Response to Satgé and Vekemans

To the Editor : I thank the editors for the opportunity to respond to the comments on my recent Hotspots in Clinical Genetics (1). As indicated, this was a summary of an article published in Nature 2009 (2). Epidemiological studies of cancer in Down syndrome (DS) patients are controversial and many present different conclusions about specific cancer types. As Baek et al. suggested the largest study to date with DS individuals examined 18,000 individuals. This study showed that mortality due to cancer is less than one-tenth from the general population in most tumour types with the exception of testicular cancer and leukaemia (3). However, as suggested, there is an inherent limitation in this type of study as it was based on cancer mortality from death certificates. The underlying cause of death based on death certificates has been shown to be incomplete or inaccurate as it is usually based on a physician’s opinion (4). The limitation of death certificates most likely applies to the general population as well. Regardless of the method used to determine cancer frequency, the observation is the same and the protective anticancer effect of DS is significant (5). Hastle et al. showed from the Danish cancer registry in 2000 that there is also a reduced incidence of solid tumours in adults with DS (6). It would be beneficial to repeat Hastle’s Danish study looking at cancer registries rather than death certificates to find a more appropriate and representative frequency of cancer in DS. The practical consequences of the tumour profile found in DS individuals not only affect the early detection of these cancers, but also the diagnosis and treatment of these patients. It has been observed that the incidence of nearly all solid tumours was reduced in DS patients while leukaemia, testicular cancer, ovarian cancer, and retinoblastomas are seen more often than expected (3). It is beneficial to take into account this tumour profile found in DS individuals as suggested. Even though we should consider the findings in DS patients, this should not reflect changes to medical practice with respect to cancer. These individuals should be treated and undergo proper medical surveillance similar to that of the general population. This will prevent biased treatment. I agree that it is necessary to determine whether the protective gene, DSCR1 is only found in the DS population. This would provide another confirmation that the gene indeed is linked to chromosome 21 and is not due to environmental factors. The antineoplastic effect of the trisomic gene on chromosome 21 is thought to result most likely from tumour initiation and progression (5). The tumours observed in DS individuals due to the antiangiogenic effect of genes in chromosome 21 result in a large number of benign neoplasms and a lower incidence of clinically detectable tumours. This could be due to tumours stalling at an early stage of development. Other studies have suggested there may be more of a bias towards tumour progression with less emphasis of initiation, which may explain the tumour formation and growth rate observed in DS patients (5). It is clear that the mechanism behind tumour formation in DS patients still needs to be investigated in greater detail. Currently, Baek et al. are studying the effects of calcineurin inhibition which may shed some light on the tumour growth observed. Understanding the specific role that DSCR1 plays in cancer protection in DS individuals may allow for tumour prevention and novel therapeutics.