Are aneuploidy and chromosome breakage caused by a CINgle mechanism?

Abstract

Genetic instability is a hallmark of cancer. Most tumors show complex patterns of translocations, amplifications and deletions, which have occupied scientists for decades. A specific problem arises in carcinomas with a genetic defect termed chromosomal instability; these solid tumors undergo gains and losses of entire chromosomes, as well as segmental defects caused by chromosome breaks. To date, the apparent inconsistency between intact and broken chromosomes has precluded identification of an underlying mechanism. The recent identification of centromeric breaks alongside aneuploidy in cells with spindle defects indicates that a single mechanism could account for all genetic alterations characteristic of chromosomal instability. Since a poorly controlled spindle can cause merotelic attachments, kinetochore distortion, and subsequent chromosome breakage, spindle defects can generate the sticky ends necessary to start a breakage-fusion-bridge cycle. The characteristic breakpoint of spindle-generated damage, adjacent to the centromere, also explains the losses and gains of whole chromosome arms, which are especially prominent in low-grade tumors. The recent data indicate that spindle defects are an early event in tumor formation, and an important initiator of carcinogenesis.