PMC9315106_01
Imaging and histology of the brain tumors. (A, B) CT scan images of the brain tumor tissue of the female (upper panels) and the male (lower panels). (C) H&E, Ki67, GFAP, Olig2, Yap1, and beta-catenin staining of the female's (left panels) and the male's (right panels) brain tumor tissue. The magnification is 20x.
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Computed tomography (CT) showed that the female had a tumor in the right frontal lobe and the male had a tumor in the cerebellar region ( Figures 1A, B ), and subsequent histopathology confirmed the diagnoses of GBM and MB, respectively ( Figures 1C ). The timeline from the episode of care in the two cases have been illustrated in  Supplementary Figure 1 .
Summary of the whole-genome sequencing results of the two brain tumor cases. (A) Sequencing depth and coverage of the tumor and blood samples. D refers to the female patient (daughter); S refers to the male patient (son); F refers to the patients' father; M refers to the patients' mother. B refers to blood samples. T refers to tumor tissue. (B) The proportion of different somatic mutation types in exons. (C) The distribution of somatic Indel length. (D) Circos plots of the female's (left) and the male's (right) brain tumor tissue illustrated distributions of all exonic mutations across the chromosomes. The outer first circle showed the chromosomes and the darker shaded areas represented large gaps. The second circle showed the somatic variants and each dot represented a single somatic variant. The third circle showed all observed tumor purity adjusted copy number changes, including both focal and chromosomal somatic events. The fourth circle represented the observed minor allele copy numbers across the chromosome. The innermost circle displayed the observed structural variants within the chromosomes. (E) Mutation number vs. Variant allele frequency (VAF) plot of the female's (left) and the male's (right) brain tumor tissue. Potential driver mutations are labeled (Red: Truncation mutation; Blue: Non-synonymous mutation).
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The tumors were sequenced at 50X and the blood samples were sequenced at 30X ( Figure 2A ). Both tumor cases harbored millions of somatic mutations, many hundreds of folds higher than the average somatic mutation numbers in either GBM or MB ( Figure 2D ). In both tumors, the predominant mutations were single base mutations ( Figure 2C ) and about half of the mutations in exons were non-synonymous mutations ( Figure 2B ). We also observed some well-known somatic mutations such as mutations in NF1, RB1, CDKN2A, TP53 and PTEN in the GBM case and mutations in TP53, NF1, SF3B1 and PTCH in the MB case ( Figure 2E ).
Summary of SBS signatures of the two brain tumor cases. (A) The distribution of different single base substitution types. (B, C) SBS signatures of the two brain tumor cases and two comparable mutational signatures: SBS44 and SBS14.
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We compared the mutational signatures of the two cases with the known mutational signatures and the result indicated strong signals of the SBS44 and SBS14 signatures for both cases; note that both of these signatures are associated with DNA mismatch repair ( Figures 3A-C ).
Summary of the MSH6 mutation in the two brain tumor cases. (A) Mutation positions of MSH6 in the two brain tumor cases and their parents. (B) MSH6 staining in the two brain tumor cases and the positive control from a glioma case (G47209) expressing MSH6. The magnification is 20x. (C) Hyperpigmented skin lesions in the male case.
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The mother carried an MSH6 c.2731C>T nonsense mutation and the father carried a single nucleotide deletion that resulted in a frameshift of the protein ( Figure 4A ). MSH6 protein in both tumor cases ( Figure 4B ). MSH6 nullizygous usually causes CMMRD syndrome, which is typically accompanied by a visible symptom called cafe-au-lait macules (CALM). We detected multiple flat patches of skin that were darker than the surrounding area in the male ( Figure 4C ).