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The Feinstein Institute for Medical Research

Empowering Imagination. Pioneering Discovery.
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Annette T. Lee, PhD

Associate Investigator, The Feinstein Institute for Medical Research

Director, Laboratory of Translational Genetics

Associate Member, North Shore-LIJ Cancer Institute

Associate Professor & Associate Dean, Elmezzi Graduate School of Molecular Medicine

Assistant Professor, Department of Molecular Medicine, Hofstra North Shore-LIJ School of Medicine

Phone: (516) 562-1108
Email: anlee@nshs.edu

About the Investigator

Dr. Annette Lee graduated from Northeastern University and received her PhD from The Rockefeller University. She joined The Center for Genomics and Human Genetics as an Assistant Professor in 2001 and worked on the genetics of autoimmune diseases such as rheumatoid arthritis, lupus and inflammatory bowel disease. More recently as an associate investigator and director of the Laboratory of Translational Genetics, she has established her own area of research investigating the genetics of cancer – including chronic lymphocytic leukemia, breast and ovarian cancers.

Dr. Lee has directed the sample genotyping for several large autoimmune genome-wide association studies to identify risk genes for rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease (Crohn’s disease and ulcerative colitis), scleroderma, alopecia areata, IgA deficiency, myasthenia gravis and myositis. All of these studies have either resulted in publications in high profile journals or are in the process of being analyzed for manuscript submission. As a follow up to genome-wide studies, she has also supervised the selection and development of targeted genetic studies which range from a few variants to dense mapping of over 12,000 SNPs for several autoimmune diseases, Alzheimer’s, Parkinson’s, diabetic nephropathy and asthma. Several key genetic variants associated with human diseases have been identified as a direct result of these studies. More recently she has begun to study biomarkers of breast and ovarian cancers.

Dr. Lee has co-authored almost 100 peer-reviewed papers. Together with her collaborators throughout the NS-LIJ Health System, she has established a biobank of breast and ovarian tissue samples for research. Together with Dr Iuliana Shapira, Dr. Lee was honored at the Moms Who Kick 2012 Gala held at The Garden City Hotel for their research in breast cancer. Dr. Lee and Dr. Shapira were recently featured in the December 2012 televised series of Medical Updates.

Research Focus

The current research focus of The Laboratory of Translational Genetics is to discover and validate new biomarkers for early detection, prediction of disease course and outcome and treatment response in cancer, in particular breast and ovarian cancers. Each year thousands of women die from these types of cancer which may have been prevented if methods of early detection and more effective treatments were available.

Biomarkers of Breast and Ovarian Cancer

The team has been studying the presence and levels of biomarkers such as microRNAs (miRNAs) in diseases. MiRNAs are small (19-25nt), noncoding RNAs that regulate gene expression post-transcriptionally by binding in the 3’ untranslated region (3’UTR) of their specific messenger RNAs and interfering with translation. They are involved in normal cellular development, differentiation and proliferation. However, dysregulation of miRNA expression can have a causal role in malignancies. The presence and expression levels of specific tissue miRNAs have been associated with different types of cancer and clinical outcome. MiRNAs are remarkably stable and are well preserved in formalin fixed, paraffin embedded tissue samples and have been detected in plasma and serum samples, making them ideal candidates for non-invasive biomarkers of disease.

Ovarian Cancer

In 2012, over 20,000 new cases of ovarian cancer will be diagnosed and over 15,000 women will die of the disease. It is the 5th leading cause of cancer deaths in women. Only 1 in 5 women are diagnosed with early stage ovarian cancer when 5 year survival rates greater than 90% can be achieved. The majority of ovarian cancer cases are not diagnosed until it has spread to other organs at which time 5 year survival is less than 30%. Currently, ovarian cancer can only be diagnosed through invasive surgery to remove the ovaries. Less than 1 in 15 surgeries identifies cancerous ovarian tumors; the remaining surgeries remove benign ovarian cysts.

In a pilot study of 60 women with confirmed ovarian cancer, they identified 15 miRNAs that had different levels in blood compared to women without ovarian cancer. The availability of a blood test to specifically and accurately detect ovarian cancer would provide a noninvasive method for early detection and give women the opportunity to have treatment when it’s the most effective and the cancer is potentially curable. Currently no blood test to detect early stage ovarian cancer exists. In addition, this type of blood test would avoid unnecessary risks and complications associated with surgeries to remove benign cysts that were suspected of being cancerous.

The contributions of this research extend far beyond ovarian cancer detection alone. There are two main directions of current research 1) Circulating ovarian cancer specific miRNAs are most likely present at lower levels before a solid tumor mass is formed. These biomarkers may identify women who are at high risk of developing ovarian cancer. 2) Since the main role of miRNA is to regulate normal cellular functions, by identifying which miRNAs are being expressed inappropriately, the team will know which cellular pathways are affected by ovarian cancer. This type of information is important for developing new therapies aimed at prevention and curative approaches.

The mortality rates due to ovarian cancer have largely remained unchanged since “the war on cancer” was initiated more than 40 years ago. Although more advanced chemotherapy treatments are available, they are most effective when used during the optimal treatment period of early stage disease, before the cancer has metastasized to other parts of the body. Currently only 20% of ovarian cancers are detected in the early stage, while 80% go undetected and progress to advanced stage disease. By identifying circulating blood biomarkers that accurately detect the presence of early ovarian cancer, more women will have the opportunity for treatment when the curable rate can potentially approach 100%.

Breast Cancer

The American Cancer Society estimates there will be 226, 870 new cases of breast cancer diagnosed in 2012 and 39,510 women will die of the disease in the US.It is the leading cause of death in American women between the ages of 30 and 50. Breast cancer accounts for over 15% of all cancer related deaths in the US.

To explore novel biomarkers in women with breast cancer, the lab generated comprehensive circulating miRNA profiles on women with breast cancer before and after surgery and compared the miRNA expression values to those found in plasma from cancer free women. They found significant differences in expression profiles between the 3 groups in our pilot dataset. They also compared the expression of miRNAs in pre- and post-operative plasma samples with miRNA levels in corresponding tissue sample women with stage I invasive ductal carcinoma. Although the results are very preliminary, they do support the hypothesis that expression levels of specific circulating miRNAs are correlated to their presence in the tumor itself.

In another ongoing research project, the lab compared the circulating miRNA profile of pre-surgical plasma in Caucasian and African American women with either ER/PR positive breast cancer or triple negative breast cancer (TNBC). Several microRNAs (miRNAs) have been associated with TNBC; however, it was unknown if miRNAs contribute to the observed disparity in TNBC progression and survival outcome between African American (AA) and Caucasian American (CA) women in the US. Our preliminary data show circulating miRNA profiles of AA and CA women with TNBC have 46 miRNAs that are differentially expressed. This suggests that although TNBC may appear clinopathologically the same in these two populations, their underlying molecular profile is not. By determining miRNA expression profiles and their respective target genes that are unique to AA or CA TNBC, we will be able to identify specific genes/pathways to explain the lower overall survival of AA women with TNBC compared to their CA counterparts and modify current treatment protocols accordingly.

Microbiome profiling

In collaboration with the department of Perinatal Medicine, Dr. Lee’s lab has been profiling the microbiome of pre-term infants to understand and predict the development of necrotizing enterocolitis.

In 2007, more than 35,000 infants were diagnosed with necrotizing enterocolitis (NEC). It is one of the leading causes of morbidity and mortality in preterm infants (<32 weeks, <1,500 grams), approximately 20-30% infants who develop NEC do not survive. There are no known causes, nor are there known cures. Those that do survive often have serious neurodevelopmental consequences (cerebral palsy, cognitive, visual and/or hearing impairments). The most immediate problem to address is the absence of reliable criteria for early diagnosis of an asymptomatic infant. Once symptomatic, the disease can rapidly progress and within hours the infant may require intensive medical and/or surgical intervention.

The goal of this research collaboration is to identify meaningful changes in microbiome profiles of preterm neonates in the NICU. Contradictory studies support and refute the role of bacterial colonization in the susceptibility and development of NEC both in terms of bacterial diversity and abundance. It is estimated that 80% of the gut microbiota cannot be detected by conventional culture methods. With the development of targeted next generation sequencing, they are able to sequence the variable regions of the bacterial 16S rRNA gene circumventing the need for bacterial cultures. By sequencing the variable region alone, they obtain enough data to accurately create genus level microbiome profiles.

Developing comprehensive microbiome profiles on preterm infants who develop necrotizing enterocolitis will provide invaluable data towards identifying and understanding the critical factors needed for prevention and early diagnosis. These results may lay the groundwork for the implementation of specific probiotic supplements as treatment for this potentially life threatening condition.

Lab Members

Lee_Lab-300wAnthony Liew
Email: aliew@nshs.edu

Houman Khalili
Email: hkhalili@nshs.edu

Cassandra Pond
Email: cpond@nshs.edu

Michael Ryan
Email: mryan@nshs.edu

Nicolas Broccoli
Email: nbroccoli@nshs.edu

Education

Northeastern University
Degree: BS
1984
Field of Study: Biology

The Rockefeller University
Degree: PhD
1989
Field of Study: Biochemistry

Publications
  1. Campagne F, Lambert JC, Dreses-Werringloer U, Vingtdeux V, Lendon C, Campion D, Amouyel P, Lee AT, Gregersen PK, Davies P, Marambaud P. “CALHM1 Association with Alzheimer’s Disease Risk.” Cell 2008 Dec 12; 135(6):994-6
  2. Gregersen PK, Amos CI, Lee AT, Lu Y, Remmers EF, Kastner DL, Seldin MF, Criswell LA, Plenge RM, Holers VM, Mikuls TR, Sokka T, Moreland LW, Bridges SL Jr, Xie G, Begovich AB, Siminovitch KA. “REL, encoding a member of the NF-kappaB family of transcription factors, is a newly defined risk locus for rheumatoid arthritis.” Nat Genet. 2009 Jul;41(7):820-3. Epub 2009 Jun 7. PMID: 19503088
  3. Surolia I, Pirnie SP, Chellappa V, Taylor KN, Cariappa A, Moya J, Liu H, Bell DW, Driscoll DR, Diederichs S, Haider K, Netravali I, Le S, Elia R, Dow E, Lee A, Freudenberg J, De Jager PL, Chretien Y, Varki A, Macdonald ME, Gillis T, Behrens TW, Bloch D, Collier D, Korzenik J, Podolsky DK, Hafler D, Murali M, Sands B, Stone JH, Gregersen PK, Pillai S. “Functionally defective germline variants of sialic acid acetylesterase in autoimmunity.” Nature. 2010 Jul 8;466(7303):243-7.Epub 2010 Jun 16. PubMed PMID: 20555325; PubMed Central PMCID: PMC2900412.
  4. Petukhova L, Duvic M, Hordinsky M, Norris D, Prices V, Shimomura Y, Kim H, Singh P, Lee A, Chen WV, Meyers KC, Paus R, Jahodo C, Amos, CI, Gregersen PK and Christiano AM. “Genome-wide association study in alopecia areata implicates both innate and adaptive immunity, Nature.” 2010 Jul 1;466(7302):113-7.PMID: 20596022
  5. Bagnara D, Kaufman MS, Calissano C, Marsilio S, Patten PE, Simone R, Chum P, Yan XJ, Allen SL, Kolitz JE, Baskar S, Rader C, Mellstedt H, Rabbani H, Lee A, Gregersen PK, Rai KR, Chiorazzi N. “A novel adoptive transfer model of chronic lymphocytic leukemia suggests a key role for T lymphocytes in the disease.” Blood. 2011 May 19;117(20):5463-72. Epub 2011 Mar 8. PubMed PMID: 21385850; PubMed Central PMCID: PMC3109718.
  6. Song JJ, Hwang I, Cho KH, Garcia MA, Kim AJ, Wang TH, Lindstrom TM, Lee AT, Nishimura T, Zhao L, Morser J, Nesheim M, Goodman SB, Lee DM, Bridges SL Jr; Consortium for the Longitudinal Evaluation of African Americans with Early Rheumatoid Arthritis (CLEAR) Registry, Gregersen PK, Leung LL, Robinson WH. P”lasma carboxypeptidase B downregulates inflammatory responses in autoimmune arthritis.” J Clin Invest. 2011 Sep;121(9):3517-27. doi: 10.1172/JCI46387. Epub 2011 Aug 1. PubMed PMID: 21804193; PubMed Central PMCID: PMC3163960.
  7. Malhotra AK, Correll CU, Chowdhury NI, Müller DJ, Gregersen PK, Lee AT, Tiwari AK, Kane JM, Fleischhacker WW, Kahn RS, Ophoff RA, Lieberman JA, Meltzer HY, Lencz T, Kennedy JL. “Association Between Common Variants Near the Melanocortin 4 Receptor Gene and Severe Antipsychotic Drug-Induced Weight Gain.” Arch Gen Psychiatry. 2012 May 7. [Epub ahead of print] PubMed PMID: 22566560.
  8. Simpfendorfer KR, Olsson LM, Manjarrez Orduño N, Khalili H, Simeone AM, Katz MS, Lee AT, Diamond B, Gregersen PK. “The autoimmunity-associated BLK haplotype exhibits cis-regulatory effects on mRNA and protein expression that are prominently observed in B cells early in development.” Hum Mol Genet. 2012 Sep 1;21(17):3918-25. Epub 2012 Jun 7. PubMed PMID: 22678060; PubMed Central PMCID:PMC3412385.
  9. Eyre S, Bowes J, Diogo D, Lee A, Barton A, Martin P, Zhernakova A, Stahl E, Viatte S, McAllister K, Amos CI, Padyukov L, Toes RE, Huizinga TW, Wijmenga C,Trynka G, Franke L, Westra HJ, Alfredsson L, Hu X, Sandor C, de Bakker PI, DavilaS, Khor CC, Heng KK, Andrews R, Edkins S, Hunt SE, Langford C, Symmons D;Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate; WellcomeTrust Case Control Consortium, Concannon P, Onengut-Gumuscu S, Rich SS, Deloukas P, Gonzalez-Gay MA, Rodriguez-Rodriguez L, Arlsetig L, Martin J, Rantapää-Dahlqvist S, Plenge RM, Raychaudhuri S, Klareskog L, Gregersen PK, Worthington J. “High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis.” Nat Genet. 2012 Nov 11;44(12):1336-40. doi: 10.1038/ng.2462. Epub 2012 Nov 11. PubMed PMID: 23143596.
  10. Manjarrez-Orduño N, Marasco E, Chung SA, Katz MS, Kiridly JF, Simpfendorfer KR, Freudenberg J, Ballard DH, Nashi E, Hopkins TJ, Cunninghame Graham DS, Lee AT, Coenen MJ, Franke B, Swinkels DW, Graham RR, Kimberly RP, Gaffney PM, Vyse TJ, Behrens TW, Criswell LA, Diamond B, Gregersen PK. “CSK regulatory polymorphism is associated with systemic lupus erythematosus and influences B-cell signaling and activation.” Nat Genet. 2012 Nov;44(11):1227-30. doi: 10.1038/ng.2439. Epub 2012 Oct 7. PubMed PMID: 23042117.

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