Hereditary Cancer Testing: BRCA, Family Risk and Prevention

Hereditary cancer testing looks for germline variants, inherited faults such as those in the BRCA genes that are present in every cell from birth, to show whether a person or their relatives carry a raised risk of cancer. Dr. Shrinidhi Nathany, Consultant Molecular Hematology & Oncology, Fortis Memorial Research Institute, Gurgaon, India, calls hereditary breast and ovarian cancer the most common genetic cancer, largely because it is the most tested for.

Knowing the gene changes what a family can do: watch more closely, catch cancer early, choose preventive surgery, or plan a pregnancy with the facts in hand. This article covers germline testing, the family and reproductive decisions it informs, and where gene therapy now stands. The tumour testing that guides cancer treatment is covered separately in how NGS tumour testing works, and the full masterclass overview is in the Genomics Revolution in Cancer complete guide.

Hereditary cancer testing: germline versus somatic

The two words at the centre of Dr. Nathany's map of genomics decide what a result means:

• Germline means inherited. A germline variant is present from birth in every cell of the body, can be passed to children, and is usually tested on a blood or saliva sample.
• Somatic means acquired. A somatic variant arises in the tumour during a person's life, is found only in the cancer, and is not passed on.

A somatic result guides treatment of the cancer in front of the doctor. A germline result reaches further: it changes the patient's risk of a second cancer and tells relatives whether they need testing. Germline testing, she explained, can be done at every stage of life, from pregnancy through infancy, childhood and adolescence to adulthood.

BRCA and hereditary breast and ovarian cancer (HBOC)

Asked which genetic cancer is most common, Dr. Nathany answered breast cancer, through the syndrome called hereditary breast and ovarian cancer (HBOC). She was precise about the reason: it is the most common largely because it is the most tested for. Many more cancers can be inherited.

HBOC is mostly caused by germline variants in BRCA1 and BRCA2, the genes often called the breast cancer genes. A harmful variant in either gene substantially raises lifetime risk of breast and ovarian cancer, and is also linked to higher risk of prostate and pancreatic cancer. The pattern is autosomal dominant: one altered copy is enough, so each child of a carrier has a 50% chance of inheriting it.

Prevention versus cure: what a positive BRCA result makes possible

A positive result makes prevention possible: closer watching, earlier detection or preventive surgery before cancer develops. Dr. Nathany's example of prevention was the actor Angelina Jolie, who learned that she carried an inherited BRCA mutation and underwent a preventive, or prophylactic, mastectomy. Her variant was in BRCA1, and she made her decision public in 2013.

The lesson Dr. Nathany drew was broader than surgery. All cancers should be tested, she argued, so that a patient knows whether he or she is at risk of developing cancer again. Asked whether genomic modification can prevent cancer, her answer was plain: not yet. What a person can do is get tested. If a relative has had cancer, testing shows whether that person carries the same risk, and if so, cancer can be caught early. Once a cancer reaches the last stage it becomes difficult to cure; caught early, it can still be cured.

For patients whose results lead towards surgery, Jivo Healthcare's breast cancer surgery cost page sets out what mastectomy involves for international patients.

Cascade testing and genetic counselling for the family

When one person is found to carry an inherited variant, testing can be extended to relatives. For any inherited genetic disease, Dr. Nathany explained, the laboratory can test the family and detect the condition early in other members. This approach is known as cascade testing: first-degree relatives (parents, siblings and children) are offered the specific variant test first, then the circle widens as carriers are found. Relatives who test negative for a known family variant are usually spared the intensified surveillance that carriers need.

Interpretation matters as much as the test. Dr. Nathany offers genetic counselling for patients where needed, supported by a certified genetic counsellor, so that the family history is understood and the correct genetic test is chosen for that particular family. The same principle applies outside cancer: answering a question on Alzheimer's disease, she noted that molecular genetics cannot treat it, but identifying the cause can help the rest of the family.

Prenatal testing: fetal DNA in the mother's blood

Germline testing can begin in pregnancy. Dr. Nathany explained that the mother's blood carries fetal DNA, which can be tested to find out whether the fetus has a genetic abnormality, and the parents can then be counselled, including on whether to continue the pregnancy.

This approach, known as non-invasive prenatal testing (NIPT) or cell-free DNA screening, is a screening test. A high-risk result is confirmed by a diagnostic procedure such as chorionic villus sampling or amniocentesis before any decision about the pregnancy is made.

Premarital genetic testing and carrier status

Dr. Nathany pointed to the United Arab Emirates, which has mandated premarital genomic testing to prevent genetic diseases in infants born of marriages between relatives. Her advice to couples was memorable: match your genome, not only your stars, before marrying the love of your life. If both partners carry the same faulty gene, there is a chance of having a child with a genetic disease.

The mechanism is carrier status. In a recessive condition, a carrier holds one altered copy of a gene and is healthy. When both parents carry an altered copy of the same gene, each pregnancy has a 25% chance of producing an affected child. Marriages between relatives raise the chance that both partners carry the same variant. Asked which test establishes genetic compatibility between partners, Dr. Nathany named genome sequencing.

Haemophilia carriers: what a family tree shows

Haemophilia shows why carrier status matters. Dr. Nathany used a pedigree most doctors know: the European royal family that carried haemophilia. In her slide, the members outlined in red were carriers, holding the abnormal gene without the disease, and those outlined in blue were affected.

Haemophilia is an inherited bleeding disorder caused by a deficiency of a clotting factor: factor VIII in haemophilia A and factor IX in haemophilia B. The genes sit on the X chromosome, which is why, as Dr. Nathany explained, it is normally males who are affected and females who are carriers. Knowing which gene a person carries is what allows complications to be prevented.

Gene therapy and CRISPR genome editing

Gene therapy aims to correct, replace or compensate for a faulty gene so that the disease it causes is treated at its source. Dr. Nathany described the idea for haemophilia as editing the gene of affected individuals so that the genetic defect is corrected. Gene-addition therapies for haemophilia A and B have been approved in the US and Europe since 2022, although access remains limited and gene-editing approaches for haemophilia are still in clinical trials.

Her clearest illustration was sickle cell anaemia, which is caused by a point mutation: a single letter in the genome is changed. In principle, she explained, if A has become B, the laboratory can turn B back into A, edit the gene, and deliver the corrected product to the patient as a solution through an intravenous cannula, where it is integrated and the disease can be cured. The sickle cell change is a single base substitution in the HBB (beta-globin) gene. The first approved CRISPR-based therapy for sickle cell disease, authorised in the UK and the US in 2023, edits the patient's own blood stem cells outside the body so that they switch fetal haemoglobin back on, rather than correcting the letter itself; the edited cells are returned by infusion after conditioning chemotherapy.

CRISPR-Cas9, which an attendee asked her to explain, is the gene-editing technology behind such therapies. CRISPR provides the editing system and Cas9 is the enzyme that cuts the DNA at the chosen point, so that the faulty gene can be edited and delivered back to the patient. Dr. Nathany noted that it is not yet available in all countries.

The limits and responsibilities of genetic knowledge

Dr. Nathany was clear about what genomics cannot yet do. Genomic modification cannot prevent cancer today, and molecular genetics cannot treat Alzheimer's disease. What testing offers is knowledge early enough to act on.

That knowledge carries obligations. A germline result is personal information and family information at once, and she identified ethical frameworks and clinical implementation as gaps that many health systems have not yet closed. The cost of testing and the barriers to uptake are covered in the complete guide, and the questions doctors raised on gene therapy, CRISPR and inherited cancer are in the Live Discussion from this masterclass. The medical genetics and haematology specialties list the partner teams that see families with inherited cancer and blood disorders.