Our studies are aimed at understanding the underlying genetic basis of pediatric cancers with the goal of applying genetic knowledge to cancer prevention and control.
The Genetic Epidemiology of Childhood Cancer
Focus 1: We are interested in defining predisposition factors unique to the Hispanic population in South Texas.
Focus 2: We are interested in identifying genetic factors that may contribute to adverse effects of ALL chemotherapy in Hispanic children.
We have enrolled over 160 patients with ALL from our South Texas facilities.
Genetics and Biology of Liver Tumorigenesis in Children
Hepatoblastoma (HB) is the most common liver tumor in children. Liver tumors in children differ from those in adults in that they are not related to cirrhosis, but rather are thought to develop from result of abnormal developmental molecular pathways. A major problem in treating children with HB is the development of drug resistance. We have identified a gene, NFE2L2, which when activated may cause tumors to be resistant.
Focus 1: Determine biologic factors which at the time of diagnosis can predict response to theraphy.
Focus 2: Determine if NFE2L2 can be specifically trageted to decrease proliferation of tumor cells.
GRACIAS TexasGenetic Risk Assessment and
Counseling in All South Texas
A grant from the Cancer Prevention and Research Institute of Texas has enabled us to provide genetic counseling services to multiple sites in South Texas including our regional campuses in Laredo and Harlingen. To date we have had direct interaction with cancer risk assessment to over 8500 individuals and provided formal genetic counseling services to 575 individuals, most of whom have undergone molecular genetic testing as part of our program.
Collaborative Program with UIW in Retinoblastoma Research
Four years ago we established a summer research program for optometry students at the Rosenberg School of Optometry, led by Dr. Patricia Sanchez-Diaz, former post-doctoral fellow at Greehey CCRI and now Assistant Professor at University of the Incarnate Word (UIW). Optometry students learn about the molecular basis of retinoblastoma, an eye tumor of very young children and infants.
Dr. Gail Tomlinson joined UT Health San Antonio in 2007 initially to lead the Division of Pediatric Hematology-Oncology and also served as Interim Director of the Greehey Children’s Cancer Research Institute from 2008-2014. She is currently Interim Chair of the Department of Pediatrics at UT Health.
Every child with cancer at our institution is invited to participate in our institutional research to investigate the causes of cancer to investigate the causes of childhood cancer as well to explore new avenues of therapy through the establishment of model systems.
We also participate in Children’s Oncology Group studies including therapeutic studies as well as the COG “Every Child” study for banking tissue nationally and Phase I studies through the POETIC consortium. Read more about clinical activities in our Division here.
At the Greehey CCRI, Dr. Tomlinson’s focuses on developing translational research studies aiming to bridge basic and clinical research.
A major focus of Dr. Tomlinson is pediatric liver tumors genetics and biology. Funded by a Multi-Investigator Award from the Cancer Prevention and Research Institute of Texas, a comprehensive genomic study of genetic changes in hepatoblastoma was conducted which led to the identification of several markers of poor prognosis in hepatoblastoma including expression of the master regulator of response to oxidative stress, NFE2L2. This was a collaborative project between investigators at GCCRI (Dr. Yidong Chen), Baylor College of Medicine (Dr. Lopez-Terrada and Dr. Milton Finegold) and UT Southwestern (Dr. Sarah Comerford and Dr. Robert Hammer).
Another focus of the lab is the identification of genetic risk markers in pediatric leukemia and other cancers including subtle genetic variants that affect cancer risks and outcomes.
The American Association of Cancer Research recently established a committee to provide a consensus based on evidence as well as expert opinion of the optimal methods of surveillance for cancer development in children with a genetic predisposition to cancer. Dr. Tomlinson was a contributor in this initiative and UT Health was listed as a site for cancer surveillance in high-risk children. Read more about the AACR initiative here and here.
A key part of working with cancer prone individuals and families is inclusion of genetic counseling to educate families about possible genetic cancer risks and to guide families through the genetic testing process where indicated.
Dr. Tomlinson’s research interests are in translational aspects of childhood cancer genetic predisposition. Currently divide her research focus approximately equally between the study of genetic etiologies of pediatric embryonal tumors, particularly the childhood liver tumor, hepatoblastoma, and population genetics of cancer predisposition.
Such interests in hepatoblastoma have focused in part on defining genetic polymorphisms, which contribute to cancer risk. Because hepatoblastoma histologically resembles fetal and embryonal liver elements, we are currently focusing on genes which are crucial to embryonic growth and development. We are also focusing on the characterization of a recurring breakpoint region on chromosome 1q12 using fine-tiling oligonucleotide array comparative genomic hybridization. We have recently identified a candidate gene, NOTCH2, involved in hepatic development which is affected by this translocation breakpoint. We are investigating the biologic role of NOTCH2 in hepatoblastoma and in addition we are in the process of determining this gene’s translocation partners on other chromosomes.
She is also embarking on a comprehensive study of genetic risk factors specific to the population of Texas which is largely made up of Hispanic children who may have specific and unique risk factors for cancer. We have identified several polymorphisms which may serve to increase cancer risk in this population and are currently planning to extend these studies to include a study of gene-environmental interactions.
Much of my current research involves the study of genetic and developmental origins of the childhood liver tumor, hepatoblastoma. This tumor type typically occurs between birth and four years of age and histologically resembles elements characteristic of the fetal and embryonal liver. I have lead a multi-institutional research (MIRA) initiative funded by the Cancer Prevention and Research Institute of Texas (CPRIT) to thoroughly explore the genomics of childhood liver tumors. This multi-site, multi-investigator program has in the past two years has
- identified activating mutation of the NFE2L2 gene as a recurring mutation and possible driver of tumorigenesis,
- extended the understanding of gene expression patterns in subsets of hepatoblastoma and
- developed the first mouse model of hepatoblastoma by manipulation of the wnt and NOTCH pathways.
We have also done a comparison study of genome wide copy number variations in hepatoblastoma in comparisons to hepatocellular carcinoma funded by an additional R21 grant. I am currently extending studies of the role of the recurring translocationa in involving chromosome 1q in hepatoblastoma, the role of NOTCH2, and the functional role of NFE2L2.
Hereditary breast cancer -
I have a long-standing research focus on hereditary breast cancer. At UTSW, I initiated a Familial Breast Cancer Registry of over 2000 breast cancer-prone families. This Registry formed the basis of participation in multiple multi-center studies in the genetic epidemiology of breast cancer, currently with an emphasis on genetic modifiers in breast cancer development in BRCA1/2 carriers and also on outcomes after BRCA1/2 testing. I have extended my interest in hereditary cancer by establishing a program for providing genetic risk assessment, counseling and testing at sites in South Texas, including San Antonio and the Rio Grande Valley along the Texas-Mexico border. This project has been supported by a Prevention grant from the Cancer Prevention and Research Institute of Texas. As our risk assessment efforts currently are targeted towards the underserved Hispanic population in South Texas, I am initiating a study of risks associated with a specific genetic alteration in Hispanic women.
Other Rare Pediatric Tumors -
Although I have focused primarily on hepatic tumorigenesis, we have extended our studies of biologic factors contributing to the unique age of onset of other pediatric tumors. These tumors of interest have included rhabdoid tumor of the kidney, a highly malignant tumor of infancy. I am also currently investigating the genomics of highly lethal tumors including mesothelioma. These occur more typically occur in adults, but occasionally occur in children. The primary goal of these studies is to identify primary driver events.
Population-specific aspects of childhood cancer -
We recently conducted a study of variations in the cytochrome P450 genes in children with acute lymphoblastic leukemia with emphasis on comparing genetic risk factors in Caucasian, Hispanic, and African-American children with acute leukemia. We found that Hispanic children with leukemia had a unique genetic profile of enzymes involved in xenobiotic metabolism. We have also studied the effects of germ line variation in other leukemia genes including MLL partner genes TOP2A, EP300, and CREBBP in Hispanic children with leukemia and have also identified germline variation in the leukemia-related gene LMO1 as a possible significant predisposition gene. I am currently working to expand this observation to study a larger population of Hispanic children in Texas as a multi-institutional project.
von Hippel-Lindau disease -
I recently completed an NIH-funded study involving von Hippel-Lindau disease. We compared serum levels of VEGF and VEGFR in mutation and non-mutation carriers. In the course of this study, my group established a von Hippel-Lindau Registry for which we collected and banked serum and DNA which will become the basis for continuing with a larger von Hippel-Lindau study.
Funding Agency Valley Baptist Legacy Foundation
Title Cancer Prevention Education In Cameron County ISD
Status Active Active
Role Principal Investigator
Grant Detail This project will provide educational sessions to teachers, parental involvement groups, and English as a Second Language students in the pubic school systems within Cameron County, Texas.
Funding Agency Cancer Prevention and Research Institute of Texas
Title Cancer Genetic Risk Assessment, Counseling and Screening of High-risk Individuals in Greater San Antonio and South Texas: Education and Implementation
Status Active Active
Role Principal Investigator
Grant Detail When determining ones risk of cancer, a family history of cancer can be a strong clue and health-care providers can often determine who is at high risk of cancer simply based on family history. For some individuals, a genetic test can determine if a person carries a genetic tendency to develop cancer. For those individuals at highest risk, many interventions have been tested and proven to decrease the risk of cancer or to detect cancer at an early stage. Using several different methods we will identify individuals at high-risk of cancer because of a family history. We will use a short questionnaire to identify individuals within the existing health care system who may be at risk of breast, colon, or other types of cancers. Those individuals who have a positive family history will be contacted by a specialist who will gather additional information to determine if a formal genetic evaluation is needed. For individuals at highest risk, we will recommend appropriate screening procedures which, depending on the type of risk, may include mammography, MRI scan, or colonoscopy. We will provide funds for those unable to pay for such screening tests. In South Texas there are few professional resources to work with families that may have an increased risk of cancer and need additional screening services. This project will fill this gap by providing specialists in the area of cancer genetic risk and counseling. In addition, this project will provide education to physicians-in-training as well as established clinicians, so that our medical community will collectively achieve a higher level of understanding of cancer risks and appropriate interventions to reduce risk. This program will service the greater San Antonio area at the UT Health San Antonio and will extend to Laredo and Harlingen, sites of our regional campus locations.