Analyses of liver cancer reveals unexpected genetic players - (Thursday, June 15, 2017)
Liver cancer has the second-highest worldwide cancer mortality, and yet there are limited therapeutic options to manage the disease. To learn more about the genetic causes of this cancer, and to identify potential new therapeutic targets for HCC, a nation-wide team of genomics researchers co-led by David Wheeler, Director of Cancer Genomics and Professor in the Human Genome Sequencing Center (HGSC) at Baylor College of Medicine, and Lewis Roberts, Professor of Medicine at the Mayo Clinic, analyzed 363 liver cancer cases from all over the world gathering genome mutations, epigenetic alteration through DNA methylation, RNA expression and protein expression. The research appears in Cell.
Part of the larger Cancer Genome Atlas project (TCGA), this work represents the first large scale, multi-platform analysis of HCC looking at numerous dimensions of the tumor. “There have been large-cohort studies in liver cancer in the past, but they have been limited mainly to one aspect of the tumor, genome mutation. By looking at a wide variety of the tumor’s molecular characteristics we get substantially deeper insights into the operation of the cancer cell at the molecular level,” Wheeler said.
The research team made a number of interesting associations, including uncovering a major role of the sonic hedgehog pathway. Through a combination of p53 mutation, DNA methylation and viral integrations, this pathway becomes aberrantly activated. The sonic hedgehog pathway, the role of which had not been full appreciated in liver cancer previously, is activated in nearly half of the samples analyzed in this study.
“We have a very active liver cancer community here at Baylor, so we had a great opportunity to work with them and benefit from their insights into liver cancer,” Wheeler said. Among the many critical functions of the liver, hepatocytes expend a lot of energy in the production of albumin and urea. It was fascinating to realize how the liver cancer cell shuts these functions off, to its own purpose of tumor growth and cell division.
“Intriguingly, we found that the urea cycle enzyme carbamyl phosphate synthase is downregulated by hypermethylation, while cytoplasmic carbamyl phosphate synthase II is upregulated,” said Karl-Dimiter Bissig, Assistant Professor of Molecular and Cellular Biology at Baylor and co-author of the study. “This might be explained by the anabolic needs of liver cancer, reprogramming glutamine pathways to favor pyrimidine production potentially facilitating DNA replication, which is beneficial to the cancer cell.”
“Albumin and apolipoprotein B are unexpected members on the list of genes mutated in liver cancer. Although neither has any obvious connection to cancer, both are at the top of the list of products that the liver secretes into the blood as part of its ordinary functions,” explained Dr. David Moore, professor of molecular and cellular biology at Baylor. “For the cancer cell, this secretion is a significant loss of raw materials, amino acids and lipids that could be used for growth. We proposed that mutation of these genes would give the cancer cells a growth advantage by preventing this expensive loss.”
Multiple data platforms coupled with clinical data allowed the researchers to correlate the molecular findings with clinical attributes of the tumor, leading to insights into the roles of its molecules and genes to help design new therapies and identify prognostic implications that have the potential to influence HCC clinical management and survivorship.
“This is outstanding research analyzing a cancer that’s increasing in frequency, especially in Texas. Notably, the observation of gene expression signatures that forecast patient outcome, which we validate in external cohorts, is a remarkable achievement of the study. The results have the potential to mark a turning point in the treatment of this cancer,” said Dr. Richard Gibbs, director of the HGSC at Baylor. The HGSC was also the DNA sequence production Center for the project.
Wheeler says they expect the data produced by this TCGA study to lead to new avenues for therapy in this difficult cancer for years to come. “There are inhibitors currently under development for the sonic hedgehog pathway, and our results suggest that those inhibitors, if they pass into phase one clinical trials, could be applied in liver cancer patients, since the pathway is frequently activated in these patients,” added Wheeler.
This work was supported by the National Institutes of Health and represents the last major cancer to be analyzed in the TCGA program. See a full list of contributors.
Fully sequenced deer genome made publicly available - (Friday, June 2, 2017)
Researchers at Baylor College of Medicine have played a leading role in sequencing the whole genome of the common white-tailed deer, which has recently been made public by the National Center for Biotechnology Information.
“We are hoping that by understanding the deer genome in greater detail, we will be able to better consider how to approach and treat bone-related illnesses and disease, such as osteoporosis,” said Dr. Brendan Lee, chair of the Department of Molecular and Human Genetics at Baylor. “For example, antler growth each season is an example of the fastest and largest regenerating organ in nature.”
The deer genome has the potential to provide insights into bone behavior, more specifically how deer are able to regenerate and repair bone after it is lost or damaged.
The sequencing of the deer genome was made possible through collaboration among the Center for Skeletal Medicine and Biology at Baylor, the Human Genome Sequencing Center at Baylor, the Rolanette and Berdon Lawrence Bone Disease Program of Texas, Berdon and Rolanette Lawrence, and the Caesar Kleberg Wild Life Research Institute. Prior to the publishing by the NCBI, the data was submitted to the National Institutes of Health.
Baylor's Human Genome Sequencing Center looks to bring adult whole genome sequencing to clinical space with unprecedented NHLBI grant - (Wednesday, March 1, 2017)
The National Heart Lung and Blood Institute’s (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program has named the Human Genome Sequencing Center (HGSC) at Baylor College of Medicine as a participant in a groundbreaking half-billion dollar program to bring whole genome sequencing and other –omic technologies that monitor the expression of the genome in response to the environment, to the forefront of clinical research.
Through its TOPMed program, NHLBI is expanding its dedication to advancing the understanding of the underpinnings of complex diseases and how they develop. Previously, the HGSC was awarded funding by NHLBI to sequence whole genomes for TOPMed studies such as sickle cell disease, and venous thromboembolism and will continue to expand this effort in the next phase of the program. The new contract will span five years. In addition to the whole genome sequencing component, the TOPMed program will also provide analysis of other datatypes over the course of the contract period, including RNA transcription sequencing, DNA methylation, metabolomics profiles, and other –omics, including analysis of the microbiome. The initial award from NHLBI supports the whole genome sequencing of 20,000 samples at the HGSC in the first year of the program.
“There is a significant need for large sample sizes; a need that goes beyond the research setting and into the clinic,” said Dr. Richard Gibbs, director of the HGSC and professor of molecular and human genetics at Baylor. “We are grateful to be a part of the TOPMed program which will allow us to access this large sample number and obtain valuable insights into adult heart disease, sickle cell disease, atrial fibrillation and other heart, lung and hematologic disorders.”
Bench to Bedside Podcast: Gene Sequencing Enables Rare Diagnosis in Twins - (Tuesday, February 28, 2017)
The Association of American Medical Colleges' "Bench to Bedside" podcast focuses on the story of Alexis and Noah Beery. For years a degenerative condition kept the twins from living a typical childhood. That changed when thanks to their mother's persistence and breakthrough genomic sequencing and analysis at the Baylor College of Medicine's Human Genome Sequencing Center, researchers were able to zero in on the genetic disorder and restore the siblings to healthy and active lives.
Fighting sickle cell disease using a type 2 diabetes medication - (Tuesday, January 10, 2017)
Researchers at Baylor College of Medicine and Texas Children’s Cancer and Hematology Centers have discovered a gene, FOXO3, involved in controlling fetal hemoglobin production and were able to target the gene and “turn on” fetal hemoglobin levels in patient samples in the lab using the diabetes drug metformin. This offers promising new treatments – the first new drug treatment for sickle cell disease in 30 years and the first ever for beta thalassemia.
Starting with 171 patient blood samples and later expanding to 400 more, Dr. Vivien Sheehan, assistant professor of pediatrics at Baylor and Texas Children’s Cancer and Hematology Centers, and her research colleagues were looking for genetic differences in sickle cell patients who make a lot of fetal hemoglobin versus those who do not. Collaborating with Baylor’s Human Genome Sequencing Center, they used whole exome sequencing and discovered that the FOXO3 gene seemed to control fetal hemoglobin. They found that patients with mutations in the FOXO3 gene made less fetal hemoglobin. Researchers proved this association in the lab by knocking out FOXO3 in human bone marrow cells, which resulted in less fetal hemoglobin, and then overexpressing the gene, which increased it.
With funding from Pfizer, a clinical trial has launched to further study the effectiveness of metformin in patients with sickle cell disease and beta thalassemia.
Newly discovered beetle genome helps to explain woodland destruction - (Friday, November 11, 2016)
The Asian longhorned beetle, or Anoplophora gladbripennis, is an invasive species impacting wooded areas across the globe. In a paper published in Genome Biology, researchers from Baylor College of Medicine and the University of Memphis detail new findings in the beetle’s genome that allow it to thrive on tree bark and other wooded plant material, causing widespread destruction in the process.
In order to understand how the beetle has evolved to be able to digest and receive nutrients from wooded plants and trees, the research team sequenced and annotated its genome, studied the degrading enzymes in the cell walls of plants and compared the genomes of 14 other types of insects with the ability to digest woody plant material.
“In this case, when we fed beetle larvae on wood material from sugar maple trees, we found that the activity of the glycoside hydrolase genes was increased, something not seen in larvae fed on an artificial diet,” said Dr. Stephen Richards, co-lead author on the paper and associate professor in the Human Genome Sequencing Center at Baylor. “This experiment, along with our complementary analysis of the beetle genome, also revealed the specific set of genes, called CYP450 genes, which are involved in the detoxification of compounds encountered by the beetle when feeding on plant tissues.”
Dr. Duane McKenna, co-lead author from the University of Memphis, added, "Our detailed genomic analysis reveals that the Asian longhorned beetle has more than 1,000 genes that aren’t present in any other arthropod. We identified a total of 86 genes for enzymes called glycoside hydrolases – more than have been found in any other insect. These enzymes enable the beetle to digest woody plant material and detoxify plant chemicals and indicate a genetic reason for their apparent success in feeding on trees worldwide.”
The study has allowed the researchers to establish a genomic basis for the evolutionary techniques and tools to manage the presence and damage of the Asian longhorned beetle and other wood-boring pests.
“This publically available genome is part of a larger group as a pilot for the i5K initiative to sequence thousands of insects. We hope that, in the long term, this foundational information about how any species works can be made available to anyone interested in biology, from researchers addressing specific questions to high school students and hobbyist entomologists at home,” Richards said.
International team discovers novel Alzheimer’s disease risk gene among Icelanders - (Thursday, October 20, 2016)
Scientists at Baylor College of Medicine and the Jan and Dan Duncan Neurological Research Institute (NRI) at Texas Children’s Hospital are part of a multicenter collaborative study that has identified a novel genetic risk factor for late-onset Alzheimer’s disease. The study appears in the journal PLoS Genetics.
Alzheimer’s disease is the most common cause of dementia among older adults, and the presence of certain genetic variants increases an individual’s risk for developing this disease.
Baylor researchers Dr. Shinya Yamamoto, assistant professor of molecular and human genetics; Dr. Joshua M. Shulman, assistant professor of neurology, neuroscience, and molecular and human genetics; Dr Eric Boerwinkle, associate director of the Human Genome Sequencing Center; and Dr. Hugo J. Bellen, professor and director of the program in developmental biology and also an investigator at the Howard Hughes Medical Institute, were part of an international team that analyzed samples from 1,393 subjects with late-onset Alzheimer’s disease and compared the results with those of 8,141 neurologically healthy individuals.
The consortium found a variant in TM2D3, a gene that has never been studied in human or other vertebrate species. Interestingly, while the probability of this variant was very rare among people of European ancestry, it was significantly enriched among Icelanders (but still less than 1 percent frequency). The researchers estimated that carriers of this variant would have an approximately six-fold increased risk of developing Alzheimer’s disease.
Mapping life took a turn through Houston - (Monday, October 3, 2016)
Dr. Richard Gibbs, director of Baylor College of Medicine's Human Genome Sequencing Center, talks with the Houston Chronicle about the legacy of the Human Genome Project (HGP). With the BCM-HGSC as one of the key sequencing centers, the HGP encouraged mass collaboration and openness in the science community, allowing research results to spur new genomic discoveries around the globe.
"The world, as we know, it doesn't change in predictable ways," Gibbs said in the interview with the Chronicle's Dug Begley. "It changes in these quantum leaps."
Baylor researchers receive grant to study canine cancer, test new therapies for translation to human cancers - (Thursday, September 29, 2016)
Researchers at Baylor College of Medicine have been awarded a $500,000 grant from the National Institutes of Health that will increase our understanding about the interactions between cancer and the immune system in dogs with naturally occurring tumors. The project will study dogs that have been diagnosed with cancer at the collaborating veterinary hospitals and apply that knowledge to the understanding of human cancer.
Dr. Jonathan Levitt, associate professor of pathology & immunology at Baylor leads the project, which involves a large group of investigators, including Drs. David Wheeler and Linghua Wang in the Human Genome Sequencing Center at Baylor.
The researchers will determine whether spontaneously arising canine organ-site tumors are sufficiently similar to those of humans to employ canine cancer as a model for trials of experimental combination therapies for human use. Another major goal of this study is to characterize the immune cells that infiltrate canine tumors and compare them with those in the respective human cancers.