Loading
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.
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.
Every triple-negative patient under 60 in the UK should be offered a BRCA test at diagnosis because the result now changes treatment, and many should be offered a trial, but no one publishes how many are. A national audit through existing cancer registration and genomic laboratory data would show the gap by region before anyone tries to close it.
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.
Fear of losing insurance is a top barrier to genetic testing in surveys. Extending non-discrimination law to life and disability cover, as Canada's 2017 Genetic Non-Discrimination Act does and the US law does not, would remove that fear and raise cascade testing in families.
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, so eligibility for genetic testing goes undetected. An app that gathers the history from the patient, feeds it into the record and checks it against NCCN or NICE criteria would identify several-fold more eligible people and, the proposal estimates, roughly double the number tested.
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.
Women who died of ovarian cancer without ever having BRCA testing leave relatives who are otherwise unreachable. Retesting archived tumour tissue and contacting families, piloted on 2,000 cases from the past 15 years, would find carriers before they develop cancer; US pilots show it is feasible and ethically acceptable.
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.
One patient in twenty with pancreatic cancer carries an inherited gene fault, and most have no family history. Guidelines now say test every patient, which finds relatives who carry it too, but the yearly scans that catch cancer at stage I in carriers are still offered only in research programmes. The proposal is to make surveillance follow the test result automatically.
About one man in eight with prostate cancer that has spread carries an inherited DNA repair fault, and about one in five has one in the tumour. The drugs for those faults have moved to the beginning of treatment, but the test is still usually done near the end, when it is too late to use the result.
Genetic testing often returns a variant of uncertain significance that cannot be acted on, most often in people of non-European ancestry. Saturation genome editing has already classified nearly all BRCA1 single-nucleotide variants; a consortium doing the same for the roughly 30 actionable hereditary cancer genes would end most uncertain results.
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.
The stage shift the pancreatic cancer page quotes (about three in four surveillance-detected cancers at stage I) and the strongest argument for offering surveillance to every germline carrier found by universal testing, which the NHS does not yet do outside research.
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.
The evidence base for setting the age at which screening starts by risk rather than by birthday. It is also a warning: the same score performs differently across ancestries, so a risk model built and validated in European cohorts will under-serve the men at highest risk.
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.
Sets the surgical and systemic rules for the one in nine to one in six triple-negative patients who carry a germline BRCA variant (11 to 17 percent by cohort); the adjuvant gap it named was filled by OlympiA the following year.
The rulebook behind the CAPS cohorts and the UK EUROPAC programme; it is also the reason surveillance for carriers is not yet a routine NHS service, because the consortium itself asked for it to stay within research until benefit was shown.
Family history misses most carriers, so the NCCN and ASCO guidelines moved to testing every patient; each carrier found is a family that can be offered surveillance and a patient who may be eligible for platinum and PARP inhibition.
Shares Jon M. Huntsman Sr., Gilda Radner, Founder variant, MEN1 and hereditary neuroendocrine syndromes.
Shares GINA (Genetic Information Nondiscrimination Act 2008), Association for Molecular Pathology v. Myriad Genetics (2013), The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews, Surveillance for every germline carrier found by universal testing, inside a registry rather than a research exception.
Shares Angelina Jolie, Mary-Claire King, OlympiA: a year of olaparib after surgery for BRCA-mutated, high-risk early breast cancer, OlympiA.
Shares Angelina Jolie, PROSE consortium: preventive surgery lowers cancer and death in BRCA1 and BRCA2 carriers, OlympiA: a year of olaparib after surgery for BRCA-mutated, high-risk early breast cancer, Olaparib.
Shares Ban life and disability insurers from using genetic results, Get every Lynch syndrome carrier onto the right dose of aspirin, Population germline screening for hereditary cancer genes with cascade testing, IBIS-I: five years of tamoxifen keeps preventing breast cancer for at least 20 years.
Shares Surveillance for every germline carrier found by universal testing, inside a registry rather than a research exception, OlympiA, Olaparib, Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question.
Shares Risk of Neoplastic Progression in Individuals at High Risk for Pancreatic Cancer Undergoing Long-term Surveillance, Surveillance for every germline carrier found by universal testing, inside a registry rather than a research exception, The Multicenter Cancer of Pancreas Screening Study: Impact on Stage and Survival, Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium.
Shares Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer, Inherited DNA-repair gene mutations in men with metastatic prostate cancer, Homologous recombination deficiency (HRD), Germline vs somatic mutations.