Publications by authors named "Jane E Churpek"

41 Publications

Validation and clinical application of transactivation assays for RUNX1 variant classification.

Blood Adv 2022 Jan 13. Epub 2022 Jan 13.

Hannover Medical School, Hannover, Germany.

Familial platelet disorder with associated myeloid malignancies (RUNX1-FPD) is caused by heterozygous pathogenic germline variants of RUNX1. In the present study, we evaluate the applicability of transactivation assays to investigate RUNX1 variants in different regions of the protein. We studied 11 variants to independently validate transactivation assays supporting variant classification following the ClinGen Myeloid Malignancies variant curation expert panel guidelines. Variant classification is key for the translation of genetic findings. We showed that new assays need to be developed to assess C-terminal RUNX1 variants. Two variants of uncertain significance (VUS) were reclassified to likely pathogenic. Additionally, our analyses supported the (likely) pathogenic classification of two other variants. We demonstrated functionality of four VUS, but reclassification to (likely) benign was challenging and suggested the need to reevaluate current classification guidelines. Finally, clinical utility of our assays was illustrated in the context of seven families. Our data confirmed RUNX1-FPD suspicion in three families with RUNX1-FPD-specific family history. Whereas for three variants identified in non RUNX1-FPD-typical families, no functional defect was detected. Applying functional assays to support RUNX1 variant classification can be essential for adequate care of index patients and their relatives at risk. It facilitates translation of genetic data into personalized medicine.
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http://dx.doi.org/10.1182/bloodadvances.2021006161DOI Listing
January 2022

Integrating germline variant assessment into routine clinical practice for myelodysplastic syndrome and acute myeloid leukaemia: current strategies and challenges.

Br J Haematol 2021 Oct 18. Epub 2021 Oct 18.

Division of Hematology, Medical Oncology, and Palliative Care, Department of Medicine, School of Medicine and Public Health, The University of Wisconsin, Madison, WI, USA.

Over the last decade, the field of hereditary haematological malignancy syndromes (HHMSs) has gained increasing recognition among clinicians and scientists worldwide. Germline mutations now account for almost 10% of adult and paediatric myelodysplasia/acute myeloid leukaemia (MDS/AML). As our ability to diagnose HHMSs has improved, we are now faced with the challenges of integrating these advances into routine clinical practice for patients with MDS/AML and how to optimise management and surveillance of patients and asymptomatic carriers. Discoveries of novel syndromes combined with clinical, genetic and epigenetic profiling of tumour samples, have highlighted unique patterns of disease evolution across HHMSs. Despite these advances, causative lesions are detected in less than half of familial cases and evidence-based guidelines are often lacking, suggesting there is much still to learn. Future research efforts are needed to sustain current momentum within the field, led not only by advancing genetic technology but essential collaboration between clinical and academic communities.
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http://dx.doi.org/10.1111/bjh.17855DOI Listing
October 2021

Approach to the diagnosis of aplastic anemia.

Blood Adv 2021 06;5(12):2660-2671

Department of Medicine, Division of Hematology, Oncology, and Palliative Care & Carbone Cancer Center, The University of Wisconsin-Madison, Madison, WI.

Establishing a diagnosis of aplastic anemia (AA) can be challenging, but it is absolutely critical to appropriate management, especially differentiating between acquired and inherited forms of the disease. The hematology field requires updated diagnostic guidelines to ensure that appropriate clinical pathways are pursued for patients and their safety. There are increasing clinical options for patients with immunosuppressive therapy and transplant once the diagnosis is made. In a case-based format, this review emphasizes the newer data on molecular (somatic and germline) findings in AA and how they are (or are not) helpful during diagnosis. There are key details on somatic mutation profiles and stated evidence where available for prognostic and treatment indications. Germline details of newer syndromes are also outlined, which make this review modern and reflect areas of uncertainty for clinicians.
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http://dx.doi.org/10.1182/bloodadvances.2021004345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270669PMC
June 2021

Telomere biology disorder prevalence and phenotypes in adults with familial hematologic and/or pulmonary presentations.

Blood Adv 2020 10;4(19):4873-4886

Section of Hematology/Oncology and Center for Clinical Cancer Genetics and.

Telomere biology disorders (TBDs) present heterogeneously, ranging from infantile bone marrow failure associated with very short telomeres to adult-onset interstitial lung disease (ILD) with normal telomere length. Yield of genetic testing and phenotypic spectra for TBDs caused by the expanding list of telomere genes in adults remain understudied. Thus, we screened adults aged ≥18 years with a personal and/or family history clustering hematologic disorders and/or ILD enrolled on The University of Chicago Inherited Hematologic Disorders Registry for causative variants in 13 TBD genes. Sixteen (10%) of 153 probands carried causative variants distributed among TERT (n = 6), TERC (n = 4), PARN (n = 5), or RTEL1 (n = 1), of which 19% were copy number variants. The highest yield (9 of 22 [41%]) was in families with mixed hematologic and ILD presentations, suggesting that ILD in hematology populations and hematologic abnormalities in ILD populations warrant TBD genetic testing. Four (3%) of 117 familial hematologic disorder families without ILD carried TBD variants, making TBD second to only DDX41 in frequency for genetic diagnoses in this population. Phenotypes of 17 carriers with heterozygous PARN variants included 4 (24%) with hematologic abnormalities, 67% with lymphocyte telomere lengths measured by flow cytometry and fluorescence in situ hybridization at or above the 10th percentile, and a high penetrance for ILD. Alternative etiologies for cytopenias and/or ILD such as autoimmune features were noted in multiple TBD families, emphasizing the need to maintain clinical suspicion for a TBD despite the presence of alternative explanations.
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http://dx.doi.org/10.1182/bloodadvances.2020001721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556157PMC
October 2020

Hematologic toxicity in BRCA1 and BRCA2 mutation carriers during chemotherapy: A retrospective matched cohort study.

Cancer Med 2019 09 12;8(12):5609-5618. Epub 2019 Aug 12.

Department of Medicine, Center for Clinical Cancer Genetics & Global Health, University of Chicago, Chicago, IL, USA.

Women who inherit a BRCA1 or BRCA2 mutation have an increased risk of breast cancer. Preliminary evidence suggests they may also have defects in bone marrow function. To test this hypothesis, we conducted a multicenter, retrospective, matched cohort study, comparing women with localized breast cancer requiring cytotoxic chemotherapy who carried an inherited BRCA1 or BRCA2 mutation to similar wild-type patients treated between 1995 and 2017 and matched based on age, race, site, and chemotherapy regimen. The proportion who developed specific hematologic toxicities, timing of these toxicities, and patterns of blood count fluctuations over time were compared among BRCA1 carriers vs matched wild-type patients and among BRCA2 carriers vs matched wild-type patients. 88 BRCA1 carriers and 75 BRCA2 carriers were matched to 226 and 242 wild-type patients, respectively. The proportions and timing of experiencing any grade or grade 3/4 cytopenias during chemotherapy were not significantly different for BRCA1 carriers or BRCA2 carriers vs matched wild-type patients. Proportions requiring treatment modifications and time to first modification were also similar. Patterns of blood count fluctuations over time in mutation carriers mirrored those in wild-type patients overall and by the most common regimens. Women with an inherited mutation in BRCA1 or BRCA2 experience similar frequency, severity, and timing of hematologic toxicities during curative intent breast cancer chemotherapy as matched wild-type patients. Our findings suggest that BRCA1 or BRCA2 haploinsufficiency is sufficient for adequate bone marrow reserve in the face of short-term repetitive hematopoietic stressors.
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http://dx.doi.org/10.1002/cam4.2471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745828PMC
September 2019

Inherited predisposition to malignant mesothelioma and overall survival following platinum chemotherapy.

Proc Natl Acad Sci U S A 2019 04 11;116(18):9008-9013. Epub 2019 Apr 11.

Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637.

Survival from malignant mesothelioma, particularly pleural mesothelioma, is very poor. For patients with breast, ovarian, or prostate cancers, overall survival is associated with increased sensitivity to platinum chemotherapy due to loss-of-function mutations in DNA repair genes. The goal of this project was to evaluate, in patients with malignant mesothelioma, the relationship between inherited loss-of-function mutations in DNA repair and other tumor suppressor genes and overall survival following platinum chemotherapy. Patients with histologically confirmed malignant mesothelioma were evaluated for inherited mutations in tumor suppressor genes. Survival was evaluated with respect to genotype and site of mesothelioma. Among 385 patients treated with platinum chemotherapy, median overall survival was significantly longer for patients with loss-of-function mutations in any of the targeted genes compared with patients with no such mutation ( = 0.0006). The effect of genotype was highly significant for patients with pleural mesothelioma (median survival 7.9 y versus 2.4 y, = 0.0012), but not for patients with peritoneal mesothelioma (median survival 8.2 y versus 5.4 y, = 0.47). Effect of patient genotype on overall survival, measured at 3 y, remained independently significant after adjusting for gender and age at diagnosis, two other known prognostic factors. Patients with pleural mesothelioma with inherited mutations in DNA repair and other tumor suppressor genes appear to particularly benefit from platinum chemotherapy compared with patients without inherited mutations. These patients may also benefit from other DNA repair targeted therapies such as poly-ADP ribose polymerase (PARP) inhibitors.
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http://dx.doi.org/10.1073/pnas.1821510116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6500142PMC
April 2019

Transcription factor mutations as a cause of familial myeloid neoplasms.

J Clin Invest 2019 02 1;129(2):476-488. Epub 2019 Feb 1.

UW-Madison Blood Research Program, Department of Cell and Regenerative Biology, Wisconsin Institutes for Medical Research, UW Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.

The initiation and evolution of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are driven by genomic events that disrupt multiple genes controlling hematopoiesis. Human genetic studies have discovered germline mutations in single genes that instigate familial MDS/AML. The best understood of these genes encode transcription factors, such as GATA-2, RUNX1, ETV6, and C/EBPα, which establish and maintain genetic networks governing the genesis and function of blood stem and progenitor cells. Many questions remain unanswered regarding how genes and circuits within these networks function in physiology and disease and whether network integrity is exquisitely sensitive to or efficiently buffered from perturbations. In familial MDS/AML, mutations change the coding sequence of a gene to generate a mutant protein with altered activity or introduce frameshifts or stop codons or disrupt regulatory elements to alter protein expression. Each mutation has the potential to exert quantitatively and qualitatively distinct influences on networks. Consistent with this mechanistic diversity, disease onset is unpredictable and phenotypic variability can be considerable. Efforts to elucidate mechanisms and forge prognostic and therapeutic strategies must therefore contend with a spectrum of patient-specific leukemogenic scenarios. Here we illustrate mechanistic advances in our understanding of familial MDS/AML syndromes caused by germline mutations of hematopoietic transcription factors.
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http://dx.doi.org/10.1172/JCI120854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355228PMC
February 2019

Glucocorticoid receptor expression is associated with inferior overall survival independent of BRCA mutation status in ovarian cancer.

Int J Gynecol Cancer 2019 Feb 25;29(2):357-364. Epub 2019 Jan 25.

Department of Medicine, Section of Hematology-Oncology, The University of Chicago, Chicago, Illinois, USA.

Objective: High glucocorticoid receptor (GR) protein expression is associated with decreased progression-free survival in ovarian cancer patients and decreased sensitivity to chemotherapy in preclinical models. Prior studies suggest wild type promotes GR activation. The objective of this study was to characterize the relationship of tumor GR gene expression to outcome in ovarian cancer, and to evaluate the relationship of GR expression with BRCA status.

Methods: Whole exome and whole genome sequencing, gene expression, and clinical data were obtained for high-grade serous ovarian cancers in The Cancer Genome Atlas. Cases with pathogenic somatic or germline or mutations were identified and classified as BRCA mutated. High or low glucocorticoid receptor expression was defined as expression above or below median of the / C1 () gene level. Overall survival was estimated by the Kaplan-Meier method and compared by Cox regression analysis.

Results: Combined germline DNA sequencing and tumor microarray expression data were available for 222 high-grade serous ovarian cancer cases. Among these, 47 had a deleterious germline and/or somatic mutation in or . In multivariate analysis, high glucocorticoid receptor gene expression was associated with decreased overall survival among ovarian cancer patients, independently of BRCA mutation status. No correlation of gene expression with BRCA mutation status or or mRNA level was observed.

Conclusions: Increased GR gene expression is associated with decreased overall survival in ovarian cancer patients, independently of BRCA mutation status. High-grade serous ovarian cancers with high GR expression and wild type BRCA have a particularly poor outcome.
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http://dx.doi.org/10.1136/ijgc-2018-000101DOI Listing
February 2019

Treatment of Acute Promyelocytic Leukemia in Adults.

J Oncol Pract 2018 11;14(11):649-657

University of Chicago, Chicago, IL.

The treatment of acute promyelocytic leukemia (APL) has evolved rapidly in the past two decades after the introduction of highly active drugs, including tretinoin (all- trans-retinoic acid) and arsenic trioxide. It is now possible to treat this disease without the use of traditional cytotoxic chemotherapy. Today's clinical guidelines include multiple regimens, some of which continue to use cytotoxic chemotherapy. This leaves the practicing oncologist with multiple treatment options when faced with a new case of APL. In an effort to standardize our approach to the treatment of newly diagnosed APL, we sought to develop a set of treatment recommendations at our institution. We identified eight major controversial issues in the treatment of APL. These controversial issues include the optimal dose and schedule of both all- trans-retinoic acid and arsenic trioxide, the optimal regimen for high-risk APL, the need for intrathecal prophylaxis, the use of prophylactic corticosteroids, and the need for maintenance therapy after consolidation. We reviewed the relevant literature and used the Delphi method among the coauthors to reach consensus for recommendations on the basis of the best available data and our own clinical experience. In this clinical review, we present our consensus recommendations, the reasoning behind them, and the grading of the evidence that supports them.
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http://dx.doi.org/10.1200/JOP.18.00328DOI Listing
November 2018

Frequency of Germline Mutations in Cancer Susceptibility Genes in Malignant Mesothelioma.

J Clin Oncol 2018 10 16;36(28):2863-2871. Epub 2018 Aug 16.

Vasiliki Panou and Oluf D. Røe, Aalborg University Hospital, Aalborg, Denmark; Meghana Gadiraju, Arthur Wolin, Caroline M. Weipert, Emily Skarda, Aliya N. Husain, Jyoti D. Patel, Buerkley Rose, Shannon R. Zhang, Madison Weatherly, Viswateja Nelakuditi, Amy Knight Johnson, Maria Helgeson, David Fischer, Arpita Desai, Nanna Sulai, Lauren Ritterhouse, Kiran K. Turaga, Dezheng Huo, Jeremy Segal, Sabah Kadri, Zejuan Li, Hedy L. Kindler, and Jane E. Churpek, The University of Chicago, Chicago, IL; Oluf D. Røe, Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger; and Oluf D. Røe, Norwegian University of Science and Technology, Trondheim, Norway.

Purpose: The aim of the current study was to determine the prevalence and clinical predictors of germline cancer susceptibility mutations in patients with malignant mesothelioma (MM).

Methods: We performed targeted capture and next-generation sequencing of 85 cancer susceptibility genes on germline DNA from 198 patients with pleural, peritoneal, and tunica vaginalis MM.

Results: Twenty-four germline mutations were identified in 13 genes in 23 (12%) of 198 patients. BAP1 mutations were the most common (n = 6; 25%). The remaining were in genes involved in DNA damage sensing and repair (n = 14), oxygen sensing (n = 2), endosome trafficking (n = 1), and cell growth (n = 1). Pleural site (odds ratio [OR], 0.23; 95% CI, 0.10 to 0.58; P < .01), asbestos exposure (OR, 0.28; 95% CI, 0.11 to 0.72; P < .01), and older age (OR, 0.95; 95% CI, 0.92 to 0.99; P = .01) were associated with decreased odds of carrying a germline mutation, whereas having a second cancer diagnosis (OR, 3.33; 95% CI, 1.22 to 9.07; P = .02) significantly increased the odds. The odds of carrying a mutation in BAP1 (OR, 1,658; 95% CI, 199 to 76,224; P < .001), BRCA2 (OR, 5; 95% CI, 1.0 to 14.7; P = .03), CDKN2A (OR, 53; 95% CI, 6 to 249; P < .001), TMEM127 (OR, 88; 95% CI, 1.7 to 1,105; P = .01), VHL (OR, 51; 95% CI, 1.1 to 453; P = .02), and WT1 (OR, 20; 95% CI, 0.5 to 135; P = .049) were significantly higher in MM cases than in a noncancer control population. Tumor sequencing identified mutations in a homologous recombination pathway gene in 52% (n = 29 of 54).

Conclusion: A significant proportion of patients with MM carry germline mutations in cancer susceptibility genes, especially those with peritoneal MM, minimal asbestos exposure, young age, and a second cancer diagnosis. These data support clinical germline genetic testing for patients with MM and provide a rationale for additional investigation of the homologous recombination pathway in MM.
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http://dx.doi.org/10.1200/JCO.2018.78.5204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804864PMC
October 2018

Universal genetic testing for inherited susceptibility in children and adults with myelodysplastic syndrome and acute myeloid leukemia: are we there yet?

Leukemia 2018 07 27;32(7):1482-1492. Epub 2018 Feb 27.

Section of Hematology/Oncology, The University of Chicago, Chicago, IL, USA.

Comprehensive genomic profiling of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) cases have enabled the detection and differentiation of driver and subclonal mutations, informed risk prognostication, and defined targeted therapies. These insights into disease biology, and management have made multigene-acquired mutation testing a critical part of the diagnostic assessment of patients with sporadic MDS and AML. More recently, our understanding of the role of an increasing number of inherited genetic factors on MDS/AML risk and management has rapidly progressed. In recognition of the growing impact of this field, clinical guidelines and disease classification systems for both MDS and AML have recently incorporated familial MDS/AML predisposition syndromes into their diagnostic algorithms. In this perspective piece, we contemplate the advantages, disadvantages, and barriers that would need to be overcome to incorporate inherited MDS/AML genetic testing into the upfront molecular diagnostic work-up of every MDS/AML patient. For centers already performing panel-based tumor-only testing, including genes associated with familial forms of MDS/AML (e.g., RUNX1, CEBPA, GATA2, TP53), we advocate optimizing these tests to detect all types of germline variants in these genes and moving toward upfront paired tumor/germline testing to maximize detection and streamline patient care.
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http://dx.doi.org/10.1038/s41375-018-0051-yDOI Listing
July 2018

Prognostic tumor sequencing panels frequently identify germ line variants associated with hereditary hematopoietic malignancies.

Blood Adv 2018 01;2(2):146-150

Section of Hematology/Oncology, Department of Medicine, The University of Chicago Comprehensive Cancer Center.

Next-generation sequencing (NGS)-based targeted gene capture panels are used to profile hematopoietic malignancies to guide prognostication and treatment decisions. Because these panels include genes associated with hereditary hematopoietic malignancies (HHMs), we hypothesized that these panels could identify pathogenic germ line variants in malignant cells, thereby identifying patients at risk for HHMs. In total, pathogenic or likely pathogenic variants in , , , , , , or were identified in 74 (21%) of 360 patients. Germ line tissue was available for 24 patients with 25 pathogenic or likely pathogenic variants with variant allele frequencies >0.4. Six (24%) of these 25 variants were of germ line origin. Three variants, 2 variants, and a variant previously implicated in Li-Fraumeni syndrome were of germ line origin. No likely pathogenic/pathogenic germ line variants possessed variant allele frequencies <0.4. This study demonstrates that NGS-based prognostic panels may identify individuals at risk for HHMs despite not being designed for this purpose. Furthermore, variants known to cause Li-Fraumeni syndrome as well as known pathogenic variants in genes such as and are especially likely to be of germ line origin. Thus, tumor-based panels may augment, but should not replace, comprehensive germ line-based testing and counseling.
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http://dx.doi.org/10.1182/bloodadvances.2017013037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5787862PMC
January 2018

A phase I study of selinexor in combination with high-dose cytarabine and mitoxantrone for remission induction in patients with acute myeloid leukemia.

J Hematol Oncol 2018 01 5;11(1). Epub 2018 Jan 5.

Department of Medicine, Section of Hematology/Oncology, University of Chicago Medicine, 5841 S. Maryland, MC 2115, Chicago, IL, 60637-1470, USA.

Background: Novel therapies for patients with acute myeloid leukemia (AML) are imperative, particularly for those with high-risk features. Selinexor, an exportin 1 (XPO1/CRM1) inhibitor, has demonstrated anti-leukemia activity as a single agent, as well as in combination with anthracyclines and/or DNA-damaging agents.

Methods: We report the findings of a phase I dose escalation trial with cohort expansion in 20 patients with newly diagnosed or relapsed/refractory AML that combined selinexor with age-adjusted high-dose cytarabine and mitoxantrone (HiDAC/Mito).

Results: Three (15%) patients received the initial dose of 60 mg of selinexor (~ 35 mg/m), and 17 (85%) received the target level of 80 mg (~ 50 mg/m). No dose-limiting toxicities were observed. Common adverse events included febrile neutropenia (70%), diarrhea (40%), anorexia (30%), electrolyte abnormalities (30%), bacteremia (25%), cardiac toxicities (25%), fatigue (25%), and nausea/vomiting (25%). None were unexpected given the HiDAC/Mito regimen. Serious adverse events occurred in 6 (30%) patients; one was fatal. Ten (50%) patients achieved a complete remission (CR), 3 (15%) achieved CR with incomplete recovery (CRi), 1 (5%) achieved partial remission (PR), and 6 (30%) had progressive disease for an overall response rate (ORR) of 70%. Eight of 14 (57%) responders proceeded to allogeneic stem cell transplantation. Correlative studies of WT1 levels showed persistently detectable levels in patients who either did not respond or relapsed quickly after induction.

Conclusion: The selinexor/HiDAC/Mito regimen is feasible and tolerable at selinexor doses of 80 mg/day (~ 50 mg/m/day) twice weekly. The recommended phase II dose is 80 mg and warrants further study in this combination.

Trial Registration: ClinicalTrials.gov , NCT02573363 . Registered October 5, 2015.
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http://dx.doi.org/10.1186/s13045-017-0550-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5756334PMC
January 2018

Old and new tools in the clinical diagnosis of inherited bone marrow failure syndromes.

Hematology Am Soc Hematol Educ Program 2017 12;2017(1):79-87

Section of Hematology/Oncology, The University of Chicago Comprehensive Cancer Center, Chicago, IL; and.

Patients with inherited bone marrow failure syndromes (IBMFSs) classically present with specific patterns of cytopenias along with congenital anomalies and/or other physical features that are often recognizable early in life. However, increasing application of genomic sequencing and clinical awareness of subtle disease presentations have led to the recognition of IBMFS in pediatric and adult populations more frequently than previously realized, such as those with early onset myelodysplastic syndrome (MDS). Given the well-defined differences in clinical management needs and outcomes for aplastic anemia, acute myeloid leukemia, and MDS in patients with an IBMFS vs those occurring sporadically, as well as nonhematologic comorbidities in patients with IBMFSs, it is critical for hematologists to understand how to approach screening for the currently known IBMFSs. This review presents a practical approach for the clinical hematologist that outlines when to suspect an IBMFS and how to use various diagnostic tools, from physical examination to screening laboratory tests and genomics, for the diagnosis of the most frequent IBMFSs: Fanconi anemia, telomere biology disorders, Diamond-Blackfan anemia, GATA2 deficiency syndrome, Shwachman-Diamond syndrome, and severe congenital neutropenia.
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http://dx.doi.org/10.1182/asheducation-2017.1.79DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142587PMC
December 2017

Familial myelodysplastic syndrome/acute myeloid leukemia.

Authors:
Jane E Churpek

Best Pract Res Clin Haematol 2017 12 4;30(4):287-289. Epub 2017 Oct 4.

Section of Hematology/Oncology, Cancer Risk and Prevention Clinic, Hereditary Hematologic Malignancies Program, The University of Chicago Medicine, 5841 S. Maryland Ave MC2115, Chicago, IL 60637, USA. Electronic address:

A growing number of inherited genetic loci that contribute to myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) development in both children as well as adults are rapidly being identified. In recognition of the clinical impact of this emerging field, the World Health Organization, National Comprehensive Cancer Network, and European LeukemiaNet have all added consideration of inherited predisposition to MDS/AML classification and management. Study of these disorders is providing unique insight into the biology of both sporadic and familial MDS/AML. International collaborative efforts to store germline tissue, document family histories, and pool data are essential to progress in diagnosing and treating both hereditary and sporadic forms of MDS/AML.
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http://dx.doi.org/10.1016/j.beha.2017.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5774636PMC
December 2017

Recognition of familial myeloid neoplasia in adults.

Semin Hematol 2017 04 18;54(2):60-68. Epub 2017 Apr 18.

Section of Hematology/Oncology, The University of Chicago Comprehensive Cancer Center, and the Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL, USA. Electronic address:

Hereditary hematologic malignancy (HM) syndromes are increasingly recognized as causative of adult hematopoietic cancers, and the advent of next-generation sequencing has accelerated the discovery of new syndromes based on dense clustering of these diseases in particular families. Updated classifications schemes for myeloid malignancies will now include recommendations for taking a family history on all patients diagnosed with hematopoietic malignancies and for genetic counseling and testing of appropriate individuals and families. Therefore, now more than ever, clinicians and pathologists will need to have a high index of suspicion and be familiar with the aspects of a patient's personal or family history that should raise suspicion regarding these syndromes as well as the options for clinical testing. Whenever possible, individuals should be tested with certified, clinical platforms that can detect both point mutations and genomic rearrangements that disrupt gene function so that results are immediately actionable. Individuals and families who test negative for mutations in the known germline predisposition genes serve as important sources of discovery for new inherited susceptibility syndromes.
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http://dx.doi.org/10.1053/j.seminhematol.2016.11.003DOI Listing
April 2017

Bad blood contaminating germline databases?

Authors:
Jane E Churpek

Hum Mutat 2017 05;38(5):469

The University of Chicago, USA.

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http://dx.doi.org/10.1002/humu.23217DOI Listing
May 2017

Efficacy of single-agent decitabine in relapsed and refractory acute myeloid leukemia.

Leuk Lymphoma 2017 09 20;58(9):1-7. Epub 2017 Feb 20.

b Department of Medicine , Section of Hematology/Oncology, The University of Chicago Medicine , Chicago , IL , USA.

Improving therapy for relapsed/refractory AML remains a challenge. We performed a retrospective analysis of outcomes following decitabine treatment in 34 patients with relapsed/refractory AML (median age, 62; median Charlson comorbidity score, 6). Decitabine, 20 mg/m daily, was given in 5- (25%) or 10-day (75%) cycles. Overall response rate (OR) was 30% with 21% complete remission and 9% partial remission rate. Patients with therapy-related myeloid neoplasm (t-MN) and secondary AML had a significantly higher OR compared to those with de novo AML (70 vs. 30%; p = .02). Median overall survival of all patients was 8.5 months. Median survival in patients with t-MN or secondary AML was 12.4 months compared to 8 months in those with de novo AML (p = .20). Fifteen (44%) patients proceeded to hematopoietic stem cell transplant. These data support using 10-day treatment cycles of decitabine in patients with relapsed/refractory AML, particularly for those with secondary or therapy-related AML.
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http://dx.doi.org/10.1080/10428194.2017.1289524DOI Listing
September 2017

Identifying Inherited and Acquired Genetic Factors Involved in Poor Stem Cell Mobilization and Donor-Derived Malignancy.

Biol Blood Marrow Transplant 2016 11 4;22(11):2100-2103. Epub 2016 Aug 4.

Section of Hematology/Oncology, Department of Medicine, and The University of Chicago Comprehensive Cancer Center, The University of Chicago, Chicago, Illinois; Center for Clinical Cancer Genetics, The University of Chicago, Chicago, Illinois. Electronic address:

Analysis of the clinical characteristics of hematopoietic stem cell transplant (HSCT) donors has proven beneficial for identifying cases of heritable hematopoietic disorders. This study examines poor peripheral blood hematopoietic stem cell mobilization after granulocyte colony-stimulating factor administration among 328 donors as a potential marker for suspected familial predisposition to myeloid malignancies. Here, we present data comparing the clinical characteristics of poor-mobilizing versus nonpoor-mobilizing donors and the results of panel-based sequencing of hematopoietic genes in poor-mobilizing donors. From this analysis, we identified a novel case of a donor-derived myelodysplastic syndrome in an HSCT recipient that is consistent with clonal evolution of TET2-mutated clonal hematopoiesis of indeterminate potential (CHIP) within the donor. This study demonstrates the potential risk of using hematopoietic stem cells from a donor with CHIP and raises the question of whether there should be increased screening measures to identify such donors.
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http://dx.doi.org/10.1016/j.bbmt.2016.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5592729PMC
November 2016

Evaluation of Patients and Families With Concern for Predispositions to Hematologic Malignancies Within the Hereditary Hematologic Malignancy Clinic (HHMC).

Clin Lymphoma Myeloma Leuk 2016 07 27;16(7):417-428.e2. Epub 2016 Apr 27.

Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX.

Introduction: Although multiple predispositions to hematologic malignancies exist, evaluations for hereditary cancer syndromes (HCS) are underperformed by most hematologist/oncologists. Criteria for initiating HCS evaluation are poorly defined, and results of genetic testing for hereditary hematologic malignancies have not been systematically reported.

Patients And Methods: From April 2014 to August 2015, 67 patients were referred to the Hereditary Hematologic Malignancy Clinic (HHMC). Referral reasons included (1) bone marrow failure or myelodysplastic syndrome in patients ≤ 50 years, (2) evaluation for germ-line inheritance of identified RUNX1, GATA2, or CEBPA mutations on targeted next-generation sequencing panels, and (3) strong personal and/or family history of malignancy. Cultured skin fibroblasts were utilized for germ-line DNA in all patients with hematologic malignancy.

Results: Eight patients (12%) were clinically diagnosed with a HCS: 4 patients with RUNX1-related familial platelet disorder (FPD)/acute myeloid leukemia (AML), and 1 patient each with dyskeratosis congenita, Fanconi anemia, germ-line DDX41, and Li-Fraumeni syndrome (LFS). Two patients with concern for FPD/AML and LFS, respectively, had RUNX1 and TP53 variants of unknown significance. Additionally, 4 patients with prior HCS diagnosis (1 LFS, 3 FPD/AML) were referred for further evaluation and surveillance.

Conclusion: In this HHMC-referred hematologic malignancy cohort, HCS was confirmed in 12 patients (18%). HCS identification provides insight for improved and individualized treatment, as well as screening/surveillance opportunities for family members. The HHMC has facilitated HCS diagnosis; with increased clinical awareness of hematologic malignancy predisposition syndromes, more patients who may benefit from evaluation can be identified. Mutation panels intended for prognostication may provide increased clinical suspicion for germ-line testing.
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http://dx.doi.org/10.1016/j.clml.2016.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4925265PMC
July 2016

Novel germ line DDX41 mutations define families with a lower age of MDS/AML onset and lymphoid malignancies.

Blood 2016 Feb 28;127(8):1017-23. Epub 2015 Dec 28.

Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia; School of Pharmacy and Medical Sciences, Division of Health Sciences, University of South Australia, Adelaide, SA, Australia; School of Medicine, University of Adelaide, Adelaide, SA, Australia; School of Molecular and Biological Sciences, University of Adelaide, Adelaide, SA, Australia; Australian Cancer Research Foundation Cancer Genomics Facility, Centre for Cancer Biology.

Recently our group and others have identified DDX41 mutations both as germ line and acquired somatic mutations in families with multiple cases of late onset myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML), suggesting that DDX41 acts as a tumor suppressor. To determine whether novel DDX41 mutations could be identified in families with additional types of hematologic malignancies, our group screened two cohorts of families with a diverse range of hematologic malignancy subtypes. Among 289 families, we identified nine (3%) with DDX41 mutations. As previously observed, MDS and AML were the most common malignancies, often of the erythroblastic subtype, and 1 family displayed early-onset follicular lymphoma. Five novel mutations were identified, including missense mutations within important functional domains and start-loss and splicing mutations predicted to result in truncated proteins. We also show that most asymptomatic mutation carriers have normal blood counts until malignancy develops. This study expands both the mutation and phenotypic spectra observed in families with germ line DDX41 mutations. With an increasing number of both inherited and acquired mutations in this gene being identified, further study of how DDX41 disruption leads to hematologic malignancies is critical.
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http://dx.doi.org/10.1182/blood-2015-10-676098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4968341PMC
February 2016

Brca1 deficiency causes bone marrow failure and spontaneous hematologic malignancies in mice.

Blood 2016 Jan 7;127(3):310-3. Epub 2015 Dec 7.

Section of Hematology/Oncology, Department of Medicine, The University of Chicago Medicine Comprehensive Cancer Center, and Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL.

BRCA1 is critical for maintenance of genomic stability and interacts directly with several proteins that regulate hematopoietic stem cell function and are part of the Fanconi anemia (FA) double-strand break DNA repair pathway. The effects of complete BRCA1 deficiency on bone marrow (BM) function are unknown. To test the hypothesis that Brca1 is essential in hematopoiesis, we developed a conditional mouse model with Mx1-Cre-mediated Brca1 deletion. Mice lacking Brca1 in the BM have baseline cytopenias and develop spontaneous bone marrow failure or diverse hematologic malignancies by 6 months of age. Brca1(-/-) BM cells have a reduced capacity to form hematopoietic colonies in vitro and to reconstitute hematopoiesis in irradiated recipients, consistent with a hematopoietic progenitor functional defect. Brca1(-/-) BM cells also show FA-like hypersensitivity to the DNA crosslinking agent mitomycin C, and karyotypes feature genomic instability. Taken together, our results show that loss of Brca1 in murine BM causes hematopoietic defects similar to those seen in people with FA, which provides strong evidence that Brca1 is critical for normal hematopoiesis and that Brca1 is a bona fide FA-like gene.
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http://dx.doi.org/10.1182/blood-2015-03-635599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4722284PMC
January 2016

Inherited mutations in cancer susceptibility genes are common among survivors of breast cancer who develop therapy-related leukemia.

Cancer 2016 Jan 7;122(2):304-11. Epub 2015 Dec 7.

Department of Medicine, The University of Chicago, Chicago, Illinois.

Background: Risk factors for the development of therapy-related leukemia (TRL), an often lethal late complication of cytotoxic therapy, remain poorly understood and may differ for survivors of different malignancies. Survivors of breast cancer (BC) now account for the majority of TRL cases, making the study of TRL risk factors in this population a priority.

Methods: Subjects with TRL after cytotoxic therapy for a primary BC were identified from the TRL registry at The University of Chicago. Those with an available germline DNA sample were screened with a comprehensive gene panel covering known inherited BC susceptibility genes. Clinical and TRL characteristics of all subjects and those with identified germline mutations were described.

Results: Nineteen of 88 survivors of BC with TRL (22%) had an additional primary cancer and 40 of the 70 survivors with an available family history (57%) had a close relative with breast, ovarian, or pancreatic cancer. Of the 47 subjects with available DNA, 10 (21%) were found to carry a deleterious inherited mutation in BRCA1 (3 subjects; 6%), BRCA2 (2 subjects; 4%), TP53 (tumor protein p53) (3 subjects; 6%), CHEK2 (checkpoint kinase 2) (1 subject; 2%), and PALB2 (partner and localizer of BRCA2) (1 subject; 2%).

Conclusions: Survivors of BC with TRL have personal and family histories suggestive of inherited cancer susceptibility and frequently carry germline mutations in BC susceptibility genes. The data from the current study support the role of these genes in TRL risk and suggest that long-term follow-up studies of women with germline mutations who are treated for BC and functional studies of the effects of heterozygous mutations in these genes on bone marrow function after cytotoxic exposures are warranted. Cancer 2016;122:304-311. © 2015 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.29615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707981PMC
January 2016

Genomic analysis of germ line and somatic variants in familial myelodysplasia/acute myeloid leukemia.

Blood 2015 Nov 22;126(22):2484-90. Epub 2015 Oct 22.

Massachusetts General Hospital Cancer Center, Boston, MA.

Familial clustering of myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML) can be caused by inherited factors. We screened 59 individuals from 17 families with 2 or more biological relatives with MDS/AML for variants in 12 genes with established roles in predisposition to MDS/AML, and identified a pathogenic germ line variant in 5 families (29%). Extending the screen with a panel of 264 genes that are recurrently mutated in de novo AML, we identified rare, nonsynonymous germ line variants in 4 genes, each segregating with MDS/AML in 2 families. Somatic mutations are required for progression to MDS/AML in these familial cases. Using a combination of targeted and exome sequencing of tumor and matched normal samples from 26 familial MDS/AML cases and asymptomatic carriers, we identified recurrent frameshift mutations in the cohesin-associated factor PDS5B, co-occurrence of somatic ASXL1 mutations with germ line GATA2 mutations, and recurrent mutations in other known MDS/AML drivers. Mutations in genes that are recurrently mutated in de novo AML were underrepresented in the familial MDS/AML cases, although the total number of somatic mutations per exome was the same. Lastly, clonal skewing of hematopoiesis was detected in 67% of young, asymptomatic RUNX1 carriers, providing a potential biomarker that could be used for surveillance in these high-risk families.
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http://dx.doi.org/10.1182/blood-2015-04-641100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4661171PMC
November 2015

Correspondence Regarding the Consensus Statement from the Worldwide Network for Blood and Marrow Transplantation Standing Committee on Donor Issues.

Biol Blood Marrow Transplant 2016 Jan 22;22(1):183-4. Epub 2015 Oct 22.

Section of Hematology/Oncology, Department of Medicine, The University of Chicago Comprehensive Cancer Research Center, Chicago, Illinois. Electronic address:

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http://dx.doi.org/10.1016/j.bbmt.2015.10.008DOI Listing
January 2016

Inherited and Somatic Defects in DDX41 in Myeloid Neoplasms.

Cancer Cell 2015 May 23;27(5):658-70. Epub 2015 Apr 23.

Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo 113-8654, Japan.

Most cases of adult myeloid neoplasms are routinely assumed to be sporadic. Here, we describe an adult familial acute myeloid leukemia (AML) syndrome caused by germline mutations in the DEAD/H-box helicase gene DDX41. DDX41 was also found to be affected by somatic mutations in sporadic cases of myeloid neoplasms as well as in a biallelic fashion in 50% of patients with germline DDX41 mutations. Moreover, corresponding deletions on 5q35.3 present in 6% of cases led to haploinsufficient DDX41 expression. DDX41 lesions caused altered pre-mRNA splicing and RNA processing. DDX41 is exemplary of other RNA helicase genes also affected by somatic mutations, suggesting that they constitute a family of tumor suppressor genes.
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http://dx.doi.org/10.1016/j.ccell.2015.03.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8713504PMC
May 2015

Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy.

Nat Genet 2015 Feb 12;47(2):180-5. Epub 2015 Jan 12.

1] Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. [2] Pediatric Hematology/Oncology, Seattle Children's Hospital, Seattle, Washington, USA. [3] Department of Pediatrics, University of Washington, Seattle, Washington, USA.

We report germline missense mutations in ETV6 segregating with the dominant transmission of thrombocytopenia and hematologic malignancy in three unrelated kindreds, defining a new hereditary syndrome featuring thrombocytopenia with susceptibility to diverse hematologic neoplasms. Two variants, p.Arg369Gln and p.Arg399Cys, reside in the highly conserved ETS DNA-binding domain. The third variant, p.Pro214Leu, lies within the internal linker domain, which regulates DNA binding. These three amino acid sites correspond to hotspots for recurrent somatic mutation in malignancies. Functional studies show that the mutations abrogate DNA binding, alter subcellular localization, decrease transcriptional repression in a dominant-negative fashion and impair hematopoiesis. These familial genetic studies identify a central role for ETV6 in hematopoiesis and malignant transformation. The identification of germline predisposition to cytopenias and cancer informs the diagnosis and medical management of at-risk individuals.
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http://dx.doi.org/10.1038/ng.3177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4540357PMC
February 2015

Spontaneous Hepatic Rupture Associated With Epstein-Barr Virus Negative Aggressive Natural Killer Cell Leukemia.

World J Oncol 2014 Dec 3;5(5-6):210-213. Epub 2014 Dec 3.

Department of Medicine, Section of Hematology/Oncology, The University of Chicago, Chicago, IL, USA.

Aggressive natural killer cell leukemia (ANKL) is a rare subtype of large granular lymphocyte (LGL) leukemia, which typically presents in young adults of Asian descent. It is an aggressive disease, characterized initially by fever, pancytopenia and hepatosplenomegaly, which rapidly progresses to organ failure and death over the course of months. Spontaneous hemorrhagic complications have been reported to occur in ANKL in a handful of case reports, including lethal intestinal and cerebral hemorrhage as well as splenic rupture. Here, we present a case of a 49-year-old man with Epstein-Barr virus (EBV)-negative ANKL who developed fatal spontaneous hepatic rupture approximately 4 months after initial diagnosis. To the best of our knowledge, this is first reported case of hepatic rupture associated with ANKL.
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http://dx.doi.org/10.14740/wjon715wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5649769PMC
December 2014
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