INTRODUCTION TO ANEUPLOIDY

One of the most impressive undertakings in the life of a somatic cell occurs when it divides into two daughter cells. Nearly 3 billion base pairs of nucleotides packed into 23 pairs of chromosomes are duplicated, line up on a mitotic plate, and are pulled away from their identical sisters, tethered to mitotic spindles. This almost always results in a perfectly symmetrical division of the duplicated genome. Anyone who has dealt with fishing line along the shore of a stream knows how daunting it can be to keep a few metres of monofilament from becoming lethally tangled. Yet, the cell does this nearly every time with ineffable ease and, moreover, detects when the process is misbehaving, and halts progress. When a cell undergoes an unbalanced mitosis, this leads to the creation of aneuploid cells. In spite of the number of mitoses that occur each day, one is hard-pressed to find aneuploid cells in normal tissues.

ANEUPLOIDY AND CANCER

Cancer cells have survival advantages over their normal progenitors, but they tolerate some degree of malfunction in mitotic homeostasis, and are frequently aneuploid. Perhaps even more surprising, the more aneuploidy one finds in a colorectal cancer (CRC) the more deadly the tumour.1 One might anticipate from first principles that a derangement in orderly cell division would be difficult to tolerate, would confer a deficit in fitness, and that mitotic instability would lead to its own demise. However, this is not the case, and understanding this paradox might provide some insight into how cancers develop, and how we might find its Achilles heel.

The conceptual challenge for understanding aneuploidy …