Intratumoral heterogeneity of cancer driver genomic alterations in myxoid liposarcomas

Figures

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  FIGURE 1. Mutational profiling and tumor heterogeneity in MLS, part 1. (A) The detected mutations after subtype‐specific target enrichment in MLS tumors are illustrated. Every pathologically confirmed MLS harbored an entity‐specific fusion event. Mutations in the TERT promoter region occurred in approximately 85% of tumors, with the C228T variant accounting for the largest proportion. Variants in PIK3CA were observed in 70% of tumors. (B–F) The figures illustrate intratumoral heterogeneity in t(12;16)‐positive MLS tumors, with only one tumor analyzed per patient. The detected variants for each tumor are depicted in a chord diagram. Each gray bar represents a segment, whereas the variants are indicated as colored bars. The colors are kept equal for all tumors. The colored links indicate which variant was detected in which sample. (B) The resected tumor from patient 1 was cut into 13 segments. Each sample harbored the C228T variant of the TERT promoter region as well as the fusion t(12;16) with its reciprocal breakpoints. (C–F) The results for the tumors from patients 2–5 are presented the same way. Most different mutations were detected in patient 4 with a very pronounced heterogeneous…

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  FIGURE 2. Tumor heterogeneity in MLS, part 2, and metastatic disease in patient 8. Each chord diagram has the same structure as described for Figure 1. (A,B) The MLS tumors that had fusion of DDIT3 and EWSR1 t(12;22) are depicted (patients 6 and 7). In every segment, the individual and fusion‐specific breakpoint was detected. The reciprocal breakpoint could not be detected in any of the tumors. Once again, the TERT promoter region was very dominant, with proven variants in almost all segments (C250T in patient 5 and C228T in patient 6). (C,D) These chord diagrams show two different tumors from the same patient. On the left, three‐dimensional reconstructions of each tumor were merged into a three‐dimensional reconstruction of a PET‐CT scan for better visualization. (C) Patient 8 initially presented with a high‐grade MLS in his left thigh (pink tumor). After resection, metastases in the lungs (blue tumors) and breast (green tumors) were observed during follow‐up care 6 months postoperatively and (D) were resected accordingly (green tumor). The primary tumor showed marked intratumoral heterogeneity regarding single‐nucleotide variants (PIK3CA, TET2, and TP53). The patient‐specific…

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  FIGURE 3. Tumor heterogeneity in metastatic disease (from patient 9 with MLS). The chord diagrams show different tumors from the same patient. The structure of the diagram is the same as described for Figure 1. In the center, three‐dimensional reconstructions of each tumor were merged into a three‐dimensional reconstruction of a PET‐CT scan for better visualization. Patient 9 initially presented with incomplete resection of a high‐grade MLS in the right thigh. After wide resection, a retroperitoneal metastasis (A) was observed 3 years postoperatively and was resected consecutively (pink tumor) followed by multiple recurrences and resections over a period of approximately 6 years, with (B) another retroperitoneal metastasis (orange tumor), (C) a mesenterial metastasis (green tumor), and (D) a metastasis in the right upper arm (light‐blue tumor). The same variants were detectable in each segment of a tumor that had positive detection of tumor mutations. This was consistent even for metastatic disease. The lack of detected tumor mutations in a few segments was probably caused by a lack of tumor cells in the tissue used for extraction rather than by genomic heterogeneity. MLS indicates myxoid…

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  FIGURE 4. Tumor heterogeneity in metastatic disease (from patient 10 with MLS). The chord diagrams show different tumors from the same patient. The structure of the diagram is the same as described for Figure 1. In the center, three‐dimensional reconstructions of each tumor were merged into a three‐dimensional reconstruction of a PET‐CT scan for better visualization. Patient 10 presented after multiple marginal resections and recurrences of a high‐grade MLS in both lower legs. (A) With no sign of distant metastasis, another resection was performed (yellow tumor). (B–D) The resection was followed by multiple local recurrences and resections (pink, green, and brown tumors) until, finally, (E) a lung metastasis was detected and resected 2 years after first presentation (red tumor). In all samples, the same patient‐specific translocation as well as the PIK3CA variant c.1035T>A were detected with few exceptions. In contrast, the TERT promoter variant C250T was present in every tumor except tumor 3 (local recurrence; green tumor in C), showing correlation of the mutation profile with a few segments in tumors 1 and 2 (A,B). MLS indicates myxoid liposarcoma; PET‐CT, positron emission…