Tumour Heterogeneity: Why One Biopsy May Not Represent the Whole Cancer

Where Heterogeneity Comes From

As a tumour grows, cells accumulate mutations at different times. Some are present in every cancer cell (truncal or clonal) because they occurred early; others are present only in a subset (branch or subclonal) because they arose later in one lineage.

This branched pattern of evolution means a tumour is better thought of as a tree of related clones than as a single genotype.

Spatial Heterogeneity

Multiregion sequencing studies have shown that different parts of the same tumour can carry different subclonal mutations, and that a driver present in one region may be absent in another.

A single needle biopsy samples a small volume and may therefore miss subclones that are clinically important, for example a resistance mutation present only in one area.

Temporal Heterogeneity

Treatment applies selective pressure. A therapy can shrink the sensitive bulk of a tumour while a small resistant subclone expands, so the tumour's dominant genotype at progression differs from that at diagnosis.

This is why repeat biopsy or circulating tumour DNA testing at progression is often more informative than relying on the original result.

Clonal vs Subclonal Drivers

Whether an alteration is clonal or subclonal affects its interpretation. A clonal driver is a target present in every cancer cell; a subclonal alteration may only account for part of the disease and targeting it may leave other clones to grow.

Some analyses, for example of tumour mutational burden as an immunotherapy biomarker, suggest the clonal fraction of the signal matters more than the total.

Interpretation Notes

A negative result for a specific mutation does not guarantee it is absent elsewhere in the tumour, particularly from a small or single-site sample.

Where available, the variant allele fraction and any estimate of clonality help gauge whether a finding represents the whole tumour or a fraction of it.

Key Takeaways

• ·Tumours evolve as branched trees of related clones, not single genotypes.
• ·Different tumour regions can carry different subclonal mutations.
• ·Treatment selects for resistant subclones, changing the tumour over time.
• ·Clonal drivers are present in every cancer cell; subclonal ones are not.