Browsing by Author "Shanafelt, Tait D."

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    Common genetic polymorphisms contribute to the association between chronic lymphocytic leukaemia and non-melanoma skin cancer
    (Oxford University Press, 2021-08-30) Besson, Caroline; Moore, Amy; Wu, Wenting; Vajdic, Claire M.; de Sanjose, Silvia; Camp, Nicola J.; Smedby, Karin E.; Shanafelt, Tait D.; Morton, Lindsay M.; Brewer, Jerry D.; Zablotska, Lydia; Engels, Eric A.; Cerhan, James R.; Slager, Susan L.; Han, Jiali; Berndt, Sonja I.; Medical and Molecular Genetics, School of Medicine
    Background: Epidemiological studies have demonstrated a positive association between chronic lymphocytic leukaemia (CLL) and non-melanoma skin cancer (NMSC). We hypothesized that shared genetic risk factors between CLL and NMSC could contribute to the association observed between these diseases. Methods: We examined the association between (i) established NMSC susceptibility loci and CLL risk in a meta-analysis including 3100 CLL cases and 7667 controls and (ii) established CLL loci and NMSC risk in a study of 4242 basal cell carcinoma (BCC) cases, 825 squamous cell carcinoma (SCC) cases and 12802 controls. Polygenic risk scores (PRS) for CLL, BCC and SCC were constructed using established loci. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Results: Higher CLL-PRS was associated with increased BCC risk (OR4th-quartile-vs-1st-quartile = 1.13, 95% CI: 1.02-1.24, Ptrend = 0.009), even after removing the shared 6p25.3 locus. No association was observed with BCC-PRS and CLL risk (Ptrend = 0.68). These findings support a contributory role for CLL in BCC risk, but not for BCC in CLL risk. Increased CLL risk was observed with higher SCC-PRS (OR4th-quartile-vs-1st-quartile = 1.22, 95% CI: 1.08-1.38, Ptrend = 1.36 × 10-5), which was driven by shared genetic susceptibility at the 6p25.3 locus. Conclusion: These findings highlight the role of pleiotropy regarding the pathogenesis of CLL and NMSC and shows that a single pleiotropic locus, 6p25.3, drives the observed association between genetic susceptibility to SCC and increased CLL risk. The study also provides evidence that genetic susceptibility for CLL increases BCC risk.
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    Epstein–Barr Virus MicroRNAs are Expressed in Patients with Chronic Lymphocytic Leukemia and Correlate with Overall Survival
    (ScienceDirect, 2015-06) Ferrajoli, Alessandra; Ivan, Cristina; Ciccone, Maria; Shimizu, Masayoshi; Kita, Yoshiaki; Ohtsuka, Masahisha; D'Abundo, Lucilla; Qiang, Jun; Lerner, Susan; Nouraee, Nazila; Rabe, Kari G.; Rassenti, Laura Z.; Van Roosbroeck, Katrien; Manning, John T.; Yuan, Yuan; Zhang, Xinna; Shanafelt, Tait D.; Wierda, William G.; Sabbioni, Silvia; Tarrand, Jeffrey J.; Estrov, Zeev; Radovich, Milan; Liang, Han; Negrini, Massimo; Kipps, Thomas J.; Kay, Neil E.; Keating, Michael; Calin, George A.; Department of Surgery, IU School of Medicine
    Although numerous studies highlighted the role of Epstein–Barr Virus (EBV) in B-cell transformation, the involvement of EBV proteins or genome in the development of the most frequent adult leukemia, chronic lymphocytic leukemia (CLL), has not yet been defined. We hypothesized that EBV microRNAs contribute to progression of CLL and demonstrated the presence of EBV miRNAs in B-cells, in paraffin-embedded bone marrow biopsies and in the plasma of patients with CLL by using three different methods (small RNA-sequencing, quantitative reverse transcription PCR [q-RT-PCR] and miRNAs in situ hybridization [miRNA-ISH]). We found that EBV miRNA BHRF1-1 expression levels were significantly higher in the plasma of patients with CLL compared with healthy individuals (p < 0 · 0001). Notably, BHRF1-1 as well as BART4 expression were detected in the plasma of either seronegative or seropositive (anti-EBNA-1 IgG and EBV DNA tested) patients; similarly, miRNA-ISH stained positive in bone marrow specimens while LMP1 and EBER immunohistochemistry failed to detect viral proteins and RNA. We also found that BHRF1-1 plasma expression levels were positively associated with elevated beta-2-microglobulin levels and advanced Rai stages and observed a correlation between higher BHRF1-1 expression levels and shorter survival in two independent patients' cohorts. Furthermore, in the majority of CLL cases where BHRF1-1 was exogenously induced in primary malignant B cells the levels of TP53 were reduced. Our findings suggest that EBV may have a role in the process of disease progression in CLL and that miRNA RT-PCR and miRNAs ISH could represent additional methods to detect EBV miRNAs in patients with CLL.