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1.
Cancer Med ; 2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31407530

RESUMO

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.

2.
Proc Natl Acad Sci U S A ; 116(18): 9008-9013, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-30975761

RESUMO

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 (P = 0.0006). The effect of genotype was highly significant for patients with pleural mesothelioma (median survival 7.9 y versus 2.4 y, P = 0.0012), but not for patients with peritoneal mesothelioma (median survival 8.2 y versus 5.4 y, P = 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.

3.
J Clin Invest ; 129(2): 476-488, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30707109

RESUMO

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.

4.
Int J Gynecol Cancer ; 2019 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-30683758

RESUMO

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 BRCA1 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 BRCA1 or BRCA2 mutations were identified and classified as BRCA mutated. High or low glucocorticoid receptor expression was defined as expression above or below median of the GR/nuclear receptor subfamily 3 C1 (NR3C1) 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 BRCA1 or BRCA2. 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 GR/NR3C1 gene expression with BRCA mutation status or BRCA1 or BRCA2 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.

5.
J Oncol Pract ; 14(11): 649-657, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30423270

RESUMO

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.

6.
J Oncol Pharm Pract ; : 1078155218801055, 2018 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-30259783

RESUMO

Drug-drug interactions between digoxin and the triazole antifungal agents, mediated via various cytochrome P450 isozymes, have been described in the literature. Posaconazole is not extensively metabolized by these isozymes but is both a p-glycoprotein (P-gp) substrate and inhibitor. To our knowledge, there have been no published cases of clinically significant posaconazole-digoxin drug-drug interactions. We report an interaction between posaconazole (300 mg by mouth daily) and digoxin (0.25 mg by mouth daily, Monday through Friday) resulting in atrial fibrillation with slow ventricular response and degenerating into polymorphic ventricular tachycardia.

7.
J Clin Oncol ; 36(28): 2863-2871, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30113886

RESUMO

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.

8.
Clin Cancer Res ; 2018 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-30154229

RESUMO

PURPOSE: To establish a cohort of high-risk women undergoing intensive surveillance for breast cancer. METHODS: We performed dynamic contrast-enhanced magnetic resonance imaging (MRI) every 6 months in conjunction with annual mammography (MG). Eligible participants had a cumulative lifetime breast cancer risk ≥ 20% and/or tested positive for a pathogenic mutation in a known breast cancer susceptibility gene. RESULTS: Between 2004-2016, we prospectively enrolled 295 women, including 157 mutation carriers (75 BRCA1, 61 BRCA2); participants' mean age at entry was 43.3 years. Seventeen cancers were later diagnosed: four ductal carcinoma in situ (DCIS) and thirteen early stage invasive breast cancers. Fifteen cancers occurred in mutation carriers (11 BRCA1, 3 BRCA2, 1 CDH1). Median size of the invasive cancers was 0.61 cm. No patients had lymph node metastasis at time of diagnosis and no interval invasive cancers occurred. The sensitivity of bi-annual MRI alone was 88.2% and annual MG plus bi-annual MRI was 94.1%. The cancer detection rate of bi-annual MRI alone was 0.7% per 100 screening episodes, which is similar to the cancer detection rate of 0.7% per 100 screening episodes for annual MG plus bi-annual MRI. The number of recalls and biopsies needed to detect one cancer by bi-annual MRI were 2.8 and 1.7 in BRCA1 carriers, 12.0 and 8.0 in BRCA2 carriers, and 11.7 and 5.0 in non-BRCA1/2 carriers, respectively. CONCLUSIONS: Bi-annual MRI performed well for early detection of invasive breast cancer in genomically stratified high-risk women. No benefit was associated with annual MG screening plus bi-annual MRI screening.

9.
Cancer Res ; 78(10): 2747-2759, 2018 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-29559475

RESUMO

Given the frequent and largely incurable occurrence of multiple myeloma, identification of germline genetic mutations that predispose cells to multiple myeloma may provide insight into disease etiology and the developmental mechanisms of its cell of origin, the plasma cell (PC). Here, we identified familial and early-onset multiple myeloma kindreds with truncating mutations in lysine-specific demethylase 1 (LSD1/KDM1A), an epigenetic transcriptional repressor that primarily demethylates histone H3 on lysine 4 and regulates hematopoietic stem cell self-renewal. In addition, we found higher rates of germline truncating and predicted deleterious missense KDM1A mutations in patients with multiple myeloma unselected for family history compared with controls. Both monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma cells have significantly lower KDM1A transcript levels compared with normal PCs. Transcriptome analysis of multiple myeloma cells from KDM1A mutation carriers shows enrichment of pathways and MYC target genes previously associated with myeloma pathogenesis. In mice, antigen challenge followed by pharmacologic inhibition of KDM1A promoted PC expansion, enhanced secondary immune response, elicited appearance of serum paraprotein, and mediated upregulation of MYC transcriptional targets. These changes are consistent with the development of MGUS. Collectively, our findings show that KDM1A is the first autosomal-dominant multiple myeloma germline predisposition gene providing new insights into its mechanistic roles as a tumor suppressor during post-germinal center B-cell differentiation.Significance: KDM1A is the first germline autosomal dominant predisposition gene identified in multiple myeloma and provides new insights into multiple myeloma etiology and the mechanistic role of KDM1A as a tumor suppressor during post-germinal center B-cell differentiation. Cancer Res; 78(10); 2747-59. ©2018 AACR.

10.
Leukemia ; 32(7): 1482-1492, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29483711

RESUMO

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.

11.
Blood Adv ; 2(2): 146-150, 2018 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-29365323

RESUMO

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 ANKRD26, CEBPA, DDX41, ETV6, GATA2, RUNX1, or TP53 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 DDX41 variants, 2 GATA2 variants, and a TP53 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 DDX41 and GATA2 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.

12.
J Hematol Oncol ; 11(1): 4, 2018 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-29304833

RESUMO

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/m2), and 17 (85%) received the target level of 80 mg (~ 50 mg/m2). 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/m2/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.

13.
Hematology Am Soc Hematol Educ Program ; 2017(1): 79-87, 2017 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-29222240

RESUMO

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.


Assuntos
Doenças da Medula Óssea/diagnóstico , Doenças da Medula Óssea/genética , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Testes Genéticos/métodos , Doenças da Medula Óssea/metabolismo , Doenças Genéticas Inatas/metabolismo , Humanos , Síndrome
14.
Best Pract Res Clin Haematol ; 30(4): 287-289, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29156196

RESUMO

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.


Assuntos
Doenças Genéticas Inatas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Doenças Genéticas Inatas/classificação , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/terapia , Humanos , Leucemia Mieloide Aguda/classificação , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicas/classificação , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/terapia
15.
Semin Hematol ; 54(2): 60-68, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28637618

RESUMO

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.


Assuntos
Neoplasias Hematológicas/etiologia , Transtornos Mieloproliferativos , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos
16.
Hum Mutat ; 38(5): 469, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28425196
17.
Leuk Lymphoma ; 58(9): 1-7, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28278716

RESUMO

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/m2 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.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/análogos & derivados , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Azacitidina/administração & dosagem , Azacitidina/efeitos adversos , Azacitidina/uso terapêutico , Terapia Combinada , Comorbidade , Decitabina , Resistencia a Medicamentos Antineoplásicos , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Transplante Homólogo , Resultado do Tratamento , Adulto Jovem
18.
Biol Blood Marrow Transplant ; 22(11): 2100-2103, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27497531

RESUMO

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.


Assuntos
Doadores de Sangue , Mobilização de Células-Tronco Hematopoéticas/normas , Neoplasias/genética , Adolescente , Adulto , Idoso , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Feminino , Predisposição Genética para Doença , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Hematopoese/genética , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/genética , Neoplasias/etiologia , Linhagem , Proteínas Proto-Oncogênicas/genética , Adulto Jovem
19.
J Genet Couns ; 25(6): 1157-1170, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27265405

RESUMO

This review provides a synopsis for genetic counselors of the major concepts of lymphoma predisposition: genomic instability, immune deficiency, inappropriate lymphoproliferation, and chronic antigen stimulation. We discuss syndromes typifying each of these mechanisms. Importantly, our review of the genetic counseling literature reveals sparse discussion of genetically-based immune-mediated lymphoma predisposition, which we address in depth here. We aim to increase awareness among genetic counselors and colleagues in oncology about familial susceptibility and facilitate critical thinking about lymphoma risk assessment. Clinical application of this knowledge is aided by recommendations for collection of personal and family history to guide risk assessment and testing. Lastly, we include a special discussion of genetic counseling issues including perceptions of the context, nature, and magnitude of lymphoma risk, as well as coping with awareness of susceptibility to lymphoma.


Assuntos
Aconselhamento Genético , Predisposição Genética para Doença , Linfoma/genética , Guias de Prática Clínica como Assunto , Feminino , Testes Genéticos , Humanos , Linfoma/epidemiologia , Linfoma/etiologia , Masculino , Medição de Risco
20.
Clin Lymphoma Myeloma Leuk ; 16(7): 417-428.e2, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27210295

RESUMO

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.


Assuntos
Família/psicologia , Predisposição Genética para Doença/psicologia , Neoplasias Hematológicas/epidemiologia , Síndromes Neoplásicas Hereditárias/epidemiologia , Pacientes/psicologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Feminino , Aconselhamento Genético , Mutação em Linhagem Germinativa , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Linhagem , Encaminhamento e Consulta , Texas , Fluxo de Trabalho , Adulto Jovem
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