Dosage, Not Mutation

01The evidence

• Whole-genome doubling is now being translated into precision medicine, with the recognition that doubled tumours carry a distinct evolutionary trajectory and a different response to therapy.Molecular Oncology, 2026
• Karyotypic evolution in hypodiploid tumours shows pervasive chromosomal instability generating a standing diversity of copy-number states, which is the substrate a dosage model requires.Genome Medicine, 2026
• Tools are now being built to predict how cancers evolve, which assumes an evolutionary process that can be forecast from measurable state rather than treated as stochastic.Moffitt, 2026

02The tension

Resistance is usually modelled as mutation-limited: a rare variant arises and is selected. That predicts resistance time should scale with mutation rate and tumour size. But resistance often appears faster than mutation supply allows, and some resistant clones carry no new point mutation at all.

03The theory

A whole-genome doubling event converts a cell with two copies of each chromosome into one with four. That immediately creates a large set of dosage variants, some of which confer partial resistance to whatever drug is applied. Selection then acts on standing variation rather than waiting for new mutation.

If this is right, resistance is a selection problem, and selection problems are predictable from the distribution of the standing variation. The gene amplified before treatment should be the gene whose further amplification confers resistance. The chromosome that is trisomic should be the one carrying the resistance locus.

This makes the order of resistance deterministic in a way mutation models do not. A tumour with extra copies of chromosome seven should fail a particular drug before a tumour with extra copies of chromosome one, regardless of mutation rate, because the first already has the raw material.

The clinical version is a forecast: karyotype the tumour before treatment and predict which drug will fail first. The theory is falsifiable because the forecast is specific and the alternative, mutation-driven resistance, predicts no such ordering.

04What this is not

05Predictions

• P1Resistance-conferring events should map to chromosomes already amplified pre-treatment more often than chance allows.
• P2Whole-genome doubling status should predict time to resistance better than mutation burden.
• P3Pre-treatment karyotype should predict which drug fails first, in a prospective cohort.

06What would refute it

If resistance order is independent of pre-treatment copy number after controlling for tumour type and burden, dosage is not the organising variable.

07What it would change

It would turn a karyotype into a resistance forecast and shift effort from mutation hunting to copy-number-aware trial design.