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  • American Association for Cancer Research (AACR)  (4)
  • 1
    Online Resource
    Online Resource
    Genetic Characterization and Prognostic Relevance of Acquired Uniparental Disomies in Cytogenetically Normal Acute Myeloid Leukemia
    American Association for Cancer Research (AACR) ; 2019
    In:  Clinical Cancer Research Vol. 25, No. 21 ( 2019-11-01), p. 6524-6531
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 25, No. 21 ( 2019-11-01), p. 6524-6531
    Abstract: Uniparental disomy (UPD) is a way cancer cells duplicate a mutated gene, causing loss of heterozygosity (LOH). Patients with cytogenetically normal acute myeloid leukemia (CN-AML) do not have microscopically detectable chromosome abnormalities, but can harbor UPDs. We examined the prognostic significance of UPDs and frequency of LOH in patients with CN-AML. Experimental Design: We examined the frequency and prognostic significance of UPDs in a set of 425 adult patients with de novo CN-AML who were previously sequenced for 81 genes typically mutated in cancer. Associations of UPDs with outcome were analyzed in the 315 patients with CN-AML younger than 60 years. Results: We detected 127 UPDs in 109 patients. Most UPDs were large and typically encompassed all or most of the affected chromosome arm. The most common UPDs occurred on chromosome arms 13q (7.5% of patients), 6p (2.8%), and 11p (2.8%). Many UPDs significantly cooccurred with mutations in genes they encompassed, including 13q UPD with FLT3-internal tandem duplication (FLT3-ITD; P & lt; 0.001), and 11p UPD with WT1 mutations (P = 0.02). Among patients younger than 60 years, UPD of 11p was associated with longer overall survival (OS) and 13q UPD with shorter disease-free survival (DFS) and OS. In multivariable models that accounted for known prognostic markers, including FLT3-ITD and WT1 mutations, UPD of 13q maintained association with shorter DFS, and UPD of 11p maintained association with longer OS. Conclusions: LOH mediated by UPD is a recurrent feature of CN-AML. Detection of UPDs of 13q and 11p might be useful for genetic risk stratification of patients with CN-AML.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-19-0725
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 2
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    Online Resource
    Abstract 3306: The clinical importance of DNA methylation signatures in chronic lymphocytic leukemia patients treated with chemo-immunotherapy
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 3306-3306
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 3306-3306
    Abstract: Variations in the CLL DNA methylome reflect modifications that occur during normal B cell maturation, along with IGHV mutated (M-CLL) and unmutated CLL (U-CLL), retaining an imprint of the DNA methylation signature of memory (m-CLL) and naive B cells (n-CLL), respectively, with a third intermediate epigenetic subgroup (i-CLL) (1-3). To further test the clinical utility of DNA methylation signatures, we performed the first analysis of patients entering clinical trials; we tested treatment-naive CLL patients [n=605] randomized to CLL4 (chemotherapy, CT) (4), ARCTIC and ADMIRE (both chemo-immunotherapy, CIT) (5, 6). We identified n-, i- and m-CLL in 49.3% (n=299), 32.0% (n=195) and 18.5% (n=112) of our patients, respectively. Fewer m-CLL patients were identified in our study compared to published data reflecting the progressive nature of our cohort, with 80% (n=245/305, P & lt;0.001) of U-CLL cases exhibiting the n-CLL signature (i-CLL: 17% and m-CLL: 3%). For M-CLL cases, 9%, 50% and 41% exhibited the n-, i- and m-CLL epigenetic signature, respectively. 68% (80/117, p & lt;0.001) of cases with del(11q), 77% (41/53, p & lt;0.001) with trisomy 12, and 68% (38/56, p=0.03) with TP53 lesions were n-CLL. Cases with NOTCH1 (p=0.01) and SF3B1 (p=0.02) mutations were also enriched in n-CLL. Next, we investigated the impact of methylation signatures on progression-free (PFS) and overall survival (OS). In CT patients, n-, i- and m-CLL patients exhibited a median PFS of 23, 34 and 35 months, and OS of 63, 66 and 106 months, respectively. n-CLL showed significantly shorter PFS than i-CLL (HR 0.64, p & lt;0.001) and m-CLL (HR 0.52, p & lt;0.001), and had the shortest OS, again compared to i-CLL (HR 0.73, p=0.01) and m-CLL (HR 0.33, p & lt;0.001). Ten-year OS differed according to epigenetic signature (P & lt;0.001) and was reached by only 14% of n-CLL patients. Multivariate Cox proportional analysis, controlling for confounding variables (incl. clinical features, IGHV status, TP53, NOTCH1 and SF3B1) in 278 patients, showed that m-CLL was an independent prognostic factor for OS (HR 0.46, p & lt;0.01). In 247 CIT patients, univariate analysis showed that the i- (HR:0.57, p=0.05) and m-CLL (HR:0.3, p=0.002) subgroups displayed longer PFS. In a multivariate model, including TP53 lesions and IGHV status (239 patients), the m-CLL subgroup retained independent prognostic significance (HR:0.25, p & lt;0.001). In conclusion, we provide important evidence that DNA methylation analysis may aid in the identification of patients destined to demonstrate durable remissions when treated with these agents. References: 1. Kulis, M. et al. Nat Genet 44, 1236-1242 (2012). 2. Queiros, A.C. et al. Leukemia 29, 598-605 (2015). 3. Oakes CC, et al. Nat Genet. 2016 Mar;48(3):253-64. 4. Catovsky, D. et al. Lancet 370, 230-239 (2007). 5. Howard, D.R. et al. Leukemia Nov;31(11):2416-2425 (2017). 6. Munir, T. et al. Leukemia Oct;31(10):2085-2093 (2017). Citation Format: Tomasz K. Wojdacz, Harindra E. Amarasinghe, Matthew JJ Rose-Zerilli, Alice Beattie, Jade Forster, Latha Kadalayil, Stuart Blakemore, Helen Parker, Marta Larrayoz, Ruth Clifford, Zadie Davis, Monica Else, Dena Cohen, Andrew J. Steele, Richard Rosenquist, Andrew Collins, Andrew Pettitt, Peter Hillmen, Christoph Plass, Anna Schuh, Daniel Catovsky, David G. Oscier, Christopher C. Oakes, Jonathan C. Strefford. The clinical importance of DNA methylation signatures in chronic lymphocytic leukemia patients treated with chemo-immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3306.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-3306
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 3
    Online Resource
    Online Resource
    Identification and Targeting of the Developmental Blockade in Extranodal Natural Killer/T-cell Lymphoma
    American Association for Cancer Research (AACR) ; 2022
    In:  Blood Cancer Discovery Vol. 3, No. 2 ( 2022-03-01), p. 154-169
    Details
    In: Blood Cancer Discovery, American Association for Cancer Research (AACR), Vol. 3, No. 2 ( 2022-03-01), p. 154-169
    Abstract: Extranodal natural killer/T-cell lymphoma (ENKTL) is an aggressive, rare lymphoma of natural killer (NK) cell origin with poor clinical outcomes. Here we used phenotypic and molecular profiling, including epigenetic analyses, to investigate how ENKTL ontogeny relates to normal NK-cell development. We demonstrate that neoplastic NK cells are stably, but reversibly, arrested at earlier stages of NK-cell maturation. Genes downregulated in the most epigenetic immature tumors were associated with polycomb silencing along with genomic gain and overexpression of EZH2. ENKTL cells exhibited genome-wide DNA hypermethylation. Tumor-specific DNA methylation gains were associated with polycomb-marked regions, involving extensive gene silencing and loss of transcription factor binding. To investigate therapeutic targeting, we treated novel patient-derived xenograft (PDX) models of ENKTL with the DNA hypomethylating agent, 5-azacytidine. Treatment led to reexpression of NK-cell developmental genes, phenotypic NK-cell differentiation, and prolongation of survival. These studies lay the foundation for epigenetic-directed therapy in ENKTL. Significance: Through epigenetic and transcriptomic analyses of ENKTL, a rare, aggressive malignancy, along with normal NK-cell developmental intermediates, we identified that extreme DNA hypermethylation targets genes required for NK-cell development. Disrupting this epigenetic blockade in novel PDX models led to ENKTL differentiation and improved survival. This article is highlighted in the In This Issue feature, p. 85
    Type of Medium: Online Resource
    ISSN: 2643-3230 , 2643-3249
    URL: Article
    DOI: 10.1158/2643-3230.BCD-21-0098
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 4
    Online Resource
    Online Resource
    A Comparison of the Natural History of HPV Infection and Cervical Abnormalities among HIV-Positive and HIV-Negative Women in Senegal, Africa
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 26, No. 6 ( 2017-06-01), p. 886-894
    Details
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 26, No. 6 ( 2017-06-01), p. 886-894
    Abstract: Background: There is evidence of an interaction between HIV and human papillomavirus (HPV) resulting in increased HPV-associated morbidity and cancer mortality among HIV-positive women. This study aims to determine how the natural history of cervical HPV infection differs by HIV status. Methods: A total of 1,320 women (47% were positive for HIV-1 and/or HIV-2) were followed for an average of two years in Senegal, West Africa between 1994 and 2010. Cytology (with a sub-sample of histology) and HPV DNA testing were performed at approximately 4-month intervals yielding data from over 7,900 clinic visits. Competing risk modeling was used to estimate rates for transitioning between three clinically relevant natural history stages: Normal, HPV, and HSIL (high-grade squamous intraepithelial lesions). Among HIV-positive women, exploratory univariate analyses were conducted examining the impact of HPV type, infection with multiple HPV types, HIV type, CD4+ count, and age. Results: HIV-positive women had higher rates of progression and lower rates of regression compared with HIV-negative women (i.e., adverse transitions). HIV-positive women had a 2.55 [95% confidence interval (CI), 1.69–3.86; P & lt; 0.0001] times higher rate of progression from HPV to HSIL than HIV-negative women (with 24-month absolute risks of 0.18 and 0.07, respectively). Among HIV-positive women, HPV-16/18 infection and CD4+ count & lt;200/mm3 were associated with adverse transitions. Conclusions: Adverse HIV effects persist throughout HPV natural history stages. Impact: In the limited-resource setting of sub-Saharan Africa where cervical cancer screening is not widely available, the high-risk population of HIV-positive women may be ideal for targeted screening. Cancer Epidemiol Biomarkers Prev; 26(6); 886–94. ©2017 AACR.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    URL: Article
    DOI: 10.1158/1055-9965.EPI-16-0700
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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