Mutation — Genetic changes in cancer cells

At a molecular level, a genetic mutation represents an alteration in the sequence of nucleotides that compose an organism's genetic blueprint. Cells duplicate their DNA continuously as tissues renew themselves. Although internal proofreading mechanisms usually repair copying errors, certain changes escape correction. When mutations alter critical genes, such as proto-oncogenes or tumour suppressor genes, cellular regulation fails, precipitating malignant growth.

Mutations are broadly categorised into germline and somatic variants. Germline mutations are inherited from parents, present in every cell of the body from birth, and can predispose individuals to hereditary cancer syndromes. In contrast, somatic mutations are acquired during a person's lifetime due to cellular ageing, lifestyle factors, or environmental carcinogens like tobacco smoke or ultraviolet radiation. Somatic changes occur solely in affected cells and are not inherited.

Discovering specific genetic mutations has revolutionised modern oncology by enabling precision medicine. Instead of classifying tumours exclusively by the anatomical site where they first appeared, doctors frequently assess their underlying molecular alterations. This information reveals how quickly a malignancy might progress and highlights specific cellular vulnerabilities. Understanding whether a mutation is somatic or germline also informs familial risk management, determining whether close biological relatives might benefit from genetic counselling, heightened screening, or preventive strategies to mitigate future cancer development.

Mutations are identified through specialised molecular pathology tests performed on biopsy tissue, surgical specimens, or peripheral blood samples (liquid biopsies). Next-generation sequencing (NGS) analyses dozens or hundreds of cancer genes simultaneously. Polymerase chain reaction (PCR) assays evaluate specific known mutations with exceptional sensitivity. Fluorescent in situ hybridisation (FISH) detects larger structural alterations, while immunohistochemistry assesses protein expression changes caused by underlying mutations.

Genetic mutations are fundamental to every form of cancer. Common somatic alterations include EGFR or KRAS mutations in non-small cell lung cancer, BRAF mutations in cutaneous melanoma, and KRAS or NRAS mutations in colorectal adenocarcinoma. Germline mutations are famously exemplified by alterations in the BRCA1 and BRCA2 genes, which substantially elevate the risk of breast, ovarian, prostate, and pancreatic malignancies, as well as mismatch repair gene variants in Lynch syndrome.

Detecting actionable mutations permits the use of targeted therapies that block abnormal proteins driving malignant proliferation. For example, tyrosine kinase inhibitors selectively neutralise mutant EGFR proteins in lung cancer, while PARP inhibitors exploit repair vulnerabilities in BRCA-mutated tumours. Additionally, high tumour mutational burden (TMB) often predicts responsiveness to immune checkpoint inhibitors. Conversely, specific variants, like KRAS mutations in bowel cancer, signal resistance to certain antibody therapies.