Mutation

A mutation is a change in a gene, which is a piece of DNA that provides instructions for how a cell should function. In a molecular pathology report, the word “mutation” means that there has been a genetic change in the tumour’s DNA. Some mutations are harmless, while others can contribute to cancer development or affect how the tumour responds to treatment.

Why do mutations happen?

Mutations can occur for many reasons. Sometimes, they happen by chance when cells make mistakes in copying their DNA. Environmental factors, such as exposure to harmful chemicals or radiation, can also damage DNA, causing mutations. Inherited mutations, passed down from parents, are present from birth, while others, known as somatic mutations, develop over time.

What happens to a cell after a mutation takes place?

Some mutations may not affect the cell at all, and the cell continues to function normally. Other mutations can disrupt how the cell behaves, causing it to grow faster, ignore signals to stop dividing or avoid the normal process of cell death. If enough harmful mutations accumulate, the cell may become cancerous and divide uncontrollably.

How do mutations cause cancer?

Some mutations affect genes involved in controlling cell growth. These can lead to cells dividing too quickly or resisting normal signals to stop growing. Mutations in key genes, such as those that repair damaged DNA or control the cell cycle, can give cancer cells a survival advantage. If these mutations spread to other cells, they can form a tumour.

Do all mutations cause cancer?

No, not all mutations lead to cancer. Some mutations are harmless and have no impact on how a cell functions. These are called benign mutations. Others may only slightly alter a cell’s behaviour without causing disease. Cancer occurs when mutations accumulate in specific critical genes, disrupting the normal control systems that keep cells healthy and balanced.

What does it mean if a mutation is described as oncogenic?

A mutation is called oncogenic if it contributes to the development of cancer. The term comes from the word oncogene, which refers to a gene that, when mutated, drives uncontrolled cell growth. Oncogenic mutations are vital in turning normal cells into cancer cells and are often targeted by specific cancer treatments.

How do pathologists test for mutations?

Pathologists use several methods to find mutations in tumour cells. The main testing methods include:

• Next-Generation Sequencing (NGS): NGS allows pathologists to sequence multiple genes simultaneously to detect a wide range of mutations. This is a powerful tool for personalized cancer treatment.
• Polymerase Chain Reaction (PCR): PCR amplifies specific segments of DNA to look for known mutations. It’s especially useful when targeting small regions of interest.
• Sanger Sequencing: An older but still reliable method to sequence smaller regions of DNA, helpful in detecting known mutations.
• Immunohistochemistry (IHC): IHC looks for proteins affected by specific mutations. For example, it can show if a tumour produces too much protein due to a mutated gene.

The results of these tests will be included in the pathology report, either confirming the presence of a mutation or stating that no mutation was found. If a specific mutation is detected, the report will name the genes involved.

Here is an example of how a mutation result might appear in a molecular pathology report:

Test: Next-Generation Sequencing (NGS) Panel
Result: Positive for IDH1 mutation (R132H)

Interpretation: A mutation was detected in the IDH1 gene, changing the amino acid at position 132 from arginine (R) to histidine (H). This mutation is frequently found in gliomas and certain other tumours and plays a role in tumour development by altering how cells process energy. Tumours with this mutation may respond to specific targeted therapies, such as ivosidenib.

In this example, the report identifies a mutation in the IDH1 gene, which produces an abnormal protein that can lead to cancer growth. The R132H mutation is a specific change within the gene, often seen in gliomas (a type of brain tumour). Knowing that the tumour has this mutation helps guide treatment because certain targeted drugs, like ivosidenib, are designed to block the effects of this mutated protein. A positive result can provide important information about prognosis and potential treatment options.

What are the most common mutations and the cancers associated with them?

Below is a list of some common mutations and the cancers in which they are often found:

• TP53: Found in breast, ovarian, and colon tumours.
• KRAS: Seen in lung, pancreatic, and colon cancers.
• EGFR: Common in lung cancer and glioblastomas.
• BRAF: Found in melanoma, thyroid, and colon tumours.
• IDH1/IDH2: Associated with gliomas and leukaemias.
• ALK: Present in lung cancer and some lymphomas.
• HER2 (ERBB2): Found in breast and gastric tumours.
• FLT3: Frequently mutated in acute myeloid leukaemia.
• NPM1: Seen in acute myeloid leukaemia.
• JAK2: Present in myeloproliferative disorders.
• PTEN: Common in endometrial and breast cancer.
• RET: Found in thyroid cancer and multiple endocrine neoplasia.
• MET: Seen in kidney and lung tumours.
• CTNNB1: Found in liver cancer and some endometrial tumours.
• PIK3CA: Common in breast, colon, and endometrial cancer.
• MYC: Present in Burkitt lymphoma and other aggressive cancers.
• GNAQ/GNA11: Found in uveal melanoma.
• CDKN2A: Seen in pancreatic cancer and melanoma.
• MLH1/MSH2: Linked with Lynch syndrome and colon, endometrial, and stomach cancer.
• NOTCH1: Found in T-cell leukaemias.
• TERT promoter: Seen in glioblastomas and thyroid cancer.
• SMAD4: Common in pancreatic and colorectal cancer.
• NF1: Associated with neurofibromatosis and gliomas.
• RB1: Seen in retinoblastoma and small cell lung cancer.
• FOXL2: Found in ovarian granulosa cell tumours.
• KIT: Seen in gastrointestinal stromal tumours (GIST).
• PDGFRA: Common in gastrointestinal stromal tumours (GIST).
• EZH2: Found in follicular lymphoma.
• IDH1/2: Seen in acute myeloid leukaemia and gliomas.
• TET2: Present in myelodysplastic syndromes.
• SRSF2: Found in myelodysplastic syndromes and chronic myelomonocytic leukaemia.
• ASXL1: Common in chronic myeloid neoplasms.
• DNMT3A: Seen in acute myeloid leukaemia.
• RUNX1: Associated with leukaemias.
• GATA2: Linked with hereditary haematological disorders.
• ETV6: Found in leukaemias and lymphomas.
• CCND1: Associated with mantle cell lymphoma.
• FGFR3: Seen in bladder and cervical cancer.
• KMT2A: Linked with acute leukaemia.
• CIC: Found in rare brain tumours.

Each mutation plays a significant role in the cancers where they are found. Identifying them confirms the diagnosis and helps doctors choose therapies specifically designed to target these genetic changes.

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