A remarkably simple genome underlies highly malignant pediatric rhabdoid cancers

Abstract

Cancer is principally considered a genetic disease, and numerous mutations are thought essential to drive its growth. However, the existence of genomically stable cancers and the emergence of mutations in genes that encode chromatin remodelers raise the possibility that perturbation of chromatin structure and epigenetic regulation are capable of driving cancer formation. Here we sequenced the exomes of 35 rhabdoid tumors, highly aggressive cancers of early childhood characterized by biallelic loss of SMARCB1, a subunit of the SWI/SNF chromatin remodeling complex. We identified an extremely low rate of mutation, with loss of SMARCB1 being essentially the sole recurrent event. Indeed, in 2 of the cancers there were no other identified mutations. Our results demonstrate that high mutation rates are dispensable for the genesis of cancers driven by mutation of a chromatin remodeling complex. Consequently, cancer can be a remarkably genetically simple disease.

Figure 1. SNP arrays of primary RT samples and matched normal DNA.

(A) Genome display of copy number changes. (B) Enlarged view of the SMARCB1 locus. Mutations are overlaid on the SCNAs and loss-of-heterozygosity (LOH) tracks. Samples with focal deletions covering SMARCB1 are marked with “@.” Samples with monosomy 22 or loss of heterozygosity across 22 are marked with “x” or “+” next to the sample label. The red box represents the highlighted region of the chromosome, including the SMARCB1 locus shown below. Red triangles represent the centromeric regions of the chromosome. Chr, chromosome.

Figure 2. Somatic mutations in RTs.

(A) Mutation multiplicity for each sample. Multiplicity is a measure of the average number of alternate alleles per tumor cell for each mutation. Heterozygous clonal mutations have a multiplicity near 1, while events below 1 are subclonal. Multiplicities close to 2 tend to be the result of mutations in loss-of-heterozygosity regions. Circles indicate the 9 SMARCB1 mutations. (B) Logarithmic plot of mutation rates in 5 other types of cancer compared with those in RTs. Blue circles represent recurrent the RT samples. For box-and-whisker plots, red horizontal bars indicate medians, boxes indicate 25th and 75th percentiles, lower whiskers indicate lowest datum within 1.5 times the interquartile range (1.5xIQR) of the lower quartile, upper whiskers indicate highest datum within 1.5xIQR of the upper quartile, and red dots represent outliers. CLL, chronic lymphocytic leukemia.

Figure 3. Recurrent RTs have more mutations than primary tumors.

(A) SNP array of 2 matched tumor/normal pairs from recurrent tumors reveals an aneuploid tumor sample (09-044). Blue represents deletion; red represents amplification; and green represents copy neutral LOH. (B) The mutation rate in recurrent RTs is significantly higher (*P < 0.005) than that in primary RT samples. (C) While primary samples had a greater proportion of C→T transitions, recurrent samples had a greater proportion of C→A and A→T transversions. Significant differences between primary and recurrent samples are indicated. *P < 0.05, **P < 0.005, ***P < 10^–5. (D) Recurrent samples have significantly more transversions than primary samples (P < 0.0005).