Precision medicine, personalized medicine, targeted drugs, next-generation sequencing, and many more words are thrown around frequently when people talk about cancer treatment. What exactly they mean and how DNA analysis of tumor is changing the way cancer is perceived and treated. To understand the whole story, lets imagine a normal cell about to become cancerous. A normal cell multiples from one to two when it gets a growth signal usually from adjacent cells. These growth signals are small proteins that bind to receptors on the surface of this particular cell. Upon binding to the receptor, the receptor protein changes its conformation and relays the signal to a specific signaling protein nearby. Let’s name it as signaling protein 1. Signaling protein 1 triggers signaling protein 2, which may trigger signaling protein 3. The last signaling protein in the chain enters nucleus and sits over specific and marked portions of the DNA inside. This act allows specific genes in the nucleus to transcribe and translate new proteins which tell our cell to divide. Thus, an external growth signal triggers a relay race of signaling proteins leading to growth and multiplication of cells. Off course this process must be tightly regulated else the cells would keep on dividing and end up in a large mass called tumor. Each of these signaling proteins are coded by genes. Genes coded by four letters, A, T, G and C. Let’s imagine signaling protein 2 is coded by a ten letter long gene ATGCGATGCT. Unfortunately, our cell was residing in the lungs of a person who was chain smoker. Through mechanisms unknown, the fourth letter of the gene changed from “C” to a “T”. While this difference may seem very small, it made a big difference in the way signaling protein 2 behaved. Earlier signaling protein 2 needed a signal from signaling protein 1 to in turn trigger signaling protein 3. However, with a change in 4th letter, even without a signal from upstream, signaling protein 2 can trigger the protein downstream of it and that too, continuously. Of course, the cell is constantly stimulated and it keeps dividing. In effect the cell has lost regulation over its own growth that leads to tumor formation. When a signaling protein gets mutated and causes cancer, they are called oncoprotein and the genes that were mutated are termed oncogenes. EGFR and KRAS are few such oncogenes that cause NSCLC type of lung cancer.
On the other hand, a group of proteins act as guards to the process that allows the cell to proceed for cell cycle and eventually multiply from one cell to two. P53 is one such example. If a mutation occurs in the gene TP53 that codes for protein P53 such that now P53 is rendered useless, the cell will continuously go into cell cycle and multiply into a tumor. Such genes are called tumor suppressor genes. We have stated the mechanism or oncogenes and tumor suppressor genes in a simplistic fashion. Also, more mechanisms exist, such as aberrations in DNA repair that can lead to tumor formation.
The knowledge that cancer is caused by specific mutations in genes led to large efforts to catalogue such mutations. The Cancer Genome Atlas https://cancergenome.nih.gov/ , International Cancer Genome Consortium http://icgc.org/ are few examples. Such international efforts are describing landscape of mutations across the entire human genome and correlating them to specific cancer types. This knowledge also triggered efforts from biotechnology and pharmaceutical companies which are devising new molecules by the month, that targets oncoproteins, tumor suppressor proteins etc. These drugs are popularly called targeted therapies as the drugs target very specific protein molecules. Gefitinib (Iressa), Imatinib, Alectinib, Crizotinib are few examples. Let’s say if signaling protein 2 was mutated and caused continuous relaying to growth signal to cause cancer, oncologist would use a targeted therapy that specifically attacked and neutralize signaling protein 2. However, such targeted therapy would not affect any other protein. Thus, to choose a targeted therapy, it is imperative to understand which protein is causing cancer and to do that one needs to know which gene is mutated. Thus, unlike chemotherapy where much of the choice and regimen of treatment relied upon the clinical presentation and histopathology of the patient, targeted therapy could be chosen only if the oncologist knew which protein is causing cancer. This opened entirely new disciplines of molecular diagnostics and molecular pathology. Molecular diagnostics deal with a gamut of technology focused on extracting tumor DNA and reading it. Since the tissue samples are limiting, laboratories use PCR to amplify tiny DNA signals. These amplified DNA are then read using Sanger method, Next Generation Sequencing method or by droplet digital PCRs. Final goal of molecular diagnostics is to read the tumor DNA and compare it with healthy tissue. The differences reveal critical characteristics of the cancer which is exploited by an oncologist to determine treatment and prognosis of the patient. The advent of molecular biology in cancer diagnosis and treatment has opened up requirement molecular pathologists. Molecular pathologists understand cancer pathology, cell biology, molecular biology. Based on molecular (DNA, RNA and proteins) differences between tumor cells and normal cells, molecular pathologists make recommendations to an oncologist in a fashion similar to a histo-pathologist.
Thus, genomics has really changed the approach towards cancer diagnosis and treatment. Need for newer specialties have been created such as Molecular pathology and molecular diagnostics.