This proposal describes a 5-year plan for the development of an academic career in epigenetics, mouse and human cell-based modeling of disease, and cancer biology. This training period will complement my training in molecular and clinical genetics. Dr. Marisa Bartolomei, a renowned expert in epigenetics and mouse models, and Dr. Garrett Brodeur, an international authority in cancer biology, will mentor my scientific and career development. To facilitate my scientific development, I have assembled an advisory committee including an eminent human geneticist and two prominent cancer biologists. My research focuses on tumor formation in Beckwith-Wiedemann syndrome (BWS). BWS is an overgrowth and tumor predisposition disorder that affects at least 1 in 13,700 children. Many of these children develop cancer, most commonly hepatoblastomas and Wilms tumors. BWS is part of a spectrum of clinical disease ranging from classic features of generalized overgrowth to subtle isolated overgrowth of a single limb or organ. My previous work demonstrated that even patients with subtle BWS features develop tumors. BWS is caused by genetic and/or epigenetic changes on chromosome 11. Similar changes occur in a number of cancers including breast and colon cancer. Studying BWS presents a unique opportunity to study a rare disorder in order to provide insight into common tumor formation pathways. In this proposal, we will use our BWS patient cohort of over 250 patients to identify subtle clinical features predictive of increased tumor risk. Using fibroblast samples collected from these patients, we are developing the first human cell-based models of BWS using induced pluripotent stem cells (iPSCs). The iPSCs will be differentiated into the cell lineages in which tumors develop (e.g. hepatocytes) and global molecular profiling will be performed to identify pathways involved in tumorigenesis. Finally, we have designed a novel mouse model to specifically look at the independent role of two of the genes on chromosome 11 (H19 and miR675) in growth and tumor formation. The completion of the proposed studies will improve tumor risk assessment in BWS patients and define the pathways leading to tumor formation in these patients. This work is a necessary first step towards improving the care of children with BWS by identifying new potential tumor screening modalities and therapeutic targets. Additionally, this patient cohort and these models will provide an invaluable resource for my career endeavors.

Public Health Relevance

A significant number of children with Beckwith-Wiedemann syndrome (BWS) develop cancer and the genetic changes that lead to these cancers are not well understood. The goal of this research is to improve the care for patients with BWS and understand why some children develop cancer. To accomplish this, we will study our large cohort of BWS patients to identify features linked to increased cancer risk and investigate how the genetic changes in BWS lead to cancer using novel cell and mouse models.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08CA193915-01
Application #
8866928
Study Section
Subcommittee I - Transistion to Independence (NCI)
Program Officer
Lim, Susan E
Project Start
2015-08-01
Project End
2020-07-31
Budget Start
2015-08-01
Budget End
2016-07-31
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
MacFarland, Suzanne P; Duffy, Kelly A; Bhatti, Tricia R et al. (2018) Diagnosis of Beckwith-Wiedemann syndrome in children presenting with Wilms tumor. Pediatr Blood Cancer 65:e27296
Brioude, Frédéric; Kalish, Jennifer M; Mussa, Alessandro et al. (2018) Expert consensus document: Clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement. Nat Rev Endocrinol 14:229-249
Duffy, Kelly A; Grand, Katheryn L; Zelley, Kristin et al. (2018) Tumor Screening in Beckwith-Wiedemann Syndrome: Parental Perspectives. J Genet Couns 27:844-853
Cielo, Christopher M; Duffy, Kelly A; Vyas, Aesha et al. (2018) Obstructive sleep apnoea and the role of tongue reduction surgery in children with Beckwith-Wiedemann syndrome. Paediatr Respir Rev 25:58-63
Davlin, Alisha S; Clarkin, Catherine M; Kalish, Jennifer M (2018) Beckwith-Wiedemann Syndrome: Partnership in the Diagnostic Journey of a Rare Disorder. Pediatrics 141:
Duffy, Kelly A; Deardorff, Matthew A; Kalish, Jennifer M (2017) The utility of alpha-fetoprotein screening in Beckwith-Wiedemann syndrome. Am J Med Genet A 173:581-584
Kalish, Jennifer M; Doros, Leslie; Helman, Lee J et al. (2017) Surveillance Recommendations for Children with Overgrowth Syndromes and Predisposition to Wilms Tumors and Hepatoblastoma. Clin Cancer Res 23:e115-e122
Tong, Carmen C; Duffy, Kelly A; Chu, David I et al. (2017) Urological Findings in Beckwith-Wiedemann Syndrome With Chromosomal Duplications of 11p15.5: Evaluation and Management. Urology 100:224-227
MacFarland, Suzanne P; Mostoufi-Moab, Sogol; Zelley, Kristin et al. (2017) Management of adrenal masses in patients with Beckwith-Wiedemann syndrome. Pediatr Blood Cancer 64:
Kalish, Jennifer M; Biesecker, Leslie G; Brioude, Frederic et al. (2017) Nomenclature and definition in asymmetric regional body overgrowth. Am J Med Genet A :

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