a tumour suppressor gene involved in regulating cell division. Pathogenic germline variants in PTEN predispose to benign and malignant growths of numerous organs, including of the breast. In the following report, we describe the first documented case of a fibroadenoma developing in ectopic breast tissue of the vulva in a patient with a germline pathogenic variant in PTEN. This highlights the risk of hyperplasia developing in any breast tissue, including rare ectopic sites, particularly in patients with underlying germline variants in cancer susceptibility genes.
    Keywords:  Cowden syndrome; Ectopic breast tissue; PTEN; PTEN hamartoma tumour syndrome; Vulval fibroadenoma
    DOI:  https://doi.org/10.1007/s10689-021-00275-9
  8. Cancer Immunol Immunother. 2021 Sep 17.
    Association between pathogenic germline mutations in BRCA2 and ATM and tumor-infiltrating lymphocytes in primary prostate cancer.
    Harsimar B Kaur, Thiago Vidotto, Adrianna A Mendes, Daniela C Salles, William B Isaacs, Emmanuel S Antonarakis, Tamara L Lotan.
      Pathogenic mutations in homologous recombination (HR) DNA repair genes may be associated with increased tumor mutational burden and numbers of tumor-infiltrating lymphocytes (TIL). Though HR-deficient prostate tumors have been anecdotally associated with improved responses to immunotherapy, it is unclear whether HR mutations or HR deficiency (HRD) scores predict for increased T-cell densities in this cancer. We evaluated 17 primary prostate tumors from patients with pathogenic germline BRCA2 mutations (gBRCA2) and 21 primary prostate tumors from patients with pathogenic germline ATM (gATM) mutations, which were compared to 19 control tumors lacking HR gene mutations, as well as the TCGA prostate cancer cohort. HRD score was estimated by targeted sequencing (gBRCA2 and gATM) or by SNP microarray (TCGA). Tumor-associated T-cell densities were assessed using validated automated digital image analysis of CD8 and FOXP3 immunostaining (gBRCA2 or gATM) or by methylCIBERSORT (TCGA). CD8 + and FOXP3 + T-cell densities were significantly correlated with each other in gBRCA2 and gATM cases. There was no significant difference between CD8 + or FOXP3 + TIL densities in gBRCA2 or gATM cases compared to controls. In the TCGA cohort, HRD score was associated with predicted CD8 + and FOXP3 + TILs. Associations were also seen for HRD score and TIL density among the germline-mutated cases. In contrast to mismatch repair-deficient primary prostate tumors, cancers from germline BRCA2 or ATM mutation carriers do not appear to be associated with elevated TIL density. However, measures of genomic scarring, such as HRD score, may be associated with increased tumor-infiltrating T-cells.
    Keywords:  ATM; BRCA2; CD8; FOXP3; PD-L1; Prostatic adenocarcinoma; T-cells; Tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.1007/s00262-021-03050-y
  9. Prostate. 2021 Sep 13.
    Efficacy of systemic therapies in men with metastatic castration resistant prostate cancer harboring germline ATM versus BRCA2 mutations.
    Alexandra O Sokolova, Catherine H Marshall, Rebeca Lozano, Roman Gulati, Elisa M Ledet, Navonil De Sarkar, Petros Grivas, Celestia S Higano, Bruce Montgomery, Peter S Nelson, David Olmos, Vadim Sokolov, Michael T Schweizer, Todd A Yezefski, Evan Y Yu, Channing J Paller, Oliver Sartor, Elena Castro, Emmanuel S Antonarakis, Heather H Cheng.
       BACKGROUND: Among men with metastatic prostate cancer, about 10% have germline alterations in DNA damage response genes. Most studies have examined BRCA2 alone or an aggregate of BRCA1/2 and ATM. Emerging data suggest that ATM mutations may have distinct biology and warrant individual evaluation. The objective of this study is to determine whether response to prostate cancer systemic therapies differs between men with germline mutations in ATM (gATM) and BRCA2 (gBRCA2).
    METHODS: This is an international multicenter retrospective matched cohort study of men with prostate cancer harboring gATM or gBRCA2. PSA50 response (≥50% decline in prostate-specific antigen) was compared using Fisher's exact test.
    RESULTS AND LIMITATIONS: The study included 45 gATM and 45 gBRCA2 patients, matched on stage and year of germline testing. Patients with gATM and gBRCA2 had similar age, Gleason grade, and PSA at diagnosis. We did not observe differences in PSA50 responses to abiraterone, enzalutamide, or docetaxel in metastatic castration resistant prostate cancer between the two groups; however, 0/7 with gATM and 12/14 with gBRCA2 achieved PSA50 response to PARPi (p < .001). Median (95% confidence interval) overall survival from diagnosis to death was 10.9 years (9.5-not reached) versus 9.9 years (7.1-not reached, p = .07) for the gATM and gBRCA2 cohorts, respectively. Limitations include the retrospective design and lack of mutation zygosity data.
    CONCLUSIONS: Conventional therapies can be effective in gATM carriers and should be considered before PARPi, which shows limited efficacy in this group. Men with gATM mutations warrant prioritization for novel treatment strategies.
    Keywords:  ATM; BRCA2; PARPi; abiraterone; docetaxel; enzalutamide; germline; homologous recombination deficiency; platinum
    DOI:  https://doi.org/10.1002/pros.24236
  10. Blood. 2021 Sep 14. pii: blood.2021012666. [Epub ahead of print]
    Childhood Acute Myeloid Leukemia shows a high level of germline predisposition.
    Saumya E Samaraweera, Paul Po-Shen Wang, Ka Leung Li, Debora A Casolari, Jinghua Feng, Mark Pinese, Kyaw Ze Ya Maung, Paul James Leo, Mark J Cowley, Kelly Perkins, Amanda M Smith, Jonathan Ellis, Amilia Wee, Devendra K Hiwase, Hamish S Scott, Andreas W Schreiber, Anna L Brown, Andrew J Deans, David M Ross, Andrew S Moore, Thomas Gonda, Christopher N Hahn, Richard J D'Andrea.
      
    DOI:  https://doi.org/10.1182/blood.2021012666
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