Overview
Tumour mutational burden (TMB) is a numeric index that represents the number of mutations present per megabase of the coding region of a tumour genome. It reflects the overall mutational load carried by tumour cells. This parameter is increasingly used as a predictive biomarker in cancer management.
TMB helps in understanding the genetic complexity of a tumour. A higher number of mutations may result in the production of abnormal proteins, which can influence tumour behaviour and treatment response. Knowing the TMB value supports the selection of appropriate therapeutic strategies.
Role of Tumour Mutational Burden
Genes carry instructions for protein synthesis, and proteins regulate essential cellular functions such as growth and division. Genetic mutations can alter protein structure and function. Certain mutations drive normal cells toward malignant transformation.
Tumour mutational burden provides insight into the genetic alterations responsible for tumour development and progression. It supports treatment planning by guiding clinicians toward therapies that are more likely to be effective. TMB also helps in identifying potential molecular targets for cancer treatment.
Role in Immunotherapy
Tumour mutational burden plays an important role in predicting response to immunotherapy. Tumours with a high mutational load are more likely to generate neoantigens that can be recognized by the immune system. This makes such tumours better candidates for immune checkpoint inhibitor therapy.
TMB helps identify patients who are more likely to benefit from immunotherapy before treatment is initiated. However, challenges remain in standardizing TMB measurement methods and interpreting results across different testing platforms.
Indications
Tumour mutational burden is used as a biomarker in several solid tumours. It is commonly advised in cancers where immunotherapy forms a key component of treatment.
Cancers where TMB testing is frequently recommended include colorectal cancer, melanoma, and non-small cell lung cancer. In these malignancies, TMB status helps in treatment selection and prognostic assessment.
Understanding Tumour Mutational Burden
Tumour development is a multistep process involving the accumulation of genetic mutations. Normal cells undergo genetic changes due to physical or chemical agents, leading to mutagenesis. With continued mutations, cells may lose regulation of growth and division.
As mutations accumulate, neoplastic cells develop and eventually progress into cancer cells. Tumour mutational burden reflects this accumulation of genetic alterations and serves as a quantitative marker of tumour evolution.
Methods of Detection
Whole exome sequencing is considered the gold standard for measuring tumour mutational burden. This method allows comprehensive analysis of mutations across the coding regions of the genome.
Next-generation sequencing is the preferred technology used for TMB assessment. It provides accurate and high-throughput detection of genetic alterations and enables calculation of mutations per megabase.
Sample Collection
Whole blood samples are collected in EDTA or citrate tubes for analysis. The samples should be maintained at ambient temperature until processing to preserve nucleic acid integrity.
Bone marrow samples may also be collected using the same type of tubes and handling conditions. Proper sample collection and handling are essential to ensure reliable TMB assessment.
Plasma Processing for ctDNA
Plasma used for circulating tumour DNA analysis requires careful processing. Blood is drawn using an anticoagulant and centrifuged to separate plasma from cellular components.
The plasma supernatant is harvested and subjected to a second high-speed centrifugation to remove residual cells. The final plasma is transferred into a fresh tube and stored at very low temperatures to maintain DNA stability.
Prognostic Significance
Tumours with low tumour mutational burden are associated with lower objective response rates and shorter progression-free survival. Patients with low TMB tend to show limited benefit from immune checkpoint inhibitor therapy.
High tumour mutational burden is associated with improved treatment response and longer survival in multiple cancer types. Patients with high TMB demonstrate better outcomes following immunotherapy, making TMB a valuable prognostic and predictive biomarker in oncology.
