CTA: Guthrie cards are archived, dried blood spots collected at birth. What did the team find when those were checked?
Dr Wiemels: This analysis revealed that CMV sequences were more common at birth in children who grew up to contract leukemia than control children who did not. We used a very sensitive method capable of finding single sequences of CMV by digital PCR [polymerase chain reaction]. Our rate of CMV in control children was about 3%, which is higher than some other studies have seen. We are sure that our method is detecting actual CMV since we verified with a second test (and are developing more methods of detection, not in this paper).
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We are not saying that this CMV is clinically evident, since it is known that CMV-related disease is not that frequent. (See the stats here).
We suggest that CMV infection before birth is either a very limited infection causing an injury before birth, or having it before your adaptive immune system developed (after birth) means that a child will have a different CMV life-course than if he or she was infected after birth. The child may carry higher levels of the virus, and the virus will be altering his or her immune response against other infectious illness in a way that promotes leukemogenesis.
This requires a lot more work to figure out and is speculative at this time.
CTA: At least 1 other recent study failed to identify signs of CMV infections in children with ALL. What did your team do differently?
Dr Wiemels: There was a Swedish study and their methods were less sensitive and perhaps more importantly, the sample size was pretty small. We would have expected to see a few positive patients with our method from that study, but it still may not have detected a difference with small numbers of subjects tested. This group published another negative study recently using a more agnostic sequencing approach and did not detect anything, also presumably due to low sensitivity.2
CTA: Your team found that the association between childhood ALL and CMV seemed to be much stronger for Hispanic children than other children. Why might that be the case?
Dr Wiemels: We are not sure if this is a true difference, or just a consequence of statistical fluctuation due to the smaller numbers of subjects within the subsets. Note that the control frequency in Hispanics was lower, but there are no data suggesting that the population prevalence of CMV in Hispanics is lower at birth. In fact, it might be slightly higher than non-Hispanic whites, though it is known that hearing loss due to CMV is lower in Hispanics, so perhaps the population prevalence data are overestimated. Well, in any case, we can’t say that there is a true difference but we are going to screen many more subjects to pin this down. Hispanics definitely have a 40% higher risk of leukemia so it would be interesting if they had this higher incidence in part due to more sensitivity to leukemia due to CMV.
CTA: How do these new findings fit the existing understanding of childhood leukemia epidemiology?
Dr Wiemels: CMV is not a firm cause of any cancer, though it is a candidate ‘oncomodulator’ in glioma and also of interest in breast cancer and maybe others. It has many immunomodulatory activities, which is one way that it could affect leukemia risk. It may alter the way that we react to other infections in a way that promotes leukemia. It may exist at a higher titre in children who did not develop a strong immunity to it being infected before birth (since their immune system would not react to it as ‘non-self’).
CMV does not get integrated in the leukemia genome and, therefore, it does not cause cancer in the fashion that HPV causes cervical cancer, for instance, but because it does appear to be growing in leukemia cells, they may be dependent on the infection in order to maintain the tumor.
What exactly CMV is contributing to the cancer is unclear at this time and should be an important research topic into the future.
The short answer suggests that the critical feature is the timing of infection, leading to an infection course that favors leukemia.
