bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2021‒11‒07
ten papers selected by
Joanna Zawacka-Pankau
Karolinska Institutet
  1. Cancer spectrum in TP53-deficient golden Syrian hamsters: A new model for Li-Fraumeni syndrome.
  2. TP53 mutation in newly diagnosed acute myeloid leukemia and myelodysplastic syndrome.
  3. Fumarate hydratase variant prevalence and manifestations among individuals receiving germline testing.
  4. Germline CEBPA mutation in familial acute myeloid leukemia.
  5. Homozygous Germline APC p.I1307K Variants: A Case Series.
  6. The context-specific role of germline pathogenicity in tumorigenesis.
  7. Complete Response of Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC)-Associated Renal Cell Carcinoma to Pembrolizumab Immunotherapy: A Case Report.
  8. A Germline Variant at 8q24 Contributes to the Serum p2PSA Level in a Chinese Prostate Biopsy Cohort.
  9. Exome-Wide Pan-Cancer Analysis of Germline Variants in 8,719 Individuals Finds Little Evidence of Rare Variant Associations.
  10. Germ Line BAP1 Mutation in Patients with Uveal Melanoma and Renal Cell Carcinoma.
  1. J Carcinog. 2021 ;20 18
    Cancer spectrum in TP53-deficient golden Syrian hamsters: A new model for Li-Fraumeni syndrome.
    Jinxin Miao, Rong Li, Arnaud J Van Wettere, Haoran Guo, Alexandru-Flaviu Tabaran, M Gerald O'Sullivan, Timothy Carlson, Patricia M Scott, Kuisheng Chen, Dongling Gao, Huixiang Li, Yaohe Wang, Zhongde Wang, Robert T Cormier.
      Background: The TP53 tumor suppressor gene is the most commonly mutated gene in human cancers. Humans who inherit mutant TP53 alleles develop a wide range of early onset cancers, a disorder called Li-Fraumeni Syndrome (LFS). Trp53-deficient mice recapitulate most but not all of the cancer phenotypes observed in TP53-deficient human cancers, indicating that new animal models may complement current mouse models and better inform on human disease development.Materials and Methods: The recent application of CRISPR/Cas9 genetic engineering technology has permitted the emergence of golden Syrian hamsters as genetic models for wide range of diseases, including cancer. Here, the first cancer phenotype of TP53 knockout golden Syrian hamsters is described.
    Results: Hamsters that are homozygous for TP53 mutations become moribund on average ~ 139 days of age, while hamsters that are heterozygous become moribund at ~ 286 days. TP53 homozygous knockout hamsters develop a wide range of cancers, often synchronous and metastatic to multiple tissues, including lymphomas, several sarcomas, especially hemangiosarcomas, myeloid leukemias and several carcinomas. TP53 heterozygous mutants develop a more restricted tumor spectrum, primarily lymphomas.
    Conclusions: Overall, hamsters may provide insights into how TP53 deficiency leads to cancer in humans and can become a new model to test novel therapies.
    Keywords:  TP53; cancer; hamsters
    DOI:  https://doi.org/10.4103/jcar.jcar_18_21
  2. Diagn Pathol. 2021 Oct 31. 16(1): 100
    TP53 mutation in newly diagnosed acute myeloid leukemia and myelodysplastic syndrome.
    Pimjai Niparuck, Pornnapa Police, Phichchapha Noikongdee, Kanchana Siriputtanapong, Nittaya Limsuwanachot, Budsaba Rerkamnuaychoke, Suporn Chuncharunee, Teerapong Siriboonpiputtana.
      OBJECTIVES: TP53 mutation is found frequently in therapy related acute myeloid leukemia (AML)/ myelodysplastic syndrome (MDS), AML and MDS patients with monosomy or complex karyotype. However, the prevalence and treatment outcome in TP53 mutated AML/MDS patients in Asian population are scarce. We therefore conducted this study to analyze the prevalence and the treatment outcomes of TP53 mutation in AML and MDS-EB patients.METHODS: Patients with newly diagnosed AML and MDS-EB were recruited, extraction of deoxyribonucleic acid from bone marrow samples were done and then performing TP53 mutation analysis, using MassArray® System (Agena Bioscience, CA, USA).
    RESULTS: A total of 132 AML/MDS patients were recruited, patients with de novo AML, secondary AML, MDS-EB1, MDS-EB2 and T-AML/MDS were seen in 66, 13, 9, 9 and 3%, respectively. TP53 mutation was found in 14 patients (10.6%), and prevalence of TP53 mutation in T-AML/MDS, secondary AML, de novo AML and MDS-EB patients were 50, 17.6, 9.2 and 8%, respectively. Three patients had double heterozygous TP53 mutation. Mutated TP53 was significantly detected in patients with monosomy and complex chromosome. Common TP53 mutation were R290C, T220C, A249S and V31I which V31I mutation was reported only in Taiwanese patients. Most variant allele frequency (VAF) of TP53 mutation in the study were greater than 40%. Three year-overall survival (OS) in the whole population was 22%, 3y-OS in AML and MDS-EB patients were 22 and 27%, respectively. The 1y-OS in patients with TP53-mutant AML/MDS were shorter than that in TP53 wild-type patients, 14% versus 50%, P = 0.001. In multivariate analysis, factors affecting OS in 132 AML/MDS patients was mutant TP53 (P = 0.023, HR = 1.20-7.02), whereas, WBC count> 100,000/μL (P = 0.004, HR = 1.32-4.16) and complex karyotype (P = 0.038, HR = 1.07-9.78) were associated with shorter OS in AML patients.
    DISCUSSION: In this study, the prevalence of TP53 mutation in de novo AML and MDS-EB patients were low but it had impact on survival. Patients with monosomy or complex karyotype had more frequent TP53 mutation.
    Keywords:  Acute myeloid leukemia; Myelodysplastic syndrome; T-AML/MDS, complex karyotype, monosomy; TP53 mutation
    DOI:  https://doi.org/10.1186/s13000-021-01162-8
  3. Cancer. 2021 Nov 01.
    Fumarate hydratase variant prevalence and manifestations among individuals receiving germline testing.
    Eric Lu, Kathryn E Hatchell, Sarah M Nielsen, Edward D Esplin, Karen Ouyang, Keith Nykamp, Shirin Zavoshi, Shantao Li, Liying Zhang, Blake R Wilde, Heather R Christofk, Paul C Boutros, Brian Shuch.
      BACKGROUND: Germline variants in fumarate hydratase (FH) are associated with autosomal dominant (AD) hereditary leiomyomatosis and renal cell cancer (HLRCC) and autosomal recessive (AR) fumarase deficiency (FMRD). The prevalence and cancer penetrance across different FH variants remain unclear.METHODS: A database containing 120,061 records from individuals undergoing cancer germline testing was obtained. FH variants were classified into 3 categories: AD HLRCC variants, AR FMRD variants, and variants of unknown significance (VUSs). Individuals with variants from these categories were compared with those with negative genetic testing.
    RESULTS: FH variants were detected in 1.3% of individuals (AD HLRCC, 0.3%; AR FMRD, 0.4%; VUS, 0.6%). The rate of AD HLRCC variants discovered among reportedly asymptomatic individuals without a clear indication for HLRCC testing was 1 in 2668 (0.04%). In comparison with those with negative genetic testing, the renal cell carcinoma (RCC) prevalence was elevated with AD HLRCC variants (17.0% vs 4.5%; P < .01) and VUSs (6.4% vs 4.5%; P = .02) but not with AR FMRD variants.
    CONCLUSIONS: The prevalence of HLRCC discovered incidentally on germline testing is similar to recent population carrier estimates, and this suggests that this is a relatively common cancer syndrome. Compared with those with negative genetic testing, those with VUSs had an elevated risk of RCC, whereas those with AR FMRD variants did not.
    Keywords:  fumarate hydratase; genetic testing; hereditary leiomyomatosis and renal cell cancer; kidney neoplasms
    DOI:  https://doi.org/10.1002/cncr.33997
  4. Hematol Rep. 2021 Sep 06. 13(3): 9114
    Germline CEBPA mutation in familial acute myeloid leukemia.
    Matilde Boada, Ana Inés Catalán, Carolina Ottati, Florencia Bentancour, Daniela Lens, Cecilia Guillermo, Sofía Grille.
      Myeloid Neoplasms with germline predisposition become part of 2016 World Health Organization (WHO) classification of hematological malignancies since 2016. CCAAT/enhancer binding protein-alpha (CEBPA) is a myeloid transcription factor located in chromosome 19q. Acute myeloid leukemia (AML) with biallelic mutations of CEBPA AML with recurrent genetic abnormalities according to WHO classification. The inheritance of a germline CEBPA mutation predisposes to the development of AML with autosomal dominant inheritance. Familial CEBPA AML share characteristics with somatic CEBPA AML. However, a higher relapse incidence is reported. We present the case of a 46-years-old male with family history of acute leukemia who was diagnosed with single mutated CEBPA acute myeloid leukemia. The same mutation was found in two of his siblings. The clinical suspicion and proper diagnosis of familial cases is necessary, especially when a related allogenic transplant is indicated in order to select an adequate donor.
    Keywords:  CEBPA; Familial leukemia; acute myeloid leukemia; germline predisposition
    DOI:  https://doi.org/10.4081/hr.2021.9114
  5. Case Rep Oncol. 2021 Sep-Dec;14(3):14(3): 1295-1303
    Homozygous Germline APC p.I1307K Variants: A Case Series.
    Alexa Rosenblum, Michelle Springer, Amanda Eppolito, Lisen Axell, Lisa Mohler.
      Approximately 10% of all colorectal cancer is estimated to be due to an inherited predisposition. Identification of a germline pathogenic variant can aid in treatment, screening, and surveillance and help stratify familial cancer risks based on gene-specific cancer associations. The APC gene contributes to a small percentage of hereditary colon cancer, with most pathogenic APC variants causing familial adenomatous polyposis syndrome. However, one specific variant in APC called p.I1307K, found in approximately 10% of Ashkenazi Jewish individuals, is associated with a moderate risk for colon cancer, but not polyposis. Heterozygous carriers of one p.I1307K variant are well documented in the literature, and guidelines recommend earlier and more frequent colonoscopies. Conversely, reports of homozygous carriers of 2 p.I1307K variants are limited, and guidelines for medical management are lacking. This case series describes 4 homozygous p.I1307K patients of Ashkenazi Jewish ancestry identified in cancer genetics clinics. Case 1 is a 73-year-old pancreatic cancer patient with a family history of melanoma and colon cancer. Case 2 is a 62-year-old patient with a personal history of 4 adenomatous colorectal polyps and a family history of breast, pancreatic, colon, and prostate cancers. Case 3 is a 52-year-old patient with a personal history of early-onset breast cancer and uveal melanoma and a family history of breast, prostate, and stomach cancers. Case 4 is a 70-year-old patient with a personal history of gallbladder adenocarcinoma and a family history of breast cancer. These cases exhibit wide phenotypic variability and contribute to the limited reports of homozygous p.I1307K variant carriers.
    Keywords:  APC; Genetic testing; Homozygote; p.I1307K
    DOI:  https://doi.org/10.1159/000518683
  6. Nat Genet. 2021 Nov;53(11): 1577-1585
    The context-specific role of germline pathogenicity in tumorigenesis.
    Preethi Srinivasan, Chaitanya Bandlamudi, Philip Jonsson, Yelena Kemel, Shweta S Chavan, Allison L Richards, Alexander V Penson, Craig M Bielski, Christopher Fong, Aijazuddin Syed, Gowtham Jayakumaran, Meera Prasad, Jason Hwee, Selcuk Onur Sumer, Ino de Bruijn, Xiang Li, JianJiong Gao, Nikolaus Schultz, Roy Cambria, Jesse Galle, Semanti Mukherjee, Joseph Vijai, Karen A Cadoo, Maria I Carlo, Michael F Walsh, Diana Mandelker, Ozge Ceyhan-Birsoy, Jinru Shia, Ahmet Zehir, Marc Ladanyi, David M Hyman, Liying Zhang, Kenneth Offit, Mark E Robson, David B Solit, Zsofia K Stadler, Michael F Berger, Barry S Taylor.
      Human cancers arise from environmental, heritable and somatic factors, but how these mechanisms interact in tumorigenesis is poorly understood. Studying 17,152 prospectively sequenced patients with cancer, we identified pathogenic germline variants in cancer predisposition genes, and assessed their zygosity and co-occurring somatic alterations in the concomitant tumors. Two major routes to tumorigenesis were apparent. In carriers of pathogenic germline variants in high-penetrance genes (5.1% overall), lineage-dependent patterns of biallelic inactivation led to tumors exhibiting mechanism-specific somatic phenotypes and fewer additional somatic oncogenic drivers. Nevertheless, 27% of cancers in these patients, and most tumors in patients with pathogenic germline variants in lower-penetrance genes, lacked particular hallmarks of tumorigenesis associated with the germline allele. The dependence of tumors on pathogenic germline variants is variable and often dictated by both penetrance and lineage, a finding with implications for clinical management.
    DOI:  https://doi.org/10.1038/s41588-021-00949-1
  7. Front Oncol. 2021 ;11 735077
    Complete Response of Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC)-Associated Renal Cell Carcinoma to Pembrolizumab Immunotherapy: A Case Report.
    Tao Wang, Yan Huang, Xing Huang, Zheng Lv, Shuo Tian, Xin Ma, Xu Zhang.
      Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare autosomal dominant disorder that results from a germline mutation in the fumarate hydratase (FH) gene; it manifests as cutaneous leiomyomas, uterine fibroids, and renal cell cancer (RCC). Patients with HLRCC-associated RCC (HLRCC-RCC) have aggressive clinical courses, but there is no standardized therapy for advanced HLRCC-RCC. Here, we describe aggressive HLRCC in a 26-year-old man who presented with RCC that exhibited a novel heterozygous germline insertion mutation in exon 2 of the FH gene (c.191dupA: p.N64fs). Systemic lymph node metastasis had already occurred. The patient underwent robot-assisted laparoscopic resection of the right kidney, but new metastases appeared within 5 months postoperatively. Histological staining of the resected tumor showed high expression levels of programmed cell death-ligand 1 (PD-L1) and programmed cell death-1 (PD-1). The patient was treated with anti-PD-1 antibody as first-line therapy. After 2 years of immune checkpoint inhibitor (ICI) treatment, all lesions had disappeared; this response was maintained at 51 months. To our knowledge, this is the first successful treatment of HLRCC-RCC with single-agent immunotherapy. Our approach might be effective for patients with advanced HLRCC-RCC.
    Keywords:  complete response (CR); follow-up; hereditary leiomyomatosis and renal cell cancer (HLRCC); immunotherapy; mutation
    DOI:  https://doi.org/10.3389/fonc.2021.735077
  8. Front Oncol. 2021 ;11 753920
    A Germline Variant at 8q24 Contributes to the Serum p2PSA Level in a Chinese Prostate Biopsy Cohort.
    Xiaoling Lin, Yishuo Wu, Fang Liu, Rong Na, Da Huang, Danfeng Xu, Jian Gong, Yao Zhu, Bo Dai, Dingwei Ye, Hongjie Yu, Haowen Jiang, Zujun Fang, Jie Zheng, Qiang Ding.
      Introduction: The clinical performance of [-2]proPSA (p2PSA) and its derivatives in predicting the presence and aggressiveness of prostate cancer (PCa) has been well evaluated in prostate biopsy patients. However, no study has been performed to evaluate the common genetic determinants that affect serum level of p2PSA.Materials and Methods: Here, we performed a two-stage genome-wide association study (GWAS) on the p2PSA level in Chinese men who underwent a transperineal ultrasound-guided prostate biopsy at Huashan Hospital, Shanghai Cancer Center, and Ruijin Hospital in Shanghai, China. Germline variants significantly associated with the p2PSA level in the first stage (n = 886) were replicated in the second stage (n = 1,128). Multivariate linear regression was used to assess the independent contribution of confirmed single nucleotide polymorphisms (SNPs) and known covariates, such as age, to the level of p2PSA.
    Results: A novel non-synonymous SNP, rs72725879, in region 8q24.21 of the PRNCR1 gene was significantly associated with the serum level of p2PSA in this two-stage GWAS (p = 2.28 × 10-9). Participants with homozygous "T" alleles at rs72725879 had higher p2PSA levels compared to allele "C" carriers. This variant was also nominally associated with PCa risk (p-combined = 3.44 × 10-18). The association with serum level of p2PSA was still significant after adjusting for PCa risk and age (p = 0.017).
    Conclusions: Our study shows that the genetic variants in the 8q24.21 region are associated with the serum level of p2PSA in a large-scale Chinese population. By taking inherited variations between individuals into account, the findings of these genetic variants may help improve the performance of p2PSA in predicting prostate cancer.
    Keywords:  Chinese; genome-wide association study; p2PSA; polymorphism; prostate cancer
    DOI:  https://doi.org/10.3389/fonc.2021.753920
  9. Hum Hered. 2021 Oct 29. 1-10
    Exome-Wide Pan-Cancer Analysis of Germline Variants in 8,719 Individuals Finds Little Evidence of Rare Variant Associations.
    Zoe Guan, Ronglai Shen, Colin B Begg.
      BACKGROUND: Many cancer types show considerable heritability, and extensive research has been done to identify germline susceptibility variants. Linkage studies have discovered many rare high-risk variants, and genome-wide association studies (GWAS) have discovered many common low-risk variants. However, it is believed that a considerable proportion of the heritability of cancer remains unexplained by known susceptibility variants. The "rare variant hypothesis" proposes that much of the missing heritability lies in rare variants that cannot reliably be detected by linkage analysis or GWAS. Until recently, high sequencing costs have precluded extensive surveys of rare variants, but technological advances have now made it possible to analyze rare variants on a much greater scale.OBJECTIVES: In this study, we investigated associations between rare variants and 14 cancer types.
    METHODS: We ran association tests using whole-exome sequencing data from The Cancer Genome Atlas (TCGA) and validated the findings using data from the Pan-Cancer Analysis of Whole Genomes Consortium (PCAWG).
    RESULTS: We identified four significant associations in TCGA, only one of which was replicated in PCAWG (BRCA1 and ovarian cancer).
    CONCLUSIONS: Our results provide little evidence in favor of the rare variant hypothesis. Much larger sample sizes may be needed to detect undiscovered rare cancer variants.
    Keywords:  Burden test; Germline variants; Rare variants; SKAT; SKAT-O; TOW test
    DOI:  https://doi.org/10.1159/000519355
  10. Ocul Oncol Pathol. 2021 Oct;7(5): 340-345
    Germ Line BAP1 Mutation in Patients with Uveal Melanoma and Renal Cell Carcinoma.
    Yusra F Shao, Meghan DeBenedictis, Gabrielle Yeaney, Arun D Singh.
      Uveal melanoma (UM) and renal cell carcinoma (RCC) can occur sporadically and as a manifestation of BAP1 tumor predisposition syndrome. We aimed to understand the prevalence of germ line BAP1 pathogenic variants in patients with UM and RCC. We reviewed patients managed at Cleveland Clinic between November 2003 and November 2019 who were diagnosed with UM and RCC. Charts were reviewed for demographic and cancer-related characteristics. RCC samples were tested for BAP1 protein expression using immunohistochemical (IHC) staining, and testing for germ line BAP1 pathogenic variants was performed as part of routine clinical care. Thirteen patients were included in the study. The average age at diagnosis of UM was 61.3 years. Seven patients underwent fine-needle aspiration biopsy for prognostic testing of UM (low risk =5, high risk =2). Twelve patients were treated with plaque radiation therapy, and 3 patients developed metastatic disease requiring systemic therapy. The median time to diagnosis of RCC from time of diagnosis of UM was 0 months. RCC samples were available for 7 patients for BAP1 IHC staining (intact =6, loss =1). All patients underwent nephrectomy (total = 3, partial = 8, unknown =2), and 1 received systemic therapy for metastatic RCC. Six patients underwent germ line BAP1 genetic testing. Of these, 1 patient was heterozygous for a pathogenic variant of BAP1 gene: c.1781-1782delGG, p.Gly594Valfs*48. The overall prevalence of germ line BAP1 pathogenic variants in our study was high (1/6; 17%; 95% CI 0-46%). Patients with UM and RCC should be referred for genetic counseling to discuss genetic testing.
    Keywords:  Germ line BAP1 pathogenic variants; Renal carcinoma; Uveal melanoma
    DOI:  https://doi.org/10.1159/000516695
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