Whole Genome Sequencing for Prostate Cancer
May 17, 2011 -- Today’s announcement regarding the sequencing of whole prostate cancer genomes is an historic development in the fight against prostate cancer. The ability to sequence whole genomes will spare some patients from unnecessary treatments and side effects while eliminating an estimated $1.5 billion that is spent each year on overtreatment. The complete research findings will be published in the February 10 issue of Nature. The following Q and A is from content discussed during a teleconference announcing the significance of the findings and of whole genome sequencing to prostate cancer research.
Why is this discovery historic for prostate cancer research, and all cancer research generally?
A great journey begins with a small step. This is PCF’s first “Lewis and Clark” moment exploring the genomic landscape of prostate cancer. For the first time, researchers have uncovered a comprehensive genetic map of seven patients’ prostate tumors. Each of the seven maps offers a macroscopic view of the complete genetic sequence and mutations that might underlie and cause each patient’s disease. The whole genome view also shows us how prostate cancer is complex in a way that is different from other cancers. Instead of having many “spelling errors” or point mutations, prostate cancer has an unprecedented number of large rearrangement segments called “DNA fusions.”
What should patients be asking urologists today that they couldn’t ask yesterday?
Although these findings have not yet been translated into widely employed clinical practices, patients can begin to ask their respective medical teams about participating in studies that use whole genome sequencing in clinical trials. Opportunities for employing genomic scans in research and treatment studies for prostate cancer patients are rapidly expanding.
How much does it cost to sequence a whole prostate cancer genome? How long does it take?
The current estimated cost of sequencing a whole genome is $20,000 or less. Experts predict that the cost of routine sequencing will ultimately be around $5,000 per genome. (This figure compares favorably to the cost of $90,000-$150,000 per patient for a radical prostatectomy followed by several years of androgen deprivation therapy using Lupron.) The process of whole genome sequencing for a single patient currently takes between 2 and 3 weeks.
How will whole genomic sequencing accelerate the development of new medicines and diagnostics for prostate cancer patients?
Knowledge of DNA fusions from leukemia genome sequencing led to breakthrough medicines for chemotherapy-resistant leukemia. PCF believes that prostate cancer genome sequencing could follow suit and lead to a cancer-specific tests or fusion-specific medicines for distinct types of prostate cancer. Additionally, information provided by sequencing a given tumor could facilitate matching up a patient to existing clinical trials targeting DNA fusions and mutations—PCF is currently monitoring 11 trials of this kind.
What does the genome look like to a doctor or a patient?
The DNA code of each of the multiple tumors sequenced contains 3 billion letters. Depicting the sequence of these letters in a linear fashion would make it hard to visualize the important patterns and features of the structural variation with the code. It would also be exceedingly long to read.
Instead of sifting through a 3-billion letter code, a diagram was developed as a short-hand tool for visualizing important relationships within the genome. It was created with Circos software and is called the Circos plot. Designed with the express purpose of aiding in the visualization of genomic data, its circular layout is analogous to a clock face. Just as a clock face displays time through the use of a fixed dial indicating the hours in a 12-hour cycle, the Circos plot displays the 23 chromosome pairs on which the entire human genome is stored.
These chromosomes are numbered clockwise on the outer circumference of a circle plot. The demarcations within the circle relate information about what might be important for a doctor or patient to know about the genome being studied. On the chart below, the green ticks represent losses of coding information and the purple arcs represent gene fusions, how genetic material goes from the “right place” to the “wrong place” in the genome.
Scientists can quickly assess a Circos plot just as patients can easily glance at a clock face and tell time. Essentially, the Circos plot is an individualized, unique portrait of each patient’s prostate cancer, akin to a CT Scan of the entire genome.
What kinds of cancers were sequenced? Does this data help us distinguish between aggressive and non-aggressive prostate cancer?
All seven patients had cancers that were Gleason Grade 7, 8, or 9 (aggressive prostate cancers). These patients’ cancers were hand-picked to represent meaningful, advanced cancers (i.e. cancers that, without surgery or treatment, could possibly progress and take the life of the patient). An important question to ask is what do lower grade tumors in patients undergoing proactive surveillance look like by whole genome sequencing on a Circos plot. It may well be that indolent tumors have a much “quieter” genome, missing far less code and showing far less damage—a Circos plot without many lines or ticks. If we broadened this study by sequencing thousands of patients and following them in the clinic, we might be better able to distinguish indolent cancers with the tendency to remain “quiet” from those that require aggressive treatment.
Were these genomes just a snapshot in time for these patients? If you were to sample the same patients again would they have changed already?
Yes. In this study, the sequencing captures a snapshot of the seven patients’ tumors at the time of surgery. Conceivably you could take multiple “snapshots” of the genome at the time of diagnosis, prognosis, treatment, and throughout survivorship.
Now that we have these genomic portraits, what do you expect scientists around the world to do with the information? How will the data be made publically available?
This data will be carefully studied to compare and contrast the prostate cancer genome with other cancer genomes (i.e. breast cancer genomes) where we might find clues for understanding how to design better drugs for both kinds of cancers. Additionally, learning more about how certain genes are mutated or fused gives us insight into the fundamental processes of why cancer is caused, how and why it does or does not spread, and why it does or does not go into remission with certain existing treatments. With regard to the seven tumors sequenced, the patients’ identities have all been protected; however, any scientist around the world who logs into a database and fills out the appropriate consent form can responsibly access the information. Every person who uses the data must identify him or herself.
Do the whole genome maps help us explain the disproportionate burden of prostate cancer incidence and death in African-Americans and other affected populations?
Not yet, but large-scale populations studies are now urgently needed to address this important question. For studies on this scale, it takes several thousand patient samples to compare and contrast the patterns that may exist in the Circos plots in order to assess whether the genome can tell us more about the undue burden.
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