Cancer genomics

    Last updated date: 13-Mar-2023

    Originally Written in English

    Cancer Genomics

    Cancer Genomics

    Cancer is a category of disorders brought on by DNA mutations that affect cell function and lead to unregulated proliferation and malignancy. These anomalies can include DNA mutations, rearrangements, deletions, amplification, and the addition or deletion of chemical markers, among other abnormalities. Cells may produce aberrant amounts or misshaped proteins that do not function normally as a result of these alterations. The majority of the time, several genetic changes interact to induce cancer.

    Genetic changes can be inherited from one's parents, brought on by the environment, or arise naturally during processes like cell division. Acquired or somatic abnormalities, which make up 90-95 percent of all cancer cases, are changes that occur throughout a person's lifetime.

    The study of the human genome, or our entire set of DNA, is done in the discipline of cancer genomics, a relatively new area of study that makes use of current technological advancements. Scientists discover genetic variations that could lead to cancer by sequencing the DNA and RNA of cancer cells and comparing the sequences to normal tissue, such as blood. To determine which proteins are abnormally active or silent in cancer cells, a method known as structural genomics may also be used to evaluate the activity of genes encoded in our DNA.

    Scientists can better grasp the molecular roots of cancer growth, metastasis, and medication resistance once cancer-causing alterations have been found. This is accomplished by laboratory research employing cell lines and model organisms, clinical data that explains how patients responded to cancer treatment, big data processing techniques, and laboratory studies. A key strategy for cancer research is to pool huge genomic datasets and make them available to researchers throughout the world, as this increases the data's value and creates new research opportunities. Researchers at the National Institutes of Health (NIH) and elsewhere in the world are putting a lot of effort into identifying the genetic abnormalities that underlie cancer, figuring out how they affect tumor growth and metastasis, and using this information to combat the disease.


    What is Cancer Genomics?

    The study of changes in gene expression and DNA sequencing between cancer cells and healthy host cells is known as cancer genomics. It aims at understanding the genetic components of tumor cell proliferation as well as how the body's microenvironment, the immune system, and therapeutic interventions have changed and selected the cancer genome over time.


    What Causes Cancer?

    What Causes Cancer?

    The genetic alterations or mutations that lead to cancer can result from a variety of causes, such as:

    • Ageing. Any age can be affected by cancer. However, the risk of more mutations developing in our cells as our age increases. Additionally, as we become older, it is more likely that we may be exposed to more cancer-causing substances. By the age of 75, approximately one in three men and one in four women in Australia will have a cancer diagnosis. By the time they become 85, one in two people will have gotten a cancer diagnosis.
    • Carcinogens. The genetic alterations that lead to cancer are known to be induced by these chemicals. Not every person who is exposed to a carcinogen develops cancer. The likelihood of developing cancer in someone who has been exposed to a carcinogen depends on a variety of factors. The substances in cigarette smoke, asbestos, and exposure to ultraviolet radiation are a few examples of known carcinogens. Some substances that are carcinogenic only cause cancer if a person has had a certain type of exposure to them or a certain amount of exposure to them.
    • Genetic inheritance. Hereditary malignancies account for 5 to 10 percent of cancer cases. When damaged or defective genes are found in the reproductive cells (sperm and egg cells), which are then passed down from parents to offspring, hereditary cancer develops. Although those with these altered genes may not necessarily acquire cancer, their lifelong risk is higher than that of the general population. Some hereditary cancers have a significant genetic correlation, such as hereditary breast and ovarian cancers, which are known to be influenced by the BRCA1 and BRCA2 genes.
    • Bacteria, parasites, and viruses. Cancer can be brought on by specific bacteria, viruses, and parasites. The Human Papilloma Virus (HPV), a common source of cervical cancer, stands as an example.


    Is Cancer Genetic?

    Cancer Genetic

    Cancer is typically not inherited and is brought on by genetic alterations that cause cells to proliferate uncontrollably. DNA mutations that cause cancer can be inherited or, more frequently, acquired over time.

    All of the offspring's bodily cells carry inherited gene mutations that were handed down from the parent’s reproductive cells (the egg or sperm). On the other hand, acquired genetic mutations begin in a single cell as a result of factors like cell division faults or exposure to carcinogens (substances that cause cancer), like cigarettes or radiation.

    The majority of cancers are multifactorial, meaning that your risk increases due to several variables, such as your genetics, environment, lifestyle, and personal medical history.


    Cancer Genomics Testing

    Genomic testing is a technique your doctor may employ to estimate how your cancer will progress and which medications may be most effective against it. Sometimes it is referred to as DNA sequencing. Instead of focusing on one gene, the test examines all of your genes.

    Genes are fragments of DNA that store the information needed to produce proteins, which are the building blocks of your body. Each of your cells has threads called chromosomes that carry your genes. Your genome is made up of about 30,000 genes that are present in each of your cells.

    Mutations in your DNA can increase your risk of developing cancer and speed up the growth and spread of the disease. You inherit some of these mutations from your parents. Others developed over your lifetime and are only present in your cancer.


    Importance of Cancer Genomics in Precision Medicine

    Precision Medicine

    Precision medicine, which is based on tumor-specific treatment plans, is improving cancer diagnosis and is made possible by genomic information. Drugs have been created to combat the disease in several ways as a result of studies into the genomic changes related to cancer:

    • Blocking the enzymes that cause cancer cells to grow and survive abnormally
    • Suppressing the abnormal gene expression that is seen in cancer cells
    • Blocking overactive molecular signaling pathways in cancer cells

    These targeted therapies particularly address the characteristics that distinguish cancer cells from healthy body cells. Consequently, they are less likely to be harmful to patients than other forms of treatment like chemotherapy and radiation, which can kill healthy cells. Several instances of precision medicine are already being used in clinical settings:

    • Patients with leukemia that are brought on by a specific chromosomal rearrangement are treated with imatinib (Gleevec), which suppresses the overactivity of a protein called Bcr-Abl tyrosine kinase.
    • In a subgroup of breast cancer, several copies of the HER2 gene produce a hyperactive signaling pathway (HER2 tyrosine kinase), which is controlled by trastuzumab (Herceptin).
    • Both erlotinib (Tarceva) and gefitinib (Iressa) inhibit the activity of the EGFR protein, which is unusually active in a subset of lung malignancies as a result of protein mutations.

    By classifying cancer types and subtypes according to their genetic make-up, cancer genomics research also advances precision medicine. This genetic classification of cancer can offer patients a more accurate diagnosis and, consequently, a more specialized course of treatment. Patients already benefit from the molecular description of cancer in several ways:

    • Based on molecular characteristics, breast cancer is divided into four distinct subgroups: Luminal A, Luminal B, Triple-negative/basal-like, and HER2 type. These subgroups differ in their aggressiveness and how they respond to treatments. Patients with breast cancer may benefit from a diagnosis and course of treatment determined by the molecular subtype of their tumor.
    • By using genomic profiling, it is possible to distinguish between individuals with the ABC and GCB subtypes of diffuse large B cell lymphoma, which responds variably to molecularly targeted therapies and existing chemotherapy protocols.
    • The Cancer Genome Atlas research discovered four endometrial cancer subtypes in 2013 that were associated with patient survival: POLE ultramutated, microsatellite instability (MSI) hypermutated, copy-number (CN) low, and CN high. New clinical studies that look into how these subtypes can strengthen the treatment of endometrial cancer have already been inspired by this discovery.
    • Patients with lung cancer who have a gene fusion including the ROS1 gene frequently benefit from treatment with the targeted therapy crizotinib. In these situations, the disease's unique genetic alteration is used to define and treat it most effectively.


    Why Genomics Research is Important to Progress against Cancer?


    The analysis of cancer genomes has uncovered anomalies in the genes that drive the emergence and spread of numerous cancer forms. As a result of this knowledge, scientists now have a better understanding of how cancer develops biologically and may be treated.

    For instance, the identification of genetic and epigenetic alterations that contribute to cancer in tumors has facilitated the development of both diagnostic tools and therapeutics that target these alterations. Vemurafenib (Zelboraf), one of these targeted therapies, was authorized by the Food and Drug Administration (FDA) in 2011 for the treatment of certain melanoma patients who had a particular mutation in the BRAF gene as identified by an FDA-approved test.

    The genetic alterations related to multiple cancer types have been the subject of extensive research projects during the past ten years. These initiatives have uncovered unexpected genetic commonalities among many tumor forms. For instance, mutations in the HER2 gene have been detected in several cancers, including breast, bladder, pancreatic, and ovarian (as opposed to amplification of the same gene, for which treatments have been developed for breast, esophageal, and gastric cancers).

    Additionally, studies have demonstrated that a single cancer type, such as breast, lung, or stomach cancer, may include several molecular subtypes. Before researchers started profiling the tumor cell genomes, some subtypes of various cancers were unknown to exist.

    The results of these efforts demonstrate the diversity of genetic changes that can occur in cancer and lay a foundation for understanding the underlying molecular causes of this class of diseases.


    Opportunities in Cancer Genomics Research

    Cancer Genomics Research

    Large-scale research investigations have found a significant number of genetic changes that influence the onset and progression of many different types of cancer, yet other tumor types remain poorly understood. The whole set of driver mutations and other DNA and RNA abnormalities in many malignancies might be identified using cutting-edge technology and the knowledge obtained from earlier genomic investigations. Researchers can identify genetic abnormalities that might be responsible for cancer by comparing the genomic data from tumors and normal tissue from the same patient in studies.

    Expanding the use of genomic techniques now being used to look into the genetic causes of clinical manifestations is another option. Using this method, researchers may be able to spot genetic variations that, for instance, set aggressive tumors apart from placid ones. Similar methods could be used to investigate the molecular basis of a specific therapy's response as well as the mechanisms underlying treatment resistance.

    Patients' health history and clinical data will increasingly be combined with the amount of information coming from cancer genomic studies. These combined findings may be utilized to improve methods for estimating cancer risk, prognosis, and therapeutic response, as well as to create more individualized approaches to cancer diagnosis and treatment.

    Analysis of the findings from precision medicine clinical trials, like those being carried out by NCI, will also require the use of genomic technologies.


    Challenges in Cancer Genomics

    Challenges in Cancer Genomics

    A thorough examination of cancer genomes has revealed a wide variety of genetic aberrations within a single form of cancer. Furthermore, only a small minority of these malignancies have recurrent genetic changes. Therefore, challenges for the research include figuring out which genetic changes lead to cancer development and finding uncommon genetic mutations that cause tumors.

    Obtaining high-quality biological samples is another obstacle, especially for tumor types that are uncommon, unusual, or that aren't usually treated through surgery.

    Another unmet need is the establishment of cell lines and animal models that accurately represent the diversity of human cancer. Many recurrent genetic lesions in human cancer have no models, and there may be no models at all for rare cancer subtypes.

    Additional difficulties for the field include managing and evaluating the huge amounts of data required in genomic investigations. An effective bioinformatics infrastructure is needed for this field of research, and multidisciplinary teams are contributing data and knowledge at an increasing rate.


    Using Cancer Genomics to Treat Cancer

    Cancer Genomics to Treat Cancer

    Dr. Lukas Wartman, a physician and researcher at Washington University, has both directed and personally undergone cancer genomics studies. Acute lymphoblastic leukemia, also known as ALL, was discovered to be Lukas' blood cancer in 2003 when he was in his fourth year of medical school. As a result, he decided to focus on treating leukemia patients and conducting laboratory research on the condition. During his university's groundbreaking work in cancer genome sequencing, Lukas experienced a serious ALL relapse. Therefore, the lab, which included Lukas' mentor, asked if they might evaluate him.

    His healthy cells and his malignant blood cells' genomic sequences were compared by the team. They discovered FLT3 gene alterations in cancer's DNA. The research team later discovered that there was a drug on the market that might be used to treat people who had mutations in this gene. They tried it even though it was initially approved for the treatment of various cancers rather than blood cancer. Lukas began taking the medication on a Friday, and by Monday, his blood counts were already improving. His cancer was in remission when the leukemia cells were no longer visible in his blood after many weeks. Although Lukas will still require medication, he might not have survived if it weren't for the genome sequencing findings that led to the discovery of a novel treatment.

    In the US, there are now over 10,000 clinical studies recruiting participants for novel cancer therapies. As a result of cases like Lukas', "n-of-1" clinical trials, in which physicians can test a novel treatment on just one patient, have also become more popular. Patients who openly or even covertly share their genomic data with other patients or researchers can help these experiments. There is growing optimism that, as clinicians assess new cancer patients, they will be able to correlate each case with these sizable databases that may include positive outcomes from treatments approved for one cancer but with the same mutation as cancer in question. This would be similar to what Lukas discovered for ALL.



    In just a few short years, the application of cancer genomics in clinical issues in cancer care has advanced significantly. There are various ways that this translational trajectory has been shown. First, using deep sequencing and analysis to assess the evolution of malignancies through changes in clonal heterogeneity has provided valuable insight into the nature of acquired resistance to chemotherapies and targeted medicines. Second, the idea of monitoring the development of therapeutic resistance has given rise to the idea of blood-based monitoring via liquid biopsy as a precise and relatively inexpensive indicator for tumor response. Third, studies of the relationship between the immune system and cancer have revealed a surprising use for cancer genomics, supporting the idea that mutational burden via genomics may be a marker of response to checkpoint blockade treatment. Importantly, if mutational or neoantigen load is a marker of checkpoint blockade response, they may be opening the door for the adoption of immunotherapies as a second-line therapeutic strategy by using DNA-damaging chemotherapy as the standard of care for many patients. Genomic analyses of post-therapy recurrent cancers or metastases demonstrate a signature of DNA damage and a correspondingly greater mutation rate brought on by DNA-damaging chemotherapies, which anticipate this.