Because 98% of the human genome doesn’t serve a direct role in gene expression, many biologists have long thought of them as nothing but “junk DNA.” But might they hold the key to helping stem the formation of deadly cancers? In episode 34, Mike Feigin from Roswell Park Comprehensive Cancer Center talks with us about his discovery of mutations in part of the human genome that most people have so far tended to ignore, but which appears to regulate the expression of genes that drive the formation of cancers. His article “Recurrent noncoding regulatory mutations in pancreatic ductal adenocarcinoma” (PDF) was published with multiple co-authors on May 8, 2017 in the journal Nature Genetics.

Decoding Cancers' Expression - Mike Feigin
Decoding Cancers' Expression - Mike Feigin
Decoding Cancers' Expression - Mike Feigin Decoding Cancers' Expression - Mike Feigin
@rwatkins says:
Just a quick interruption to explain that G protein-coupled receptors detect molecules outside of cells, and allow the transmission of a wide variety of signals over long distances in the body.
@rwatkins says:
Lastly, we asked Mike what he hopes that his study will contribute to cancer research in the future.
@rwatkins says:
Mike and his team also validated these mutations in the lab experimentally. In doing so, they identified prognostic markers in the promoter regions of DNA which might suggest the outcomes that are likely when a patient is diagnosed with cancer. So Ryan and I asked Mike to discuss what this suggests about the role of mutation in gene expression.
@rwatkins says:
Mike and his team not only verified that mutations in regulatory regions exist, but also found patterns of mutations in non-coding regions which appear to be expressed during the progression of tumors. Doug and I asked Mike to provide more details on the specifics of these findings.
@rwatkins says:
The genetic data that Mike and his team used to examine these mutations were obtained from the Pancreatic Cancer Genome Project, which is coordinated by the International Cancer Genome Consortium, or ICGC. We asked Mike to explain how researchers make use of such atlases, as well as how he engaged with international collaborators to check that the cells which he and his team studied derived from the typical cells, called somatic cells, rather than those that are specialized for reproduction.
@rwatkins says:
To analyze genetic commonalities among these patients, Mike and his team developed computational tools to identify and prioritize mutations. The algorithm they programmed, called GECCO, looks through the genome to identify mutations in the noncoding, regulatory elements of genes, as Mike explains next.
@rwatkins says:
Promoters are regions of DNA that initiate the chemical bond between nearby genes. They help ensure that those genes are expressed correctly via proteins known as “transcription factors” that control the rate at which genetic information from DNA is copied to RNA. Here, Mike describes how he and his team sequenced the entire genome from over 300 patients with pancreatic cancer in order to identify promoters which may be related to mutations in the non-coding components of DNA.
@rwatkins says:
When we left off, Mike was about to explain why he and his team chose to examine so-called “junk DNA,” as well as what’s known about their roles in gene expression.
@rwatkins says:
Since the 1970s, some scientists have speculated that non-coding genes serve no genetic function, and so have dubbed them “junk DNA.” In fact, though, the purpose of many these non-coding elements has yet to be examined at all. So Ryan and I wondered what led Mike and his team to explore these non-coding regions of the genome, as well as what is known about their potential roles in gene expression. We’ll hear what Mike had to say about this question after this short break.
@rwatkins says:
“Transcription” is the first step of gene expression. Through transcription, segments of DNA are copied into RNA using nucleotides as a complementary language. Mike likens this process to a Broadway production, in which genes and the proteins they encode are the actors, with the backstage crew as the non-coding, regulatory elements of the DNA.
@rwatkins says:
The process by which the genetic makeup of a cell, called a genotype, gets interpreted into an observable trait, or phenotype, is known as “gene expression.” Given that Mike and his team identified mutations at sites related to the expression of neighboring genes, we asked him to describe how this process works, particularly when cells interact through the tissue between them in an area called the epithelium.
@rwatkins says:
Permanent changes to the DNA sequence are called genetic mutations, and these can occur within the building blocks of nucleic acids, called nucleotides, or among amino acids which are responsible for forming the vast array of proteins in our metabolism. Ryan and I were curious to learn how such mutations can impact our health.
@rwatkins says:
While pancreatic cancer may not cause recognizable symptoms in its early stages, many patients experience substantial pain when it spreads beyond the pancreas itself. Doug and I were interested in learning why this is, as well as whether therapies to improve the management of this pain might improve in the future.
@rwatkins says:
Even when diagnosed early, the five-year survival rate of pancreatic cancer is only 20% … and when it’s not, this figure drops to just 5%. Ryan and I started our conversation by asking Mike what makes this form of cancer so deadly.
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Cold Springs Harbor Laboratory | eCancer | MedicalXpress | EurekAlert

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Hosts / Producers

Ryan Watkins & Doug Leigh

How to Cite

Watkins, R., Leigh, D., & E. Feigin, M.. (2018, October 16). Parsing Science – Decoding Cancers’ Expression. figshare. https://doi.org/10.6084/m9.figshare.7216019

Music

What’s The Angle? by Shane Ivers

Transcript

Mike Feigin: It’s this behind-the-scenes DNA that no one really thinks about, but that really controls when genes are turned on and turned off. And, no one really thinks about kind of the effects of mutations in those regions.

Doug Leigh: This is Parsing Science. The unpublished stories behind the world’s most compelling science, as told by the researchers themselves. I’m Doug Leigh…

Ryan Watkins: And I’m Ryan Watkins. The South African biologist and Nobel Prize recipient, Sydney Brenner, predicted that, “getting the sequence [of the human genome] [would] be the easy part, [as] only technical issues are involved. The hard part will be finding out what it means, because [it] poses intellectual problems [in understanding how] … genes participate in the functions of living cells.” Today, we’ll talk with Mike Feigin, from Roswell Park Comprehensive Cancer Center in Buffalo, New York, about his discovery of mutations in part of the human genome that most people have so far tended to ignore, but which regulates the expression of genes that drive the formation of deadly cancers.

Feigin: Hi, I’m Mike Feigin. I’m an assistant professor at Roswell Park Comprehensive Cancer Center. I’ve been interested in science my whole life. I don’t really know why. It’s just, I guess, one thing that I was good at in school, and I always enjoyed it. And, so one day in high school, I decided that I wanted to study pharmacology, and that’s what I did. So, I don’t know why that was my choice, but I’ve always been interested in diseases. I thought for a while I wanted to be an MD, but decided I liked research more, based on some research experiences I had. And, all the work I do is really trying to understand cancer, with the goal of trying to find new drug targets to hopefully, one day, help somebody out there.

Leigh: Even when diagnosed early, the five-year survival rate of pancreatic cancer is only 20%, and when it’s not, this figure drops to just 5%. Ryan and I started our conversation by asking Mike what makes this form of cancer so deadly.

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