We’re presenting the first research from a large project that we have initiated at St Jude to look at the genetic component to the long-term complications of cancer survivorship. That is we know that cancer survivors, because of the treatment they have received, are at high risk for a number of adverse outcomes and we’ve characterised quite well what the therapeutic component is, that is what therapies are associated with what risks. But we also understand that not everybody develops the adverse outcomes and we think that genetics is playing the determining role in terms of who may or may not develop a late effect after treatment.
How many people participated?
We used a new cohort that we have developed and established at St Jude which is called the St Jude Lifetime Cohort. This cohort represents all long-term survivors of paediatric cancer ever treated at St Jude since it opened its doors in 1962. So the current cohort has over 4,500 survivors; for the studies we were reporting on today we did whole genome and whole exome sequencing on the first 3,007 participants in that project.
Are the logistics challenging?
It is challenging to track people down but what’s really remarkable is the commitment the patients who come and have been treated at St Jude have to the institution; many of them do keep in contact. So we’ve had really remarkable participation in our project where of the total eligible 85% participate in the project. Of those that we do actually locate it’s 95% agree to participate. This is a pretty demanding study to be a part of because what they have to do is travel back to Memphis and they actually stay on campus for 3-4 days while they undergo a very rigorous battery of clinical evaluations.
What were your findings?
In this first study there were two objectives. One is to understand what the proportion of survivors are that actually have a mutation in a gene that we currently know predisposes them to cancer. Then once we identified what that proportion was, we were interested in whether or not having one of those mutations has an impact on whether or not they develop subsequent cancers which is a very high risk for childhood cancer survivors in general. So we had this twofold objective for the first analysis out of all the data that we generated. The study found that 11.5% of the survivors actually had a mutation in one or more of these known 156 cancer predisposition genes. If we break it down and look at a subset of 60 genes that are known to be highly penetrant and inherited in an autosomal dominant fashion there we found 5.7% of the patients had one of these mutations, so very high. Some of the mutations we expected to see because we know that they were associated with their first cancer but that’s for a relatively small proportion of paediatric cancers that have actually a known gene mutation that is involved in the aetiology of the original cancer. So in essence what this is telling us is there is a high proportion. What’s interesting is if we took that proportion and the distribution within the different cancers and we applied it to population rates from the SEER programme of the National Cancer Institute. So with those data we can project that right now in the United States there’s over 32,000 survivors of childhood cancer that have a mutation in one of these 156 cancer predisposition genes.
How do these mutations occur?
Actually a very small proportion of these, we think, can be related to the treatment, only about 3% or what we refer to as a mosaicism. So the vast majority of these, we feel, are germline mutations that the individual is born with. They could have inherited, likely they inherited the mutation from a parent but not always. Some of these can be new mutations that occurred but we have to find that out. Now that’s one of our next steps is to look at the family to be able to test parents and other family members to help inform where the origin of the mutations came from. But the vast majority likely are inherited from a parent.
How is this information put into practice?
The strong recommendation that we’re making right now is that any survivor who develops a subsequent neoplasm should be referred for genetic counselling if, first of all, they developed a second neoplasm and didn’t receive prior radiation therapy or the subgroup of patients who did receive prior radiation therapy if they developed a breast cancer, thyroid cancer or a sarcoma that arose within an irradiated field, they also should be immediately referred for genetic counselling to determine family history, to look and determine whether or not they should have formal genetic testing to identify the presence or absence of a genetic mutation.
Were there any limitations?
Yes, there are several limitations that impact the overall interpretation. First of all, because of their very nature, we’re studying survivors, the only people that we had available to study are those that were still living. So anyone who may have died prior to our recruitment, recruiting them into St Jude Life from either their primary cancer or from a second cancer, we don’t have them available to test. So what we think might happen is if these mutations are associated with risk of death from either of those two causes then our estimate is an underestimate, it’s conservative.
The other limitation of our study is that the cohort is still relatively young. The group that we studied has a median age of about 35 years and they’ve been followed a mean of almost 30 years from their cancer diagnosis which is a very long time. But in the overall scheme of things they’re still a relatively young population. So with the additional follow-up that will come over the next one or two decades the risk pattern could change as these individuals get older and the effect of the mutations that they have in their genes may come into play in terms of higher rates of cancer. So our conclusions may change as we follow them longer.
