Health
One in eight women will be diagnosed with breast cancer during her lifetime. The earlier cancer is detected, the better the chance of successful treatment and long-term survival.
However, early cancer diagnosis is still challenging as testing by mammography remains cumbersome, costly, and in many cases, cancer can only be detected at an advanced stage.
A team based in the Department of Biomedical Engineering at McGill University's Faculty of Medicine has developed a new microfluidics-based microarray that could one day radically change how and when cancer is diagnosed.
Their findings are published in the April issue of the journal Molecular & Cellular Proteomics.
For years, scientists have worked to develop blood tests for cancer based on the presence of the Carcinoembryonic Antigen (CEA), a protein biomarker for cancer identified over 40 years ago by McGill's Dr. Phil Gold.
This biomarker, however, is also found in healthy people and its concentration varies from person to person depending on genetic background and lifestyle. As such, it has not been possible to establish a precise cut-off between healthy individuals and those with cancer.
"Attempts have been made to overcome this problem of person-to-person variability by seeking to establish a molecular 'portrait' of a person by measuring both the concentration of multiple proteins in the blood and identifying the signature molecules that, taken together, constitute a characteristic 'fingerprint' of cancer," explained Dr. David Juncker, the team's principal investigator. "However, no reliable set of biomarkers has been found, and no such test is available today. Our goal is to find a way around this."
Dr. Mateu Pla-Roca, the study's first author, along with members of Juncker's team, began by analyzing the most commonly used existing technologies that measure multiple proteins in the blood and developing a model describing their vulnerabilities and limitations.
Specifically, they discovered why the number of protein targets that can be measured simultaneously has been limited and why the accuracy and reproducibility of these tests have been so challenging to improve.
Armed with a better understanding of these limitations, the team then developed a novel microfluidics-based microarray technology that circumvents these restrictions.
Using this new approach, it then became possible to measure as many protein biomarkers as desired while minimizing the possibility of obtaining false results.
Juncker's biomedical engineering group, together with oncology and bioinformatics teams from McGill's Goodman Cancer Research Centre, then measured the profile of 32 proteins in the blood of 11 healthy controls and 17 individuals who had a particular subtype of breast cancer (estrogen receptor-positive).
The researchers found that a subset of six of these 32 proteins could be used to establish a fingerprint for this cancer and classify each of the patients and healthy controls as having or not having breast cancer.
"While this study needs to be repeated with additional markers and a greater diversity of patients and cancer subsets before such a test can be applied to clinical diagnosis, these results nonetheless underscore the exciting potential of this new technology," said Juncker.
Looking ahead, Juncker and his collaborators have set as their goal the development of a simple test that can be carried out in a physician's office using a droplet of blood, thereby reducing dependence on mammography and minimizing attendant exposure to X-rays, discomfort and cost.
His lab is currently developing a hand-held version of the test and is working on improving its sensitivity so as to be able to accurately detect breast cancer and ultimately, many other diseases, at the earliest possible stage.
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A team of researchers at Case Western Reserve University School of Medicine have identified a new mechanism by which colon cancer develops.
By focusing on segments of DNA located between genes, or so-called "junk DNA," the team has discovered a set of master switches, i.e., gene enhancer elements, that turn "on and off" key genes whose altered expression is defining for colon cancers.
They have coined the term Variant Enhancer Loci or "VELs," to describe these master switches.
Importantly, VELs are not mutations in the actual DNA sequence, but rather are changes in proteins that bind to DNA, a type of alteration known as "epigenetic" or "epimutations." This is a critical finding because such epimutations are potentially reversible.
Over the course of three years, the team mapped the locations of hundreds of thousands of gene enhancer elements in DNA from normal and cancerous colon tissues, pinpointing key target VELs that differed between the two types.
"What is particularly interesting is that VELs define a 'molecular signature' of colon cancer. Meaning, they are consistently found across multiple independent colon tumor samples, despite the fact that the tumors arose in different individuals and are at different stages of the disease," said Peter Scacheri, PhD, senior author of the study and assistant professor, Genetics and Genome Sciences, School of Medicine, and member, Case Comprehensive Cancer Center at Case Western Reserve University. "The set of common VELs govern a distinct set of genes that go awry in colon cancer."
"The VELs signature is notable because it cuts through the complexity of the many genes that are changed in colon cancer, to identify genes that are direct targets of alterations on chromosomes,” said Sanford Markowitz, MD, PhD, Ingalls Professor of Cancer Genetics in the Division of Hematology-Oncology at the School of Medicine, member, Case Comprehensive Cancer Center, and oncologist at University Hospitals Seidman Cancer Center, whose team collaborated on the study. "The key next step will be to determine whether we can use VELs for 'personalized medicine,' to molecularly define distinct groups of colon cancers that differ in their clinical behavior, and to enable selection of specific drugs that will best treat a given colon tumor."
In addition to finding that VELs are a "signature" of colon cancer, the team showed that genetic variants which predispose individuals to colon cancer are located within VELs. This suggests that individual differences within VELs may play significant roles in determining different individuals' susceptibility to colon cancer.
"Epigenetics has transformed the way we think about genomes. The genetic code isn't just a series of As, Ts, Gs, and Cs strung together. Epigenetic 'marks' on DNA tell genes when, where, and how much to turn on or off to keep cells healthy," said Batool Akhtar-Zaidi, PhD candidate in Dr. Scacheri's lab and lead author of the study. "When this epigenetic machinery is disrupted, as we see with VEL events, this can tip the balance to cancer."
Co-authors on the study, "Epigenomic enhancer profiling defines a signature of colon cancer" published advanced online in Science Express, include Olivia Corradin, Alina Saiakhova, Cynthia F. Bartels, Dheepa Balasubramanian, Lois Myeroff, James Lutterbaugh, Paul J. Tesar, Thomas Laframboise, Joseph Willis at Case Western Reserve School of Medicine; Awad Jarrar, Matthew F. Kalady at Cleveland Clinic; and Richard Cowper-Sal lari, Jason H. Moore, Mathieu Lupien at Dartmouth Medical School.
This research was supported by the National Cancer Institute, as well as the Case Comprehensive Cancer Center.
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