Inherited risk is mostly unidentified
Most people who carry a high-risk cancer gene do not know it until they or a relative gets cancer.
Pathogenic germline variants in BRCA1/2, the Lynch syndrome mismatch-repair genes, TP53, PALB2, CDH1 and others confer lifetime cancer risks of 40-80%, and effective risk reduction exists (risk-reducing surgery, intensified surveillance, aspirin, PARP inhibitors when cancer occurs). Yet most carriers are identified only after a cancer diagnosis, and often not even then: fewer than a fifth of US women with a history of breast or ovarian cancer who met testing criteria had been tested. Cascade testing of relatives, the cheapest way to find healthy carriers, reaches a minority of eligible family members. Germline testing is also inequitable, with reference databases dominated by European ancestry, so variants of uncertain significance are more common in other populations. Polygenic risk scores could stratify screening for common cancers but are not yet implemented or validated across ancestries.
- Testing is triggered by family history, which is often unknown, incomplete or not asked about.
- Cascade testing depends on the index patient informing relatives, with no systematic follow-through.
- Genetic counselling capacity is limited and testing criteria are complex.
- Reference databases under-represent non-European ancestries, producing more uncertain variants.
- Population screening for germline variants has been considered too costly, although sequencing costs have fallen sharply.
- The NHS Jewish BRCA Testing Programme offers population-based BRCA testing to people with Jewish ancestry in England.
- Universal tumour screening for Lynch syndrome in all colorectal and endometrial cancers is guideline-recommended and being audited in the UK and US.
- NCCN and ESMO guidelines have broadened germline testing criteria, including all patients with pancreatic, ovarian and metastatic prostate cancer.
- The WISDOM trial tests risk-based breast screening incorporating polygenic risk scores against annual mammography.
- ClinVar and ENIGMA/InSiGHT expert panels curate variant classification and reduce uncertain variants.
- Mainstreaming programmes let oncologists order germline tests directly, bypassing the counselling bottleneck.
BRCA1 breast cancers seem to grow from cells driven by the RANK signal. Denosumab blocks it and is already used for bone. A trial is testing whether it prevents these cancers.
There are far too few genetic counsellors. A validated chatbot can do the standard pre-test education, leaving people with complex needs for humans.
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.
Anyone with ovarian, pancreatic, metastatic prostate or mismatch-repair-deficient cancer should be tested for inherited mutations, but many are not. Make it an automatic, opt-out lab step.
Fear of losing insurance stops many people having genetic tests. Extending non-discrimination law to life and disability cover, as Canada has, would remove that fear.
Genetic risk scores were built mostly on Europeans and work worse in others. Funding non-European cohorts and setting a portability standard would prevent screening that widens inequality.
For people at very high cancer risk, install a small population of engineered immune cells that live for years and destroy cells showing early cancer signals before a tumour forms.
Doctors rarely take a full family history. An app that gathers it from the patient and checks it against testing guidelines would find many people who qualify.
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.
Many women who died of ovarian cancer were never tested for BRCA. Testing their stored tumour samples and contacting their relatives would find carriers before they get cancer.
When someone tests positive for a BRCA or Lynch mutation, relatives are told only if the patient passes the message on. Most do not. Letting clinics contact relatives directly, with consent, could double testing.
Most people with BRCA or Lynch mutations do not know until they get cancer. Testing everyone once for a short list of high-impact genes would find them in time to prevent it.
There are too few genetic counsellors to see every patient who should have an inherited-risk test. Let the cancer team order the test with a short consent script, and use video counsellors for those with results that matter.
Most people carrying a high-risk cancer gene do not know it until someone in the family gets cancer. Offer testing to all adults so carriers can be protected before that happens.
Newborn sequencing programmes exclude adult cancer genes because babies cannot consent. Storing those results and offering them at 18 would preserve choice and give a lifetime of prevention.
Many people get a genetic result of uncertain significance, which cannot be acted on. Lab methods now let us test every possible variant in a gene in advance.
Sequence every cancer at diagnosis, along with the patient's inherited genes, and pool the results with treatments and outcomes so every patient teaches the system how to treat the next.
Common gene variants shift a person's cancer risk several-fold. A one-time genetic score could tell each person when to start breast, bowel or prostate screening.
People with an inherited TP53 mutation face a near-certain lifetime cancer risk. Yearly whole-body MRI catches cancers early; adding blood DNA tests may catch them earlier still.
Everyone with HER2-negative early breast cancer that meets high-risk criteria should be offered germline BRCA testing, because a positive result now changes treatment: a year of olaparib after chemotherapy reduces relapse and death. It does not apply to low-risk tumours, HER2-positive disease, or somatic-only BRCA mutations.
People with Lynch syndrome should be offered daily aspirin, which roughly halves bowel cancer risk with a delayed and durable effect. Whether a lower dose (as tested in CAPP3) is as effective, and whether the finding extends to the general population, are separate questions.
Because Lynch syndrome tumours make the same abnormal proteins in almost every patient, a single vaccine could in principle be given to carriers before cancer develops. This small trial showed the concept is safe and immunogenic; whether it prevents cancer requires the randomised trials now being planned.
Every woman diagnosed with advanced high-grade ovarian cancer should be tested for BRCA mutations at diagnosis, because those who carry one should receive two years of olaparib after chemotherapy, which greatly extends the time in remission and improves long-term survival. The plateau in the survival curves suggests some patients are cured by this approach. Toxicity is mostly anaemia, fatigue and nausea, and the two-year limit appears sufficient.
For women at raised risk, a 5-year course of tamoxifen offers long-lasting protection against the commonest kind of breast cancer. Uptake is low because of side effects and fear of rare serious harms; low-dose tamoxifen (TAM-01) is now being tested to improve the balance. It has not been shown to save lives.
For women who carry a BRCA mutation, preventive removal of the ovaries and tubes saves lives, and preventive mastectomy almost eliminates breast cancer. These are the strongest prevention effects in oncology, which is why finding carriers before they develop cancer matters so much.
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