Is Cancer in Your DNA? What You Need to Know About Genetic Mutations and Your Risk - Dr Thangarajan Rajkumar

A fundamentally complex disease like cancer is primarily driven by the changes in our genes. Understanding these genetic alterations and mutations is crucial, especially in the context of genetic testing, as it helps in structuring a personalised treatment plan that caters to the patient’s needs.

However, there are two key concepts that one needs to understand – germline genetic testing, somatic mutations.

Understanding Germline Mutations

Germline genetic testing examines the genes inherited from our parents, making it a crucial first step in genetic analysis. Normally, we inherit one copy of each gene from our mother, and the other from our father.

When irregularities are found in these gene copies, they are known as germline mutation. These mutations are present in every cell of the body. While most commonly associated with cancer, germline mutations can also be linked to a range of non-cancerous diseases.

For individuals diagnosed with specific types of cancer, such as breast cancer, germline testing is often the most effective tool for identifying an appropriate treatment plan.

This testing can help reduce the risk of cancer in other family members and, with the use of a pedigree chart, provides valuable insight for counselling and planning the preventative / therapeutic strategies for those family members who carry the disease-causing mutations but not developed the disease yet.

Role of NGS in Germline Mutation Analysis

The use of NGS also known as Next-Generation Sequencing technology in cancer detection has been transformative. The information gained from NGS has enabled doctors to not only determine the genetic causes of disease onset and progression, but also to redefine clinical diagnosis and treatment paradigms.

NGS serves as a guide for selecting genes to analyse for abnormalities. Currently, NGS technology allows for the simultaneous analysis of multiple genes and their mutations, expanding the spectrum of genetic mutations and, consequently, cancers with a hereditary background.

For example, the BRCA1 gene is associated with a precise mechanism of DNA repair. When a patient is diagnosed with a mutation in this gene, it can lead to complications, allowing the development of more mutations.

The body attempts to repair itself, but without functional BRCA1, the repair process is less efficient. These mutations can trigger uncontrolled cell proliferation and the ability of the tumour cell to survive in harsh environments, including those with limited blood and oxygen supply.

As a result, the body is at a higher risk of breast cancer due to local tissue invasion, the entry of mutated cells into the bloodstream, and the spread to distant organs (metastasis).

While benign variants require no intervention, disease-causing mutations necessitate careful management, which is made possible through NGS technology. This testing can identify disease-causing mutations, benign variants (harmless variations present in most individuals), and variants of unknown significance (VUS).

Understanding Somatic Mutations

Somatic mutations are genetic alterations that occur after conception. Unlike germline mutation, somatic mutations are not present in most body cells and develop sporadically, without a known family history of genetic mutations.

For example, in breast cancer, a single cancerous cell develops from a single normal cell, acquiring more mutations over time that enable it to proliferate and invade neighbouring tissues, eventually forming malignant tumours.

Role of NGS in Somatic mutation analysis

Somatic mutations are analysed by NGS (both DNA sequencing called Exome Sequencing and/or RNA sequencing) can be used on the DNA and RNA extracted from tumour biopsies or surgical specimens, of for example breast cancer.

This analysis, combined with standard tests such as immunohistochemistry for estrogen, progesterone, HER2, and Ki-67, provides crucial information for treatment decisions and prognosis.

The sequencing identifies a range of genomic abnormalities, including single nucleotide variants, small indels, copy number aberrations, and even structural variants like gene rearrangements or fusions.

By working with a single test and using relatively small amounts of DNA/RNA, this analysis helps identify somatic mutations against a background of normal cells, including one or more subpopulations of tumour cells.

Next-generation sequencing (NGS) plays a crucial role in understanding somatic mutations and personalizing cancer treatment. In triple-negative breast cancer (TNBC), an aggressive subtype of breast cancer that lacks estrogen, progesterone, and HER2 receptors, NGS can identify somatic mutations in genes like BRCA1/2 or other genes involved in homologous recombination repair (HRR).

HRR is a vital DNA repair mechanism, and when it is deficient, it presents a therapeutic opportunity. PARP inhibitors, which specifically target cancer cells with HRR deficiencies, can be used to exploit this weakness, potentially causing severe damage to the cancer cells.

NGS is also essential for detecting Homologous Recombination Deficiency (HRD), identifying characteristic "scars" in the DNA caused by defective repair. Fortunately, affordable HRD testing is now available in our country, making it accessible to a wider patient population.

In lung cancer, NGS plays a pivotal role in identifying mutations in the EGFR gene, which predict a patient's response to targeted tyrosine kinase inhibitors. Additionally, NGS can detect fusion genes like ALK or ROS1 gene fusions, which can be targeted with drugs such as crizotinib.

Furthermore, NGS can assess tumour mutational burden (TMB), which measures the total number of mutations within a tumour. A high TMB often correlates with a better response to immunotherapy, particularly with immune checkpoint inhibitors.

Clinical Implications, Screening Measures and Personalised Medicine

1. Germline Mutations and Hereditary cancers

Identifying the disease-causing mutations in genes associated with different hereditary cancers has profound implications for both the affected individual (proband) and their family members.

For the proband (one has sought help with the doctor and has been found to have a disease-causing mutation), treatment decisions, particularly surgical approaches, are influenced by the presence of a germline mutation.

For example, individuals with a deleterious BRCA1 mutation may consider mastectomy over breast conserving approaches and might even want the unaffected breast removed due to the increased risk.

However, before getting to therapy discussions, the oncologists will need to provide the risk to the other breast, which with proper management including lifestyle changes can reduce the risk by nearly 50%.

In women who have completed their family, and if willing, prophylactic removal of both ovaries and fallopian tube can be advised. This not only reduces the opposite side breast cancer risk by 50%, but it also avoids the risk of ovarian cancers, which they are predisposed to.

Family members can undergo predictive testing to determine if they carry the same disease-causing mutation. In these subjects, the risk is not absolute – meaning, that if there are 100 women with the same disease-causing mutation, only 50 – 70 of them would develop breast cancer during their lifetime; conversely, 30 – 50 of them may not develop the disease.

Those who test positive can benefit from enhanced surveillance, preventative measures, and early intervention strategies.

• Lifestyle modifications are crucial for individuals with germline mutations, including regular exercise, a balanced diet with plenty of fruits and vegetables, reducing red meat, and avoiding tobacco and alcohol consumption.
• Interventional measures, like prophylactic surgeries (mastectomy, removal of ovaries fallopian tubes) and chemo prevention (medicines to reduce cancer risk), can further mitigate the risk.
• Regular screenings are essential for early detection and improved outcomes, including mammograms, breast MRIs, and clinical breast exams.

2. Somatic Mutation and sporadic cancers

Somatic mutation analysis also guides treatment decisions by identifying targetable mutations and predicting responsiveness to specific therapies. This personalised approach maximizes treatment efficacy while minimizing unnecessary side effects and costs.

The ongoing development of targeted therapies and immunotherapies, coupled with the power of NGS, promises to further refine cancer treatment and improve patient outcomes.

Inherited genetic alterations increase cancer risk, while acquired tumour-specific changes drive cancer growth. Testing for both, using advanced techniques like NGS, enables personalised treatment by revealing drug targets and predicting responses.

This information empowers patients to make informed health decisions and helps doctors determine the necessary preventive measures and targeted therapies.