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Alleles: Secrets to Cancer Risk

by Cecilia Lacks, PhD

Allele infoFor the past decade, scientists have been attempting to crack the genetic code underlying the development of prostate cancer.

While many scientists came up with possibilities, other researchers were seldom able to reproduce their findings.

However, in 2006 Dr. Catalona, and other scientists from around the world, collaborated with deCODE Genetics, an Icelandic research firm, to discover a reproducible genetic cause of prostate cancer susceptibility.

The deCODE group used cutting edge technologies to research the genetics of cancer by looking at several risk alleles and studying how they interact with each other.

This method replaced the traditional perspective of studying one gene carried through generations of a family.

Now, this method and these discoveries have changed the face of cancer research.

deCODE examined non-coding regions of DNA (areas that seemingly do not have messages or specific characteristics organized in identifiable genes) and, in their search, found reproducible signals that correlate with the frequency of prostate cancer development.

The discovery did not reveal how these signals enable prostate cancer susceptibility.

Large studies on large numbers of cancer tissue samples, prepared and stored properly for accurate DNA examination, are key to unlocking the unanswered mysteries inherent in this new research.

Dr. Catalona is one of the co-chairs of the recently appointed working group from the National Cancer Institute and the National Institutes of Health to ensure collaboration and DNA sample sharing from the various SPORE (Specialized Program of Research Excellence) groups across the United States.

The purpose of SPORE’s Prostate Cancer Biorepositories is to obtain tumor tissues, seminal vesicle and prostate fluid, and blood serum and white blood cell samples for genetic testing.

Big Change

"An unprecedented and rapid chain of discoveries of DNA markers associated with a susceptibility to common diseases has been reported in recent months. These discoveries have the potential to radically change medicine," Catalona said.

Dr. Catalona's genetic research is focused on the genetics of prostate cancer and, in this area, he notes that the discovery (June 2006) and validation (November 2006) of prostate cancer risk alleles on chromosome 8q24 (in which he participated) "makes it an exciting time for prostate cancer genetics."

"Prostate cancer is a common but complex disease. Although the causes of prostate cancer are not yet fully understood, genetic variation clearly has an impact on this disease. Determining genetic variants that indisputably affect prostate cancer risk has proven challenging. This situation improved recently... with independently detected overlapping signals for prostate cancer on chromosome 8q24," Dr. John Witte (Institute for Human Genetics at University of California, San Francisco) said.

These discoveries have turned out to be related to other cancers as well because it appears, from additional studies, that the risk alleles in the area of 8q24 also relate to other cancers and diseases such as: colorectal cancer, lung cancer, lymphoma and even epilepsy.

What Is Going On

The study of risk alleles in the area of 8q24 has raised some interesting questions but no real answers, at least not yet.

One of the bigger mysteries is that the results for prostate cancer risk were not consistently replicated across different ethnic groups. And, now, new reports have found other regions very close to 8q24 with variants that appear connected to higher risks for prostate cancer in some populations.

In addition, "Based on current understanding, none of the variants seems to be functional, and none resides within or near known genes," Witte said.

So, research has discovered variant alleles with risk connections to prostate cancer (and to other diseases) but with no evidence as to the biological relationship of the alleles to the development of the disease.

Current thinking is that these changes in non-gene areas could affect activities of genes somewhere else. (One major activity of genes is to initiate various protein productions that regulate bodily functions.)

And, as important, it is likely that a combination of risk alleles – as opposed to one or even a few–carried through generations of a family – create the higher risk for a disease.

That perspective would explain why some members of a family carry certain risk alleles but do not get the disease when others in the family do.

It seems that certain risk alleles need to be in combination before they initiate biological activity.

Direction for New Study

The idea that combinations of risk alleles initiate biological changes in the body introduces new possibilities for thinking about what causes cancer and how it can be prevented.

As researcher Dr. David Goldgar from the University of Michigan said, "The challenge for the future will be to identify DNA sequence variants that confer increased disease risk, but may do so only in specific combination with each other, and/or in the context of specific environmental exposures."

Bottleneck to Progress and Fixing It

A "bottleneck" to progress in prostate cancer genetics research is the need for large numbers of well-annotated DNA samples.

"But there are abundant, rich resources for accelerating discovery in this area among the 13 prostate SPORES repositories throughout the US," Catalona said.

He proposed the formation of an inter-SPORE collaborative research group to develop an infrastructure and methods for understanding the genetic mechanisms involved in prostate cancer, using the 8q24 locus as a prototype.

The National Cancer Institute accepted his suggestion and expanded it "to establish the infrastructure and logistical methods for evaluating future genetic discoveries in prostate and other cancers."

Now, a working group co-chaired by William Catalona, MD (Northwestern University), Kathleen Cooney, MD, (University of Michigan) and Janet Stanford, PhD, (Fred Hutchinson Cancer Center) are coordinating the collection and sharing of data and research from the 11 centers.

Practical Applications of Research

The initial aim will be to study samples from patients and from controls for 8q24 risk alleles and correlate the carriers of those risk alleles to clinical, pathological and molecular changes of prostate cancer.

Also, the studies will try to determine the proportion of families in which familial clustering of prostate cancer appears to be due to 8q24 risk alleles.

Future goals will be to:

"I am pleased that so many scientists and institutions will be working together to demystify one area in this extraordinarily complex cancer research. The work is theoretical now, but the implications for practical application are enormous," Catalona said.

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