Mutation and mutational signatures

Some tumours change fast and escape drugs quickly; others are stable. A single validated score for how evolvable a tumour is would tell doctors how aggressively to combine treatments.

Subsets of lung, bladder and breast cancers carry raised APOBEC enzyme activity that keeps generating new mutations, feeding resistance. Blocking APOBEC3 alongside a targeted drug aims not to kill cells but to slow the rate at which resistant variants arise; the inhibitors are still in discovery.

Under treatment stress, cancer cells switch on sloppy DNA copying that generates the mutations they need to survive. Blocking that machinery could stop resistance being invented.

For some cancers, drugs and radiotherapy can now cure without removing the organ, sparing patients a stoma, a lost voice or a removed bladder. A dedicated programme would run the trials to prove where this is safe.

Anyone with ovarian, pancreatic, metastatic prostate or mismatch-repair-deficient colorectal cancer should be tested for inherited mutations, yet testing rates fall well short. Making it an automatic, opt-out laboratory step triggered by pathology, as reflex mismatch-repair testing already is, would close the gap.

Scotland and Wales put a floor under the price of alcohol. Deaths from liver disease have already fallen. Cancer takes longer to show, so someone has to keep measuring for a decade.

Aspirin roughly halves bowel cancer in Lynch syndrome, and a dose trial is defining how little is needed. Most carriers are still not prescribed it; the task is to fix prescribing.

Give adjuvant treatment by the tumour's molecular class rather than by stage and grade: nothing for POLE-mutated, immunotherapy for MMRd, chemotherapy plus targeted agents for p53-abnormal, hormones for NSMP.

For each cancer type, agree the set of stains and tests that are always needed, and have the lab run them automatically on diagnosis rather than waiting for someone to ask.

People with Lynch syndrome have a very high lifetime cancer risk from a predictable set of mutations. Vaccinate them against those shared mutations before cancer appears.

Lynch syndrome tumours share predictable mutations the immune system can target. A vaccine in early trials could be tested to see if it prevents polyps and cancers in carriers.

Tumour mutational burden decides who gets immunotherapy in some settings, but every sequencing panel calculates it differently. A shared calibration would make the number mean the same thing everywhere.

Ninety-five percent of bowel cancers ignore immunotherapy. Combinations that heat the tumour up (targeted drugs, radiation, new checkpoints) are the main hope.