Genomics Revolution in Cancer

Genomics in cancer means reading the genetic changes inside a tumour and in a person's inherited DNA, to decide what the cancer is, which medicine will work, who in the family is at risk and how disease can be prevented. For Dr. Shrinidhi Nathany, Consultant Molecular Hematology & Oncology, Fortis Memorial Research Institute, Gurgaon, India, that shift is a revolution: a cancer can no longer be fully diagnosed without it.

Dr. Nathany trained in medicine and pathology before moving into genomics, the branch that tests genes directly, and at the time of the masterclass she had five years of experience in molecular diagnostics. Her session was built for clinicians who order tests rather than run them, and its aim was practical: what genomic testing tells a treating doctor, where it applies across medicine, and what still holds it back. The two deeper articles in this series cover the laboratory and treatment side in how NGS tumour testing works and guides targeted therapy, and the family side in hereditary cancer testing, BRCA and prevention.

Genetics versus genomics: the clinic and the laboratory

Genetics is the study of genes and of the disorders caused by faults in them; genomics studies the alterations themselves, across many genes at once. Dr. Nathany put the distinction in terms every clinician recognises. Genetics is the snapshot: the abnormality a doctor can see in the patient, whether in a body part, the skin, a cancer or a child's development. Genomics is the bigger picture that explains why it is happening.

Her shortest version came in answer to a question from the audience: what the clinician sees in the patient is genetics; what she does in the laboratory is genomics. One faulty gene producing visible damage is a genetic problem. Looking at all the genes together, in the laboratory, is genomics.

The human genome in four numbers

A few figures explain why genomic testing is both possible and targeted:

• About 20,000 protein-coding genes. Every person carries roughly the same set of genes, and current reference counts put the protein-coding total at about 20,000.
• 99.9% shared. Any two people are about 99.9% identical in their DNA sequence. The remaining 0.1% is what makes each person an individual, and it is also where many disease-causing differences sit.
• About 1.5% codes for proteins. Only a small fraction of the genome carries the instructions for the proteins that run the body; the rest has regulatory and other roles.
• Testing concentrates on that 1.5%. Dr. Nathany noted that most cancer tests examine only this protein-coding portion.

When the laboratory examines a sample, it is reading the DNA itself and the molecules attached to it, change by change. That is what turns a biopsy into a molecular report.

Why the WHO classification made genomic testing essential

Genomic testing became essential because the classification pathologists use to name a cancer now rests on molecular findings as well as appearance. The World Health Organization (WHO) classification of tumours is the reference that tells pathologists what to call a cancer. When it began, it rested entirely on what the biopsy showed under the microscope: whether a tumour was, for example, an adenocarcinoma (a cancer of gland-forming cells) or a squamous cell carcinoma (a cancer of flat lining cells). Dr. Nathany's central point is that this is no longer enough, and she described genetic testing as mandated for reaching a cancer diagnosis. The current fifth edition of the WHO Classification of Tumours combines microscopic appearance with molecular features, and for several tumour types, including many brain tumours, the molecular result is part of the definition itself.

The practical consequence is stark. Without a molecular report, she explained, a pathologist cannot conclusively name the tumour and has to label it "not otherwise specified" (NOS), the term used when a cancer cannot be assigned to a defined subtype. That label is not a formality: it changes the treatment the patient receives.

Four uses of genomics in cancer care

Genomics in cancer answers four questions: what the cancer is, who in the family is at risk, which medicine will work and how disease can be prevented. Dr. Nathany built her case around these four uses and returned to them in the closing discussion.

1. Diagnosis. As above, the molecular profile is now part of what a cancer is.
2. Risk and hereditary predisposition. Testing shows whether a cancer arose from an inherited fault, which matters for the patient's own future risk and for relatives. This is covered in depth in hereditary cancer testing, BRCA and prevention.
3. Which medicine will work. Testing the tumour shows which drug is likely to work best, which is what personalised or precision medicine means. She noted that the US Food and Drug Administration (FDA) has approved drugs linked to at least 10 different genes, so that a patient with the matching mutation can receive a medicine with a much better outcome, and that NCCN (National Comprehensive Cancer Network) guidelines for tumour after tumour now include molecularly directed therapy. The laboratory process and the lung cancer example she used are in how NGS tumour testing works.
4. Prevention. Tests now exist that estimate the risk of disease before it starts. Her example was whole genome sequencing to find out whether a person is at risk of cardiac disease; if a heart attack is likely at some point in life, lifestyle changes can be made to prevent it. These are often called longevity tests, and in the closing discussion she described the same idea applied to biological age: a person who is 30 by date of birth may, because of stress, have a body that behaves as if it were 40. Testing can study why the body is ageing faster and support a personalised plan for diet, lifestyle and therapy.

Germline and somatic: two kinds of sample

Germline means inherited, present from birth in every cell; somatic means acquired, found in the tumour. The slide that mapped the whole field placed these two words at its centre. Germline testing can be done at any stage of life, from pregnancy through childhood and adolescence to adulthood. Somatic testing is done on the cancer itself. The difference decides what a result means for the family, and it is explained fully in the hereditary cancer article.

Pharmacogenomics: the same drug, different responses

Pharmacogenomics is the study of how a person's genes shape their response to a medicine. Dr. Nathany's example was paracetamol: two people can take the same drug, and because of their genes one may have fewer side effects and the other more. Pharmacogenomics, in her definition, is the genetics associated with any kind of therapy.

She singled out three areas where it is especially important: some childhood cancers, some adult cancers such as colon cancer, and psychiatric patients. Each has well-established examples. In childhood acute lymphoblastic leukaemia, variants in the TPMT and NUDT15 genes predict severe toxicity from thiopurine drugs. In colorectal cancer, DPYD variants predict dangerous toxicity from fluoropyrimidine chemotherapy, and UGT1A1 variants affect tolerance of irinotecan. In psychiatry, CYP2D6 and CYP2C19 variants alter how many antidepressants are metabolised. In each case, a gene test before treatment allows the dose or the drug to be adjusted.

Genomics beyond cancer, specialty by specialty

Dr. Nathany's argument was that genomics now runs across all of medicine, from childhood to old age:

• Paediatrics. Identifying inherited genetic diseases and childhood cancers.
• Geriatrics. Predicting how an older patient will respond to medication.
• Cardiology. A polygenic risk score, which combines the small effects of many gene variants into one estimate, shows whether an individual is at risk of a cardiac event, so that lifestyle modification can be advised early.
• Neurology. From non-cancerous disorders such as Alzheimer's disease and other dementias to brain tumours, many of which can no longer be diagnosed without molecular testing under the WHO classification of central nervous system tumours published in 2021. Asked whether molecular genetics can treat Alzheimer's disease, she was direct: it cannot, but identifying the cause can help other family members.
• Gastroenterology. From liver disease to cancers to common gastric problems such as peptic ulcer disease and acidity, which she noted can carry inherited predispositions, with treatment changing according to the gene detected. For infection-driven liver cancer linked to chronic hepatitis, she explained that hepatitis B virus DNA can be measured in the blood, and the amount tracked over time to show whether a patient is responding to treatment.
• Haematology. As in neurology, from benign disorders to blood cancers, genome sequencing is now central to establishing what is wrong with the patient.
• Oncology. Every cancer, in her view, should undergo genomic sequencing, a position she tied to the NCCN and European Society for Medical Oncology (ESMO) guidelines. The detail of what those guidelines recommend is set out in the NGS article.

Why cancer is rising, and how much of it is genetic

Asked what has caused the rise in cancer worldwide, Dr. Nathany called it multifactorial. Lifestyle comes first. Environmental insults follow: radiation, the food people eat and stress. The factor she considers underrated and underdiagnosed is genetics, which is why the testing matters. Estimates of strictly inherited cancer, caused by a single high-risk variant passed down in a family, are usually put at 5 to 10% of all cases; a further share shows family clustering without a single identified gene.

Her slide of global cancer statistics made a related point. Cancer affects every region of the world, and the purpose of genetic and genomic testing before cancer is diagnosed is to bring that risk down, particularly for inherited cancer. Screening, she explained, can happen in two ways: radiology imaging, and genetic testing of blood, known as liquid biopsy. As she clarified in the discussion, blood-based screening for early cancer is still under research for most cancers.

Barriers to genomic testing: awareness, ethics and cost

Three barriers hold genomic medicine back: low awareness, gaps in ethics and implementation, and limited reimbursement. Dr. Nathany was candid about each:

• Awareness. Knowledge of the branch and its tests is very low, even among clinicians. General practitioners, and doctors practising in the countryside and smaller cities, are often unaware of the tests, so uptake is low.
• Ethics and implementation. A genomic result is personal information and family information. The ethical frameworks, the clinical implementation and the evidence base to support them are still lacking in many parts of the world.
• Reimbursement. The tests are costly, few governments and insurers cover them, and in most countries the patient pays out of pocket. The cost figures she gave are in the NGS article.

Her prescription was aimed at doctors. Educate patients about why the test is needed. Read more, so that the case for offering it can be made well. And understand the regulations of one's own country, so that clinicians in different health systems can help each other.

Genetic counselling and collaboration with referring doctors

Genetic counselling and shared review of results connect the laboratory to the treating doctor, and the masterclass closed on that cooperation rather than competition. Dr. Nathany offered genetic counselling for patients where needed, supported by a certified genetic counsellor who takes the family history and advises the right test for that particular family. She also described sending samples for sequencing and discussing the results jointly with the referring doctor. The questions doctors put to her after the lecture, on liquid biopsy, gene therapy, CRISPR and the most common inherited cancer, are collected in the Live Discussion from this masterclass. Related reading across the site covers precision oncology and targeted therapy from the treating oncologist's side, and Jivo Healthcare's medical genetics, oncology and haematology specialties list the partner teams working in this field.