News

Expanding the landscape of breast cancer drivers

In comparison with a previous study (Stephens et al., 2012, shown in gray), a new computational approach that focuses on somatic copy number mutations increased the number of known driver mutations in breast tumors to a median of five for each tumor. The findings could raise the likelihood of finding actionable targets in individual patients with breast cancer.

For many years, researchers have known that somatic copy number alterations (SCNA’s) — insertions, deletions, duplications, and transpositions of sections of DNA that are not inherited but occur after birth — play important roles in causing many types of cancer. Indeed, most recurrent drivers of epithelial tumors are copy number alterations, with some found in up to 40% of patients with specific tumor types. However, because SCNA’s occur when entire sections of chromosomes become damaged, biologists have had difficulty developing effective methods for distinguishing genes within SCNA’s that actually drive cancer from those genes that might lie near a driver but do not themselves cause disease.

Helios nearly doubled the number of high-confidence predictions of breast cancer drivers.

In a new paper published in Cell, researchers in the laboratories of Dana Pe’er (Columbia University Departments of Systems Biology and Biological Sciences) and Jose Silva (Icahn School of Medicine at Mount Sinai) report on a new computational algorithm that promises to dramatically improve researchers’ ability to identify cancer-driving genes within potentially large SCNA’s. The algorithm, called Helios, was used to analyze a combination of genomic data and information generated by functional RNAi screens, enabling them to predict several dozen new SCNA drivers of breast cancer. In follow-up in vitro experimental studies, they tested 12 of these predictions, 10 of which were validated in the laboratory. Their findings nearly double the number of breast cancer drivers, providing many new opportunities towards personalized treatments for breast cancer. Their methodology is general and could also be used to locate disease-causing SCNA’s in other cancer types.

Leading this effort was Felix Sanchez-Garcia, a recent PhD graduate from the Pe’er Lab and a first author on the paper. The story of how this breakthrough came about illuminates how the interdisciplinary research and education that take place at the Department of Systems Biology can address important challenges facing biological and biomedical research.

Fluidigm C1 Single-Cell Plate

At the core of the Fluidigm C1 Single-Cell Auto Prep System is a 96-well plate containing microfluidics. After individual cells are isolated in their own wells, the device amplifies their cDNA for genome-wide gene expression profiling. Scientists at the Columbia Genome Center are developing methods for addressing the technical and analytical challenges of single-cell RNA sequencing, and have begun generating some exciting data.

Since the invention of the first microscope, a procession of new technologies has enabled scientists to study individual cells at increasingly fine levels of detail. The last two years have witnessed an important next stage in this evolution, with the arrival of the first devices for genetically profiling single cells on a genome-wide scale.

The first commercial product in this field is the Fluidigm C1 Single-Cell Auto Prep System, which uses microfluidics to isolate single cells and offers the ability to generate gene expression profiles for up to 96 cells at a time. But because of the novelty of the technology and the inherent difficulties of working with single cells, it has presented a number of technical challenges for researchers interested in exploring biology at this level.

Now, scientists at the JP Sulzberger Columbia Genome Center led by Assistant Professors Peter Sims and Yufeng Shen have developed an experimental and computational pipeline that optimizes the C1’s capabilities. And even as they work to solve some of the challenges that are inherent to single-cell research, their approach has begun generating some exciting data for studying genetics in a variety of cell types.

Calendar

The Department of Systems Biology is pleased to announce the speakers in its 2014-2015 Seminar Series. The seminar series features leading investigators working in a diverse set of fields, including cancer genomics, systems biology, computational biology, human genetics, cancer biology, RNA splicing regulation, chromatin and cell signaling, and microfluidics and sequencing. Please save the dates!

All events will be held in the Department of Systems Biology Common Room (ICRC 816), unless indicated otherwise. Additional details about these events will be provided at the links below as they become available.

For a continually updated calendar of all Department of Systems Biology events, and to see an archive of past seminars, visit systemsbiology.columbia.edu/events.

DIGGIT identifies mutations upstream of master regulators.

A new algorithm called DIGGIT identifies mutations that lie upstream of crucial bottlenecks within regulatory networks. These bottlenecks, called master regulators, integrate these mutations and become essential functional drivers of diseases such as cancer.

Although genome-wide association studies have made it possible to identify mutations that are linked to diseases such as cancer, determining which mutations actually drive disease and the mechanics of how they do so has been an ongoing challenge. In a paper just published in Cell, researchers in the lab of Andrea Califano describe a new computational approach that may help address this problem.

Dana Pe'er and Kyle Allison

Dana Pe'er has received the Pioneer Award for high-risk, high-reward research, and postdoctoral scientist Kyle Allison has won an Early Independence Award.

Two members of the Columbia University Department of Systems Biology have been named recipients of NIH Director’s Awards from the National Institutes of Health Common Fund.

Associate Professor Dana Pe’er is one of 10 winners of the 2014 NIH Director’s Pioneer Awards. The Pioneer Awards provide up to $2.5 million over 5 years to support exceptionally creative investigators who are pursuing “high risk, high reward” science that holds great potential to transform biomedical or behavioral research. The award will support an ambitious new project to develop the technological and computational methods necessary to create a comprehensive, high-resolution atlas of development for all cell types in the human body.

In addition, Kyle Allison, a postdoctoral scientist in the laboratory of Professor Saeed Tavazoie, has received the NIH Director’s Early Independence Award. (Dr. Tavazoie is also a past winner of the Pioneer Award.) This program enables outstanding young investigators who have recently completed their PhD’s to move rapidly into independent research positions. Dr. Allison is one of just 17 scientists to receive this award this year. In combination with the Department of Systems Biology Fellows program, this five-year, $1.25 million grant will allow him to open his own laboratory at Columbia and pursue independent research to investigate the problem of bacterial persistence. He is the second Department of Systems Biology investigator to receive the Early Independence Award, joining Assistant Professor Harris Wang in being recognized with this honor.

“Having four recipients of NIH Director’s Awards within the Department of Systems Biology — and particularly two in one year — is quite remarkable,” said Department Chair Andrea Califano. “I think it’s a testimony to the timeliness of the perspectives and tools that systems biology offers and to the high quality of research being conducted at Columbia. I look forward to the discoveries that will undoubtedly come from Dana’s and Kyle’s extremely exciting efforts.”