Figure 1.
Tumor development of TH-MYCN mice on the 129X1/SvJ background.
A. Event-free survival. The y-axis shows the proportion of animals that remain free of an event, here defined as palpable tumor development, spontaneous death by unknown cause including missing animals, and euthanization due to general signs of discomfort. The x-axis shows weeks from birth. Negative n = 125, hemizygous n = 206 and homozygous n = 64. B. Frequency distribution diagram showing the age at palpable tumor. Homozygous mice developed palpable tumors between 4.0–6.9 weeks of age, mean of 5.6 and median of 5.4 weeks (n = 45). The hemizygous mice that developed tumors were palpated with a tumor between 5.6–19 weeks of age, mean 9.9 and median 9.1 weeks (n = 88). The two-sided unpaired t test was used for comparison between the two groups p<0.01.
Figure 2.
Tumor imaging using high resolution ultrasound.
A. Tumor free animal visualizing abdominal landmarks shown by high resolution ultrasound. B. Detection of a non-palpable small tumor lesion (9.8 mm2) growing on the left side of the spine attached to the muscles. C and D. Imaging of a large palpable tumor (49 mm2). Growing around the aorta and inferior vena cava (IVC), displacing the left kidney. The pictures shown are transverse sections, oriented with the dorsal side down and the ventral up.
Figure 3.
Time from a palpable tumor to sacrifice – the treatment window.
A. Treatment window for homozygous and hemizygous mice. Mean number of treatment days for homozygous mice was 5.2 days (median 5, n = 30) and for hemizygous mice 15 days (median 11, n = 54). Statistical analysis was performed using two-sided t test on log-transformed data; p<0.01. B. Treatment window for hemizygous mice as a function of age at tumor palpation. Linear regression analysis yielded R2 = 0.012 and the correlation was assessed using two-sided Spearman test; p = 0.83. C. Treatment window for homozygous mice as a function of age at tumor palpation. Linear regression analysis yielded R2 = 0.30 and the correlation was assessed using two-sided Spearman test; p<0.05. D. Treatment window for homozygous mice versus hemizygous mice with an early tumor development (5.6–7.0 weeks of age). Mean number of treatment days for homozygous mice was 5.2 days (median 5, n = 30) and for hemizygous mice with an early tumor development 15 days (median 18, n = 5). Statistical analysis was performed using two-sided t test on log-transformed data; p<0.01. Box plots show median, inter quartile range (25–75%), min and max, and + represent the mean.
Figure 4.
Whole genomic profile of two representative cases of the ten analyzed TH-MYCN tumors.
TG1–TG7 showed flat profiles with no segmental or numerical aberrations (TG7 is shown here). TG8, TG9 and TG10 showed a few numerical aberrations. TG8 shown here display whole chromosome gain of mouse chromosome 3 and 11 (indicated by arrows).
Table 1.
Summary of genomic aberrations in ten different TH-MYCN tumors.