Non-clonal interphase markers of chromosomal instability in malignancy acquisition and cancer progression

Chromosomal instability (CIN) is a pervasive feature of cancer and a major driver of tumor heterogeneity, evolution, and therapeutic resistance. Arising predominantly from defects in chromosome segregation, DNA repair, and mitotic fidelity, CIN promotes continuous genomic diversification within tumor cell populations, enabling adaptive responses to intrinsic and extrinsic selective pressures. While clonal chromosomal alterations reflect stabilized genomic configurations selected during tumor evolution, non-clonal interphase markers of chromosomal instability represent transient, low-frequency events that capture ongoing microevolutionary dynamics and genomic plasticity. This review provides a comprehensive synthesis of current knowledge regarding both classical and non-classical markers of CIN evaluated during interphase, including micronuclei, nucleoplasmic bridges, nuclear buds, cytoplasmic chromatin, massive chromosomal segregation errors, chromosomal fragmentation, and genomic chaos-related phenomena. We discuss the cellular mechanisms underlying their formation, their contribution to structural and numerical chromosomal alterations, and their role in shaping intratumoral heterogeneity, adaptive potential, malignancy acquisition, and cancer progression. Particular emphasis is placed on the "just-right" dual nature of CIN, which can either drive tumor aggressiveness or precipitate mitotic catastrophe and cell death, depending on its magnitude and cellular context. By integrating cytogenetic, molecular, and evolutionary perspectives, this review highlights the relevance of these non-clonal interphase cytogenetic markers as sensitive indicators of genome instability and tumor dynamics. Understanding the interplay between clonal and non-clonal chromosomal alterations may provide valuable insights for the development of prognostic tools and therapeutic strategies aimed at exploiting the vulnerabilities of genomically unstable cancers.