Table 2.
The six phases of cancer evolution and clinical correlates.
| Phase | Biologic status | Clinical correlates (examples) |
|---|---|---|
| 0 | Genetic Background (SNPs, mutations, absent TSGs) | Familial predispositions and familial clustering of cancer |
| I | Somatic evolution: step-wise acquisition of somatic passenger lesions over time (during aging) | Passenger mutations found in healthy individuals; e.g. CHIP with DNMT3A mutation; or clonal IGH/IGL or TCR gene rearrangements (but without a morphologic or phenotypic correlate) |
| II | Acquisition of driver lesions in small-sized sub-clones | Low levels of JAK2 V617F or BCR-ABL1 in apparently healthy individuals; or clonal persistent BCL2 rearrangements in healthy individuals (CHOP); microadenomas, BRAF-mutated pigment-lesions in the skin, small-sized T cell or B cell clones with aberrant specific immunophenotype |
| III | Expansion of sub-clones carrying driver lesions – until replacement of the normal organ system, but no evidence of invasive or aggressive expansion; in many instances, neoplastic cells replace the normal tissue/organ | Indolent neoplasms, pre-invasive carcinomas, early stages of indolent NHL, in situ indolent NHL; LR-MDS; early chronic phase CML, early stages of JAK2-mutated MPN; indolent systemic mastocytosis |
| IV | Overt expansion beyond the affected organ system; but may still be more or less indolent | Chronic phase CML; overt MPN; MDS, minimal invasive tumors; overt indolent NHL; smoldering systemic mastocytosis |
| V | Aggressive/advanced malignancy⁎ | Accelerated CML or MPN; local solid tumors/carcinoma; grade IIIa FL, myeloma, aggressive systemic mastocytosis |
| VI | Progressive malignancya Metastatic cancer | Blast phase of CML, (secondary) AML, grade IIIb FL, aggressive NHL; mast cell sarcoma, mast cell leukemia; metastatic solid tumor/carcinoma |
a
In some phase V/VI malignancies such as aggressive NHL or mast cell leukemia, the previous (preceding) phases of cancer evolution remain undetected in most patients. Abbreviations: CHIP, clonal hematopoiesis of indeterminate potential; CHOP, clonal hematopoiesis with substantial oncogenic potential; NHL, Non Hodgkin lymphoma; LR-MDS, low-risk myelodysplastic syndrome; CML, chronic myeloid leukemia; MPN, myeloproliferative neoplasm; AML, acute myeloid leukemia; FL, follicular lymphoma.