Researchers impact final round in The Cancer Genome Atlas - (Friday, April 6, 2018)
When The Cancer Genome Atlas (TCGA) was initiated in 2006, it brought together broad and talented research teams from around the country. By the time it ended in 2017, it had involved faculty from numerous departments across Baylor College of Medicine, the Dan L Duncan Comprehensive Cancer Center and the Human Genome Sequencing Center.
This week, a collection of 27 papers is being published reporting on the integrated project to analyze all 33 cancer types and to classify mutations and specific pathways. The release of 29 papers, many of them with significant contributions from Baylor researchers, and findings from the 11,000 patient cohort data appear in the current editions of Cell publications. The project has produced game changers for translational research and clinical trials.
The things we learn from the TCGA have the potential to impact clinical practice, drug development and the way we diagnose and treat a wide range of cancers
“The TCGA project allowed us to apply team science to biology, and the things we learn from the TCGA have the potential to impact clinical practice, drug development and the way we diagnose and treat a wide range of cancers,” said Dr. David Wheeler, professor of molecular and human genetics in the Human Genome Sequencing Center at Baylor.
The papers are grouped into three key themes that explore Cancer Pathways, Cell of Origin and Oncogenic Processes. Wheeler co-organized and co-led the Oncogenic Processes theme.
Primate genomics study reveals clues into AIDS resistance - (Wednesday, January 3, 2018)
Simian immunodeficiency virus (SIV) infection in macaques behaves in a similar way as infection by human immunodeficiency virus (HIV) in humans, progressing into acquired immunodeficiency syndrome (AIDS) over time. However, in sooty mangabeys, a primate species native to West Africa, SIV infection is non-pathogenic. Researchers from an international group of institutions, organized and led by Baylor College of Medicine and Emory University, set out to sequence and analyze the genomes of two nonhuman primates to investigate the mechanisms that drive disease progression, and thus to develop new insights into the behavior of the HIV virus in humans. The research appears in Nature.
“Primates are natural hosts for certain diseases, and sooty mangabeys in particular are natural hosts for SIV, meaning they can be naturally infected with the virus and sustain long-term infection without ever progressing to disease. However, macaques rapidly progress into AIDS-like disease and succumb to SIV when infected,” said Dr. Jeffrey Rogers, associate professor in the Human Genome Sequencing Center (HGSC) and Department of Molecular and Human Genetics at Baylor.
Researchers at the Yerkes National Primate Research Center, Emory University, led by Dr. Guido Silvestri, shared sooty mangabey samples with Rogers and his team at the HGSC to be sequenced and assembled. Once sequenced, the mangabey genome results were sent back to Emory for analysis, including direct comparison with the rhesus macaque and human genomes.
Rare Whole Genome Duplication Gave Rise To Arizona Bark Scorpion - (Wednesday, August 23, 2017)
Dr. Kim Worley of the Baylor College of Medicine Human Genome Sequencing Center spoke with science journalist Nicholas Gerbis of KJZZ in Phoenix about the genome study of the common house spider and the Arizona bark scorpion appearing in BMC Biology.
Analysis of these genomes indicates that spiders and scorpions share an ancestor that made new copies of all the genes in its genome over 400 million years ago. This process, known as whole genome duplication, is one of the largest evolutionary changes that can happen to a genome and is relatively rare during animal evolution.
"One copy can continue to provide the functions that it was used for originally," remarked Worley, "and the new copy is not constrained to provide those functions because the original copy's already providing it."
Researchers sequence megapest genome, aim to stop spread - (Tuesday, August 8, 2017)
The Human Genome Sequencing Center at Baylor College of Medicine, in collaboration with the Australian Commonwealth Scientific and Industrial Research Organisation (CSIRO) and an international team of renowned researchers, has sequenced the genomes of the world’s most destructive caterpillar pests of broad-acre crops. The research appears in BCM Biology.
Helicoverpa armigera and Helicoverpa zea, commonly known as the Cotton Bollworm and Corn Earworm, respectively, cause in excess of $5 billion in control costs and damage each year across Asia, Europe, Africa, the Americas and Australia. The old-world bollworm, which is dominant in Australia, attacks more crops and develops much more resistance to pesticides than its new-world earworm counterpart.
“The bollworm is the single most important pest of agriculture in the world, making it humanity’s greatest competitor for food and fiber," said CSIRO scientist Dr. John Oakeshott. "Its genomic arsenal has allowed it to outgun all our known insecticides through the development of resistance, reflecting its name armigera, which means armed and warlike.’
In Brazil, the recently arrived bollworm H. armigera has been spreading rapidly, and cases of it hybridizing with the earworm have been found, posing a real threat that this new “superbug” could spread into the United States.
Because they are good fliers, populations of the old-world bollworm range across Europe to China and as far as Australia, with the oceans separating them from the new-world Corn Earworm known in the Americas.
“There has been good control of the Cotton Bollworm with Bt Cotton, a plant that expresses a toxic bacterial insecticide, which enabled far less use of chemical pesticides. But the species is adept at overcoming both plant resistance and pesticides as evidenced by the many genes encoding detoxifying enzymes found in its genome – a major reason for its megapest status,” said Dr. Stephen Richards, assistant professor in the Human Genome Sequencing Center at Baylor.
Identifying pest origins will enable resistance profiling that reflects countries of origin when developing a resistance management strategy, while identifying incursion pathways will improve biosecurity protocols and risk analysis at biosecurity hotspots, including national ports. These genome sequences also allow the application of new genetic tools such as RNA interference and CRISPR to be used in an attempt to control these pests.
Grant to compare large-scale genomic sequencing, standard clinical tests for childhood cancer patients - (Tuesday, August 8, 2017)
Baylor College of Medicine is one of six U.S. institutions to receive a grant through the National Human Genome Research Institute’s Clinical Sequencing Evidence-Generating Research Consortium, or CSER2. The four-year grant, including $2.8 million for fiscal year 2017, co-funded by the National Cancer Institute, will support Baylor’s new KidsCanSeq program that will compare the results of large-scale genomic testing, such as whole exome sequencing, to targeted clinical tests in childhood cancer patients at five sites across the state that serve a highly diverse patient population, including Texas Children’s Cancer Center.
This study includes a comprehensive set of genomic tests that will be performed by a unique collaboration between multiple diagnostic facilities with the involvement of Dr. Richard Gibbs, director of the Human Genome Sequencing Center, Drs. Christine Eng and Shashikant Kulkarni, professors of molecular and human genetics, all of Baylor, and Dr. Angshumoy Roy, assistant professor of pathology & immunology at Baylor and Texas Children’s Hospital.
KidsCanSeq follows the Baylor Advancing Sequencing in Childhood Cancer Care (BASIC3) study at Baylor and Texas Children’s Cancer Center, which developed the initial protocols for performing clinical genomic testing of pediatric cancer patients, reporting results and communicating those results to families and oncologists. BASIC3 was part of the NHGRI Clinical Sequencing Exploratory Research program, a precursor to CSER2.
Genome sequencing shows spiders, scorpions share ancestor - (Monday, July 31, 2017)
In collaboration with scientists from the U.K., Europe, Japan and the United States, researchers at the Human Genome Sequencing Center at Baylor College of Medicine have discovered a whole genome duplication during the evolution of spiders and scorpions. The study appears in BMC Biology.
Researchers have long been studying spiders and scorpions for both applied reasons, such as studying venom components for pharmaceuticals and silks for materials science, and for basic questions such as the reasons for the evolution and to understand the development and ecological success of this diverse group of carnivorous organisms.
As part of a pilot project for the i5K, a project to study the genomes of 5,000 arthropod species, the Human Genome Sequencing Center analyzed the genome of the house spider Parasteatoda tepidariorum – a model species studied in laboratories – and the Arizona bark scorpion Centruroides sculpturatus, – the most venomous scorpion in North America.
Analysis of these genomes revealed that spiders and scorpions evolved from a shared ancestor more than 400 million years ago, which made new copies of all of the genes in its genome, a process called whole genome duplication. Such an event is one of the largest evolutionary changes that can happen to a genome and is relatively rare during animal evolution.
Dr. Stephen Richards, associate professor in the Human Genome Sequencing Center, who led the genome sequencing at Baylor, said, “It is tremendously exciting to see rapid progress in our molecular understanding of a species that we coexist with on planet earth. Spider genome analysis is particularly tricky, and we believe this is one of the highest quality spider genomes to date.”
“Many people fear spiders and scorpions, but this research shows what a beautiful part of the evolutionary tree they represent,” said Dr. Richard Gibbs, director of the Human Genome Sequencing Center and the Wofford Cain Chair and professor of molecular and human genetics at Baylor.
“Costs have now dropped rapidly enough from tens of millions of dollars to merely a few thousand dollars for this genomic analyses to now be performed on any species,” Richards said. “There is still so much more to learn about the life on earth around us, and I believe this result is just the beginning of understanding the molecular make up of spiders.”
For a full list of contributors and funding sources, click here.
Cancer Researchers Report Progress in Studying Exceptional Responders - (Thursday, July 6, 2017)
Researchers who study exceptional responders—patients who have dramatic and long-lasting responses to treatments for cancer that were not effective for most similar patients—met recently to exchange ideas and discuss the state of the science in this emerging field.
The NCI-sponsored meeting, held May 11 at NCI’s Shady Grove campus in Rockville, Maryland, featured updates on the Exceptional Responders Initiative, a pilot study that aims to gain insights into the biological mechanisms that give rise to these unusual responses to treatments.
In the NCI study, patient samples are analyzed by investigators at the Baylor College of Medicine Human Genome Sequencing Center and the cancer genomics company Foundation Medicine. This process includes sequencing DNA and RNA, as well as assessing the number of copies of certain DNA segments.
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.