Recently I was helping a customer with an unexpected mosaic event in a control sample. Since the sample origin was from blood, I had initially suspected an undiagnosed blood malignancy. However, the whole genome profile showed a single mosaic loss event of several Mb which suggested a different origin.SNP Microarrays are a fundamental instrument in detecting mosaic copy number aberrations thanks to the combination of LogR and BAF measurements across the genome. Nexus Copy Number has helped many researchers to detect and interpret the profiles from cancer samples where contamination by normal cells is quite common. However, mosaic events can also appear as the clonal expansion of acquired post-zygotic mutations. Compared to constitutional defects in the same regions, mosaic abnormalities can result in milder phenotypes but they may also appear in otherwise seemingly healthy individuals.
How often do these events occur in the normal population? An attempt to describe the occurrence of mosaic events in the general population has been performed by Machiela et al. on a large dataset of over 120,000 samples generated as part of the Gene-Environment Association Studies (GENEVA) and the total GWAS sets I and II (1). From this large number of samples, it has emerged that the incidence of individuals showing at least one mosaic event (>2Mb in size) on autosomal chromosomes is about 0.73%. Approximately half of the detected events were mosaic copy-neutral uniparental disomy, followed by mosaic losses and mosaic gains. Hotspots were identified for mosaic gains at chromosomes 8, 12, and 15, mosaic losses on chromosomes 13 and 20, and mosaic copy-neutral events on chromosomes 9 and 14.
From a meta-analysis it appears that age is a risk factor with a higher occurrence in mosaic events later in life (see figure), more likely in males but affecting individuals of African ancestry less commonly.
Figure Caption: Proportion of Mosaic Individuals across 5-Year Age Groups in the Combined GENEVA, TGSI, and TGSII Dataset by Cancer Status. Affected individuals are in red, and cancer-free control individuals are in blue. Error bars represent 95% CIs. An overall significant relationship in the proportion of individuals with mosaic events was observed with age (p value = 1.1×10−30). Machiela, M. J., Zhou, W., Sampson J. N., Dean M. C., Jacobs K. B., Black A.,…Chanock S. J. (March 2015). AJHG, Volume 96, Issue 3, 487–497.
So when performing analysis on cancer samples, keep in mind that the human genome is not static and even the normal samples can have some mosaic abnormalities and the extent of change can be correlated to factors such as age, ethnicity, etc.
1. Machiela, M. J., Zhou, W., Sampson J. N., Dean M. C., Jacobs K. B., Black A.,…Chanock S. J. (March 2015). Characterization of Large Structural Genetic Mosaicism in Human Autosomes. AJHG, Volume 96, Issue 3, 487–497.