Table 1.
Summary of evolutionary analyses of the 16 RCC VTT cases.
| Patient | Evolutionary subtype | Trunk/early | Branch/late | Parallel mutation | Dominant mutational signature(s) | Dominant signature etiology | Metastasis emergence | Earliest branching region | Possible clonal selection | Polyclonality | Pattern |
|---|---|---|---|---|---|---|---|---|---|---|---|
| PT1 | Undetermined | VHL, SETD2, 3p loss | KDM5C, PTEN, VHL, 5q gain, 4q loss, 14q loss | KDM5C, PTEN, 14q, 4q | SBS39 | Unknown | Early | P1/LU | P1, P2, VTT, LU | Stable polyclonal trunk, secondary fixation of PTEN + KDM5C | |
| PT2 | Undetermined | VHL, KDM5C, 4q loss | ARID1A, KDM6A, SETD2, CSMD3, 3p loss, 5q gain, 8p loss, 14q loss | ARID1A | SBS15 | MMR deficiency | Early | LU | P2 | P1, P3 | Multi-modal, secondary fixation of ARID1A |
| PT3 | Undetermined | VHL, PBRM1, 3p loss, 5q gain, 14q loss | TP53, BAP1, 4q loss, 8p loss | BAP1 | SBS26 | MMR deficiency | Early | P1 | P1, VTT2, LU | P2, VTT1, LN | Multi-modal, secondary convergence to BAP1 mut |
| PT4 | Na (papillary RCC) | ARID1A | SBS39 | Unknown | Early | P3 | P1, P3, BN | VTT, AG | Multi-modal, secondary subclonal diversification | ||
| PT5 | Undetermined | VHL, KDM5C, 3p loss, 5q gain, 14q loss | PBRM1, 8p loss | SBS1,SBS39 | 5mC deamination (age/mitotic clock), Unknown | P1 | P1? | P2, P3, VTT | Multi-modal, secondary fixation of PBRM1 + 8p | ||
| PT6 | Subtype 4 (PBRM1 → SETD2) | VHL, PBRM1, 3p loss, 5q gain | SETD2 | SETD2 | SBS39 | Unknown | VTT | Clonal trunk, secondary subclonal diversification | |||
| PT7 | Subtype 7 (VHL monodriver) | VHL, 3p loss, 5q gain | 14q loss, 4q loss | SBS1, SBS29, SBS39,SBS6 | 5mC deamination (age/mitotic clock), Tobacco chewing, Unknown, MMR deficiency | VTT | VTT? | P1, P2, P3 | Multi-modal, secondary fixation of 14q, 4q | ||
| PT8 | Undetermined | VHL, KDM5C, 3p loss, 5q gain | SBS5 | Unknown (possibly age) | P3 | P1, P2, P3, VTT | Stable polyclonal trunk, secondary subclonal diversification | ||||
| PT9 | Subtype 4 (PBRM1 → SETD2) | VHL, PBRM1, 3p loss, 5q gain | KDM5C, SETD2, 8p loss | KDM5C | SBS15, SBS39 | MMR deficiency, Unknown | P2/VTT | Clonal trunk, secondary subclonal diversification | |||
| PT10 | Subtype 5 (PBRM1 → PI3K) | VHL, PBRM1, 3p loss, 5q gain, 14q loss | TSC1, 4q loss, 8p loss | SBS39 | Unknown | Early | AG1/AG2 | Clonal trunk, secondary subclonal diversification | |||
| PT11 | NA (papillary RCC) | PBRM1, SETD2, ARID1A, 4q loss, 14q loss | FAT1, 3p loss, 5q gain | SBS39 | Unknown | Early | LN1/LN2 | LN2? | Clonal trunk, secondary subclonal diversification | ||
| PT12 | Undetermined | VHL, SETD2, 3p loss, 5q gain | PBRM1, NFE2L2, SETD2, MTOR, TSC1, TP53, 4q loss, 8p loss, 14q loss | PBRM1, SETD2, 14q | SBS24,SBS39 | Aflatoxin, Unknown | Secondary | P1 | Clonal trunk, secondary subclonal diversification | ||
| PT13 | Subtype 7 (VHL monodriver) | VHL, 3p loss, 5q gain, 14q loss | SBS19,SBS25,SBS26,SBS6 | Unknown, Chemotherapy, MMR deficiency, MMR deficiency | P2 | P1, P2, P3, VTT | Stable polyclonal trunk, secondary subclonal diversification | ||||
| PT14 | Undetermined | VHL, PTEN, 3p loss, 5q gain, 4q loss | TP53, PBRM1, 8p loss, 14q loss | SBS1,SBS31, SBS4,SBS5, SBS8 | 5mC deamination (age/mitotic clock), Patient chemotherapy, Smoking, Unknown (possibly age),Unknown | Equivalent | P1 | Clonal trunk, secondary subclonal diversification | |||
| PT15 | Undetermined | VHL, PBRM1, 3p loss, 5q gain | SBS39 | Unknown | equiv. | Clonal trunk, secondary subclonal diversification | |||||
| PT16 | Undetermined | BAP1, 3p loss, 5q gain, 8p loss, 14q loss | SBS6 | MMR deficiency | P3 | Clonal trunk, secondary subclonal diversification |
Note: Phylogenetic placement of driver alterations (trunk/early vs. branch/late) and assignment of each tumor using previously described evolutionary subtypes (6). In addition to the assigned subtypes listed, PT12 had potential overlap with both “PBRM1 → SETD2” and “PBRM1 → PI3K” subtypes, PT14 showed the reverse pattern of the “PBRM1 → PTEN” subtype, and PT16 had some overlap with the “BAP1 alone” subtype but lacked VHL mutation. Tumor regions with possible clonal selection (based on region-specific fixation of a clone that appeared subclonal in the trunk) or persistent polyclonality are listed (see Supplementary Figs. S3–S18). Dominant mutational signatures (see Fig. 2) and metastasis emergence class (see Fig. 3) are also listed for each tumor.