I am a molecular oncologist with experience in chromatin control of transcription in cancer. I pioneered studies of the BET bromodomains proteins, a family comprised of BRD2 (originally named RING3), BRD3 and BRD4 in somatic cells, which are important as transcriptional co-regulators. I was the first to report a function for a BET protein, and to link these co-regulators to human cancer. The BET protein field has grown from sixteen papers, when I first published my work, to over 1,300 to date; they have since been implicated in several cancer types. Our recent data have established that BET bromodomain proteins provide a functional link between abnormal metabolism, inflammation and breast cancer progression in post-menopausal African American women. We are now realizing that BET proteins regulate cytokine/chemokine production in the immune cells that infiltrate the breast cancer microenvironment, which are important for immune exhaustion, chemoresistance and metastasis.
More detailed study of these pathways, in African American women in particular, is essential. Risks for breast cancer incidence and progression are not distributed evenly in the population, and are likely stratified by abnormal metabolism such as is found in Type 2 diabetes; yet, the current standard of care in breast oncology does not fully consider the role of diabetes and obesity-associated inflammation as drivers of progression and metastasis. African American women bear a disproportionate burden of poor-prognosis triple negative breast cancer, as well as higher prevalence of obesity, obesity-driven Type 2 diabetes and chronic inflammation, compared to white women. Deeper mechanistic and clinical studies must focus on these more vulnerable patients.
Molecular models and population studies also now suggest that metabolic disease and its associated imbalances in cytokines are more important for breast cancer initiation and progression than obesity per se. My intensive involvement over the last eight years with collaborators in population science, immunology, endocrinology and molecular oncology have prompted me to investigate a new area of high public health significance: breast cancer in non-obese women with metabolic disease and chronic inflammation. New thinking must consider drivers of metastasis, and the role the BET bromodomain proteins play in regulating metastasis potential. We hypothesize the BET proteins are equally important for breast cancer progression in lean women with metabolic disease and its associated chronic inflammation.
Recently, we have also explored the role of the BET bromodomain proteins in advanced prostate cancer, particularly in men with similar co-morbid conditions such as obesity and Type 2 diabetes. These inflammatory conditions also promote tumor progression in androgen-independent prostate cancer, eliciting greater cell migration and invasion, and raising the risk of metastasis. Advanced prostate cancer is a complex, heterogenous disease, with varying functional states of the androgen receptor and expression patterns across individual tumor cells. As the disease progresses, prostate tumor cells can become less reliant on androgen receptor signaling and use alternative signaling mechanisms to sustain growth and dissemination. Several of the pathways of progression are also relevant to triple negative breast cancer. Work in our lab is identifying ‘druggable’ BET protein targets to block prostate cancer progression in tumors that are either reliant on, or independent of, androgen receptor signaling. The research will benefit men with advancing prostate cancer, for whom initial therapeutic regimens have lost efficacy.
Diversity, Equity, Inclusion and Accessibility
Obesity and metabolic disease have high prevalence (>50%) in our Boston Medical Center population and are associated with worse outcomes, including early treatment failure and recurrence for breast cancer, prostate cancer and a number of other solid tumors associated with obesity. My work on Bromodomain and ExtraTerminal (BET) protein regulation of cancer progression in obesity has brought me into close contact with cancer disparities and health equity concerns.
Specifically, our knowledge base that informs and refines the medical oncology standard of care for these tumor types has generally been built on clinical trials with patients without metabolic comorbidities. We do not know if treatment decisions are properly justified for diverse patient populations where the prevalence of these comorbidities is high. Health equity concerns are at the core of basic research questions into why patients, such as African American women with triple negative breast cancer and co-morbid obesity-driven diabetes, are likely not receiving optimal treatment in the U.S. health care system. This theme is a central motivator for my work and has played a deepening role in the clinical translational experiments I am developing with Boston Medical Center collaborators.
Although I am a health disparities researcher and advocate for cancer disparities, one of my most meaningful public speaking engagements was in a church basement in Salem, MA on a snowy January evening. I presented histopathology slides of normal bone marrow and leukemic bone marrow to a lay audience of about 15 members of the local community. When audience members’ hands shot up to ask earnest questions, some with urgency to understand the clinical and biological implications of the histology, I realized the widespread hunger for compassionate expert opinion, reassurance, education and partnership with our cancer patients and their families. Questions of trust and doubt swirl around a cancer diagnosis, and I think that our mission as researchers, clinicians and public health advocates must be informed first by this fact.
The Boston neighborhoods that experienced high COVID19 mortality are the same neighborhoods where screening for lung, prostate and colorectal cancer are low, and closely overlap with food deserts, obesity and diabetes. It is no accident that these same streets were subject to historic red-lining, emphasizing the pervasive impact of structural racism on cancer outcomes, not only in Boston but in every region of the United States.
My work with underserved patients at Boston Medical Center have catalyzed my focus on the mechanisms behind race-based cancer disparities. The current models to understand risks for cancer incidence, progression, treatment failure and recurrence are not well designed to meet the needs of Black women with breast cancer or Black men with prostate cancer. For example, data reveal that Oncotype scores for Black women under-estimate risk for progression of ER+, node-negative breast cancer. In retrospect, this disappointment is unsurprising because the models are built on metabolically healthy white women and fail to account fully for metabolic and obesity co-morbidities that disproportionately affect Black women. Innovative modeling of the tumor microenvironment and analysis of BET protein mechanism that likely drives some of these differences will suggest new avenues for clinical trials for breast cancer progression. The impact of our approach will be to bring cardiometabolic variables to inform to clinical decision making in breast oncology.
Similarly, recent work is revealing that prostate cancer patients with obesity and diabetes have very different biology in the tumor microenvironment, compared to patients with the same prostate cancer stage and subtype, who are otherwise metabolically normal. Metabolic biomarkers do not yet inform prostate oncology practice and Black men (who bear a greater burden of obesity and diabetes than European American men) are uniquely underserved. Research, both basic and clinical-translational, at Boston Medical Center where our ~50% representation of Black men with prostate cancer is much higher than at neighboring hospitals in Boston or elsewhere in New England, is an ideal location for cancer disparities work to make a difference for needful patients.
Professor
Boston University School of Medicine
Pharmacology & Experimental Therapeutics
Co-Director
Boston University
BU-BMC Cancer Center
Member
Boston University
Evans Center for Interdisciplinary Biomedical Research
Full Member
Boston University Medical Center
Boston Nutrition Obesity Research Center
Member
Boston University
Family Medicine
Graduate Faculty (Primary Mentor of Grad Students)
Boston University School of Medicine, Graduate Medical Sciences
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Multiscale analysis of metabolic inflammation as a driver of breast cancer09/09/2020 - 08/31/2025 (Multi-PI)
PI:
Gerald V. Denis, PhDNIH/National Cancer Institute5U01CA243004-02
Mechanisms of BET bromodomain metabolic reprogramming in triple negative
breast cancer08/07/2018 - 07/31/2023 (PI)
NIH/National Cancer Institute5R01CA222170-04
Uncoupling Obesity from Breast Cancer in African American Women09/01/2016 - 08/31/2020 (Multi-PI)
PI:
Gerald V. Denis, PhDNIH/National Cancer Institute5U01CA182898-05
Uncoupling Obesity from Breast Cancer in African American Women09/24/2013 - 08/31/2016 (Multi-PI)
PI:
Gerald V. Denis, PhDNIH/National Cancer Institute5U01CA182898-03
Mechanisms of Brd2 Immunoprotection for Insulin Resistance09/30/2011 - 08/31/2013 (PI)
NIH/National Diabetes & Digestive & Kidney Diseases1R56DK090455-01A1
Mechanisms of Brd2 Immunoprotection for Insulin Resistance09/30/2011 - 08/31/2013 (PI)
NIH/National Diabetes & Digestive & Kidney Diseases1R56DK090455-01A1
Ultrasound-Directed Delivery of Cancer Chemotherapeutic Drugs01/01/2009 - 12/31/2009 (PI)
Massachusetts General Hospital DOD Army Med Resrch
Proteomic Biomarkers for Lymphoma06/01/2007 - 05/31/2009 (PI)
NIH/National Cancer Institute5 R03 CA128006 02
The Role of Brd2 in Energy Homeostasis04/01/2007 - 03/31/2009 (PI)
Massachusetts General Hospital Boston Diab Endo Res
Molecular Analysis of BRD2 Signaling and B Cell Function01/01/2005 - 12/31/2008 (PI)
American Cancer Society
Showing 10 of 12 results.
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Biomarkers for Lymphoma in a New Transgenic Mouse Model03/01/2004 - 02/28/2006 (PI)
NIH/National Cancer Institute5 R03 CA102889 02
A Novel, Inducible Nuclear Kinase Linked to Leukemia09/15/1997 - 09/29/2002 (PI)
NIH/National Cancer Institute5 R29 CA75107 05
Showing 10 of 35 results.
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Publications listed below are automatically derived from MEDLINE/PubMed and other
sources, which might result in incorrect or missing publications. Faculty can
login
to make corrections and additions.
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Sergesketter AR, Geng Y, Shammas RL, Denis GV, Bachelder R, Hollenbeck ST. The Association Between Metabolic Derangement and Wound Complications in Elective Plastic Surgery. J Surg Res. 2022 Oct; 278:39-48. PMID: 35588573; PMCID: PMC9329200; DOI: 10.1016/j.jss.2022.03.017;
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Alhousami T, Diny M, Ali F, Shin J, Kumar G, Kumar V, Campbell JD, Noonan V, Hanna GJ, Denis GV, Monti S, Kukuruzinska MA, Varelas X, Bais MV. Inhibition of LSD1 Attenuates Oral Cancer Development and Promotes Therapeutic Efficacy of Immune Checkpoint Blockade and YAP/TAZ Inhibition. Mol Cancer Res. 2022 May 04; 20(5):712-721.View Related Profiles. PMID: 35105672; PMCID: PMC9081163; DOI: 10.1158/1541-7786.MCR-21-0310;
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Mori JO, Shafran JS, Stojanova M, Katz MH, Gignac GA, Wisco JJ, Heaphy CM, Denis GV. Novel forms of prostate cancer chemoresistance to successful androgen deprivation therapy demand new approaches: Rationale for targeting BET proteins. Prostate. 2022 Jun; 82(10):1005-1015.View Related Profiles. PMID: 35403746
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Jafari N, Kolla M, Meshulam T, Shafran JS, Qiu Y, Casey AN, Pompa IR, Ennis CS, Mazzeo CS, Rabhi N, Farmer SR, Denis GV. Adipocyte-derived exosomes may promote breast cancer progression in type 2 diabetes. Sci Signal. 2021 11 23; 14(710):eabj2807.View Related Profiles. PMID: 34813359; PMCID: PMC8765301; DOI: 10.1126/scisignal.abj2807;
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Sebastiani P, Federico A, Morris M, Gurinovich A, Tanaka T, Chandler KB, Andersen SL, Denis G, Costello CE, Ferrucci L, Jennings L, Glass DJ, Monti S, Perls TT. Protein signatures of centenarians and their offspring suggest centenarians age slower than other humans. Aging Cell. 2021 02; 20(2):e13290.View Related Profiles. PMID: 33512769; PMCID: PMC7884029; DOI: 10.1111/acel.13290;
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Lombardi FL, Jafari N, Bertrand KA, Oshry LJ, Cassidy MR, Ko NY, Denis GV. Novel semi-automated algorithm for high-throughput quantification of adipocyte size in breast adipose tissue, with applications for breast cancer microenvironment. Adipocyte. 2020 12; 9(1):313-325.View Related Profiles. PMID: 32633194; PMCID: PMC7469507; DOI: 10.1080/21623945.2020.1787582;
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Shafran JS, Jafari N, Casey AN, Gyorffy B, Denis GV. BRD4 regulates key transcription factors that drive epithelial-mesenchymal transition in castration-resistant prostate cancer. Prostate Cancer Prostatic Dis. 2021 03; 24(1):268-277.View Related Profiles. PMID: 32690869; PMCID: PMC7855805; DOI: 10.1038/s41391-020-0246-y;
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Dean LT, Ransome Y, Frasso-Jaramillo L, Moss SL, Zhang Y, Ashing K, Denis GV, Frick KD, Visvanathan K, Schmitz KH. Drivers of cost differences between US breast cancer survivors with or without lymphedema. J Cancer Surviv. 2019 Oct; 13(5):804-814. PMID: 31446591; PMCID: PMC6828620; DOI: 10.1007/s11764-019-00799-1;
Showing 10 of 68 results.
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Shafran JS, Andrieu GP, Györffy B, Denis GV. BRD4 Regulates Metastatic Potential of Castration-Resistant Prostate Cancer through AHNAK. Mol Cancer Res. 2019 08; 17(8):1627-1638. PMID: 31110158; PMCID: PMC6677600; DOI: 10.1158/1541-7786.MCR-18-1279;
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Andrieu GP, Denis GV. BET Proteins Exhibit Transcriptional and Functional Opposition in the Epithelial-to-Mesenchymal Transition. Mol Cancer Res. 2018 04; 16(4):580-586. PMID: 29437854; PMCID: PMC5882530; DOI: 10.1158/1541-7786.MCR-17-0568;
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Denis GV, Sebastiani P, Andrieu G, Tran AH, Strissel KJ, Lombardi FL, Palmer JR. Relationships Among Obesity, Type 2 Diabetes, and Plasma Cytokines in African American Women. Obesity (Silver Spring). 2017 Nov; 25(11):1916-1920.View Related Profiles. PMID: 28840653; PMCID: PMC5669048; DOI: 10.1002/oby.21943;
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Strissel KJ, Nicholas DA, Castagne-Charlotin M, Ko N, Denis GV. Correction to "Barriers to Obtaining Sera and Tissue Specimens of African-American Women for the Advancement of Cancer Research". Clin Med Insights Womens Health. 2016; 9:35.View Related Profiles. PMID: 27695380; PMCID: PMC5022798; DOI: 10.4137/CMWH.S40655;
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Strissel KJ, Nicholas DA, Castagne-Charlotin M, Ko N, Denis GV. Barriers to Obtaining Sera and Tissue Specimens of African-American Women for the Advancement of Cancer Research. Clin Med Insights Womens Health. 2016; 9(Suppl 1):57-61.View Related Profiles. PMID: 27441007; PMCID: PMC4946585; DOI: 10.4137/CMWH.S34698;
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Berger SM, Gislason G, Moore LL, Andersson C, Torp-Pedersen C, Denis GV, Schmiegelow MD. Associations between metabolic disorders and risk of cancer in Danish men and women--a nationwide cohort study. BMC Cancer. 2016 Feb 22; 16:133.View Related Profiles. PMID: 26900131; PMCID: PMC4762170; DOI: 10.1186/s12885-016-2122-7;
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Bragdon B, Burns R, Baker AH, Belkina AC, Morgan EF, Denis GV, Gerstenfeld LC, Schlezinger JJ. Intrinsic Sex-Linked Variations in Osteogenic and Adipogenic Differentiation Potential of Bone Marrow Multipotent Stromal Cells. J Cell Physiol. 2015 Feb; 230(2):296-307.View Related Profiles. PMID: 24962433; PMCID: PMC4317374; DOI: 10.1002/jcp.24705;
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LeBrasseur NK, Huffman DM, Denis GV. Impact of Energy Balance on Cancer Disparities. In "Energy Balance and Cancer". D.J. Bowen, G. V. Denis, N. A. Berger, Eds. The biology of aging: Role in cancer, metabolic dysfunction and health disparities. Springer. New York. 2014; 91-118. View Publication
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Goodson JM, Kantarci A, Hartman ML, Denis GV, Stephens D, Hasturk H, Yaskell T, Vargas J, Wang X, Cugini M, Barake R, Alsmadi O, Al-Mutawa S, Ariga J, Soparkar P, Behbehani J, Behbehani K, Welty F. Metabolic disease risk in children by salivary biomarker analysis. PLoS One. 2014; 9(6):e98799. PMID: 24915044; PMCID: PMC4051609; DOI: 10.1371/journal.pone.0098799;
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Chung J, Karkhanis V, Tae S, Yan F, Smith P, Ayers LW, Agostinelli C, Pileri S, Denis GV, Baiocchi RA, Sif S. Protein arginine methyltransferase 5 (PRMT5) inhibition induces lymphoma cell death through reactivation of the retinoblastoma tumor suppressor pathway and polycomb repressor complex 2 (PRC2) silencing. J Biol Chem. 2013 Dec 6; 288(49):35534-47. PMID: 24189068; PMCID: PMC3853299; DOI: 10.1074/jbc.M113.510669;
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Gerald V. Denis, Deborah J. Bowen. Energy Balance and Cancer. A. J. Dannenberg, N. A. Berger, Eds. Uncoupling obesity from cancer: bromodomain co-regulators that control inflammatory networks. Springer. New York. 2013; 7:61-82. View Publication
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DeFuria J, Belkina AC, Jagannathan-Bogdan M, Snyder-Cappione J, Carr JD, Nersesova YR, Markham D, Strissel KJ, Watkins AA, Zhu M, Allen J, Bouchard J, Toraldo G, Jasuja R, Obin MS, McDonnell ME, Apovian C, Denis GV, Nikolajczyk BS. B cells promote inflammation in obesity and type 2 diabetes through regulation of T-cell function and an inflammatory cytokine profile. Proc Natl Acad Sci U S A. 2013 Mar 26; 110(13):5133-8.View Related Profiles. PMID: 23479618; PMCID: PMC3612635; DOI: 10.1073/pnas.1215840110;
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Banerjee C, Archin N, Michaels D, Belkina AC, Denis GV, Bradner J, Sebastiani P, Margolis DM, Montano M. BET bromodomain inhibition as a novel strategy for reactivation of HIV-1. J Leukoc Biol. 2012 Dec; 92(6):1147-54.View Related Profiles. PMID: 22802445; PMCID: PMC3501896; DOI: 10.1189/jlb.0312165;
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Denis GV. Bromodomain coactivators in cancer, obesity, type 2 diabetes, and inflammation. Discov Med. 2010 Dec; 10(55):489-99. PMID: 21189220; PMCID: PMC3025494
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Longe HO, Romesser PB, Rankin AM, Faller DV, Eller MS, Gilchrest BA, Denis GV. Telomere homolog oligonucleotides induce apoptosis in malignant but not in normal lymphoid cells: mechanism and therapeutic potential. Int J Cancer. 2009 Jan 15; 124(2):473-82.View Related Profiles. PMID: 19003960; PMCID: PMC2888476; DOI: 10.1002/ijc.23946;
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Denis GV. Imatinib Mesylate (Gleevec®) and the Emergence of Chemotherapeutic Drug-Resistant Mutations. 2008. View Publication
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You J, Srinivasan V, Denis GV, Harrington WJ, Ballestas ME, Kaye KM, Howley PM. Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen interacts with bromodomain protein Brd4 on host mitotic chromosomes. J Virol. 2006 Sep; 80(18):8909-19. PMID: 16940503; PMCID: PMC1563901; DOI: 10.1128/JVI.00502-06;
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Denis GV, McComb ME, Faller DV, Sinha A, Romesser PB, Costello CE. Identification of transcription complexes that contain the double bromodomain protein Brd2 and chromatin remodeling machines. J Proteome Res. 2006 Mar; 5(3):502-11.View Related Profiles. PMID: 16512664; PMCID: PMC2823066; DOI: 10.1021/pr050430u;
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Greenwald RJ, Tumang JR, Sinha A, Currier N, Cardiff RD, Rothstein TL, Faller DV, Denis GV. E mu-BRD2 transgenic mice develop B-cell lymphoma and leukemia. Blood. 2004 Feb 15; 103(4):1475-84.View Related Profiles. PMID: 14563639; PMCID: PMC2825482
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Denis GV, Yu Q, Ma P, Deeds L, Faller DV, Chen CY. Bcl-2, via its BH4 domain, blocks apoptotic signaling mediated by mitochondrial Ras. J Biol Chem. 2003 Feb 21; 278(8):5775-85.View Related Profiles. PMID: 12477721
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Peulen O, Denis G, Defresne MP, Dandrifosse G. Spermine-Induced alteration of small intestine in suckling rat: involvement of apoptosis or Zn2+ enzymes? Dig Dis Sci. 2001 Nov; 46(11):2490-8. PMID: 11713959
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Denis GV. Bromodomain motifs and "scaffolding"? Front Biosci. 2001 Sep 1; 6:D1065-8. PMID: 11532602; PMCID: PMC3042883
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Denis GV. Duality in bromodomain-containing protein complexes. Front Biosci. 2001 Aug 1; 6:D849-52. PMID: 11487463; PMCID: PMC3034383
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Verlaet M, Deregowski V, Denis G, Humblet C, Stalmans MT, Bours V, Castronovo V, Boniver J, Defresne MP. Genetic imbalances in preleukemic thymuses. Biochem Biophys Res Commun. 2001 Apr 27; 283(1):12-8. PMID: 11322760
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Guo N, Faller DV, Denis GV. Activation-induced nuclear translocation of RING3. J Cell Sci. 2000 Sep; 113 ( Pt 17):3085-91.View Related Profiles. PMID: 10934046
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Denis GV, Vaziri C, Guo N, Faller DV. RING3 kinase transactivates promoters of cell cycle regulatory genes through E2F. Cell Growth Differ. 2000 Aug; 11(8):417-24.View Related Profiles. PMID: 10965846
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Humblet C, Denis G, Greimers R, Boniver J, Defresne MP. Apoptosis during the development of radiogenic thymic lymphomas: effects of treatments inhibiting lymphoma development. Anticancer Res. 1998 Sep-Oct; 18(5A):3469-74. PMID: 9858926
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Ostrowski J, Florio SK, Denis GV, Suzuki H, Bomsztyk K. Stimulation of p85/RING3 kinase in multiple organs after systemic administration of mitogens into mice. Oncogene. 1998 Mar 5; 16(9):1223-7. PMID: 9528865
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Denis GV, Green MR. A novel, mitogen-activated nuclear kinase is related to a Drosophila developmental regulator. Genes Dev. 1996 Feb 1; 10(3):261-71. PMID: 8595877
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Tegge W, Denis GV, Ballou CE. Synthesis and Ca(2+)-release activity of D- and L-myo-inositol 2,4,5-trisphosphate and D- and L-chiro-inositol 1,3,4-trisphosphate. Carbohydr Res. 1991 Sep 18; 217:107-16. PMID: 1797394
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Denis GV, Ballou CE. The Ca2+ release activities of D-myo-inositol 1,4,5-trisphosphate analogs are quantized. Cell Calcium. 1991 Jun; 12(6):395-401. PMID: 1884394
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Denis GV, Toyoshima S, Osawa T. Concanavalin A- and calcium-dependent phosphorylation of a protein of 80 kDa in mouse lymphocytes rendered permeable to exogenously added [gamma-32P]ATP. Biochim Biophys Acta. 1986 Feb 21; 885(2):136-45. PMID: 3947677
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Goodman MS, Denis GV, Hall M, Karpovsky A, Wilson R. IEEE Transactions on Nuclear Science. Liquid argon as an electron/photon detector in the energy range of 50 MeV to 2 GeV :A Monte Carlo investigation. 1981; 28(1):524-527.
This graph shows the total number of publications by year, by first, middle/unknown,
or last author.
| Year | Publications |
|---|
| 1981 | 1 |
| 1986 | 1 |
| 1991 | 2 |
| 1996 | 1 |
| 1998 | 2 |
| 2000 | 2 |
| 2001 | 4 |
| 2002 | 1 |
| 2003 | 1 |
| 2005 | 1 |
| 2006 | 3 |
| 2008 | 1 |
| 2009 | 3 |
| 2010 | 3 |
| 2011 | 1 |
| 2012 | 4 |
| 2013 | 7 |
| 2014 | 4 |
| 2015 | 1 |
| 2016 | 8 |
| 2017 | 3 |
| 2018 | 3 |
| 2019 | 3 |
| 2020 | 2 |
| 2021 | 2 |
| 2022 | 4 |