-There are 21 amino acids that are the building blocks of proteins in humans. The order of the amino acids that make up a given protein is determined by the DNA code. All 21 amino acids have an amine group (nitrogen,-NH2) and carboxylic acid (-COOH). However, each amino acid is distinguished by it unique side chain., It sounds complicated to name all the amino acids, but if you think of each as a just a letter in the chain of a protein, it makes it easier to think about. The amino acids and their letter nicknames are listed below.
List of Amino Acids (AA’s) that make up proteins in humans:
The amino acids are shown below as grouped by category. Included with each amino acid is their 3 letter or 1 letter abbreviation that is commonly used when reporting genetic testing results.
3 AA’s are Positively charged: arginine (Arg or R); histidine (His or H); lysine (Lys or K).
2 AA’s are Negatively charged: aspartic acid (Asp or D); and glutamic acid (Glu or E).
4 AA’s have polar uncharged side chains: serine (Ser or S); threonine (Thr or T); asparagine (Asn or N) and glutamine (Glu or Q).
4 AA’s have special characteristics: cysteine (Cys or C); selenocystein (Sec or U); glycine (Gly or G); proline (Pro or P).
8 AA’s are Hydrophobic (repelled by water): alanine (Ala or A); valine (Val or V); isoleucine (Ile or I); leucine (Leu or L); methionine (Met or M); phenylalanine (Phe or F); tyrosine (Tyr or Y); tryptophan (Trp or W).
-A protein produced by the immune system that functions to identify and neutralize a pathogen (bacteria, viruses, parasites, fungi) or other harmful substances in the body. Since each antibody binds to a unique target known as an antigen, this property has been exploited for therapeutic benefit. Therapeutic antibodies have now been developed that stimulate the immune system to attack tumor cells, to localize radiation and chemotherapy to target cells, and to interfere with specific signaling mediators important in the tumorigenic process.
A carefully regulated process in cells, “Programmed cell death” occurs due to a series of biochemical steps in the cells of multicellular organisms. This is one method used by organisms to eliminate unneeded or defective cells. In cancer cells, apoptosis may be blocked or ineffective due to genetic alterations in the biochemical steps controlling apoptosis. (source: molecular biology of the cell, 4th
–A rare recessive immunodeficiency disorder of childhood that affects multiple organs. In the disease, the immune system doesn’t function correctly, making the patient susceptible to diseases. The condition is characterized by neurological symptoms including lack of balance, sinus and respiratory illnesses, and dilated blood vessels in the eyes and on the skin surface. In addition to immune system abnormalities, patients with AT are extremely sensitive to radiation. About 20% of young AT patients develop cancers, including leukemias and lymphomas. The disease is often fatal by the time a patient reaches their 20’s. The study of AT patients by scientists has led to many insights in terms of some of the genes that are involved in the development of cancers.
(genetics home reference)
When studied, Ataxia telangiectasia patients were found to have a mutated protein kinase, and because of this, it was called “ATM protein kinase” for AT ‘mutated” kinase. DNA can be damaged via a number of different mechanisms, including breaks in both strands of the double helix of DNA. Normally when DNA is damaged, especially in double-strand breaks (DSB’s) in the DNA, ATM reacts by activating a broad signaling network in the cell. One pathway that is “turned on” by ATM is that of a tumor suppressor called P53, which is activated by ATM, causing p53 to accumulate in the cell. This accumulation of P53 causes the cell to stop dividing, a process called “growth arrest” or ‘cell cycle arrest’. Growth arrest occurs in the G1 phase of the cell cycle, which allows normal cells to repair damage to the DNA before they resume the cell cycle and are allowed to proceed with cell division and growth. P53 is genetically altered in half of all cancers, resulting in a failure to stop dividing when there is a problem with the DNA, increasing the risk of cancer. In AT patients, ATM is either missing or genetically altered so that it is unable to function in activating P53 and having it accumulate to arrest cell growth.
(source nature reviews; wikipedia)
- Adenosine triphosphate. This compound serves as the primary energy currency of cells; ATP is the chemical energy form that drives the metabolism of cells and most ATP is produced in an enzymatic reaction called “cellular respiration” (other names for this reaction are the “Citric Acid Cycle” or the “Krebs Cycle”) in the cytoplasm of cells. ATP contains phosphate groups, which are high energy components of ATP, and are involved in many growth signal pathways in cells. ATP is recycled in the cell after being used as energy.
An intracellular process in which normal cells can destroy unwanted proteins or other substances in the cell cytoplasm, which can lead to cell death. Substances to be destroyed or recycled in this process are transported to the lysosome, an intracellular organelle that degrades proteins. This process can prevent normal cells from developing into cancer cells. However, autophagy can at times protect cancer cells from death by destroying chemotherapy agents that are aimed at killing cancer cells. Autophagy plays a complex variety of roles in physiology and pathology. (sources: Genes and Development: PMID 18006683)
A shortened term to refer to a biological marker. It is a measure of a biological state that has a strong predictive value. For instance, certain gene mutations found in some cancers can serve as a biomarker of response to particular therapies.
Describes a disease in which abnormal cell growth that can invade into local adjacent tissues, or can spread to other parts of the body through the blood or lymph system. Tumor cells that initiate a tumor in a second location are said to have metastasized.
Cancer Stem Cells-
Cancer stem cells are thought to be a rare subset of tumor cells that possess self-renewal properties and continuously proliferate to give rise to the bulk of cancer cells that comprise the tumor. They are believed to persist during treatment and are the cause of relapse and metastasis. Therefore, therapies are being developed to target this population of cells in hopes of offering long-term therapeutic benefits. However, some doctors still doubt the existence of cancer stem cells.
The “Cylclin-dependent kinase inhibitor 2A” gene (CDKN2A gene) provides the DNA code for producing several genes, depending on multiple factors that regulate gene expression. The best studied of these genes regulated by CDKN2A in cancer are p16(INK4a) and the p19(ARF) proteins. Both function as tumor suppressor proteins, controlling cell growth and division during the cell cycle. Genetically altered versions of both P19/ARF as well as P16/INK4A have been found in several types of human cancer. (Source: Genetics Home Reference)
The cell cycle is an ordered series of events that eventually results in replication of the cell’s DNA, and division of one cell into two identical daughter cells. The stages of the cell cycle are usually represented in a circle with 4 phases; These phased are designated G1-S-G2-M. G1 stands for GAP1, during which the cell is metabolically active and continuously grows. S stands for synthesis, as it is during this part of the cell cycle that DNA replication occurs. G2 stands for GAP2, during which the growth of the cell continues and the cell prepares for division. And M stands for mitosis, which occurs in 4 stages during which the duplicated nuclear DNA (in the form of chromosomes) separate into two daughter nuclei, and the cell divides, forming two daughter cells with identical chromosomes (DNA). The regulation of the cell cycle is complex, involving cyclin dependent kinases (Cdk’s), cyclins, maturation promoting factor (MPF) which triggers progression through the cell cycle, the tumor suppressor p53 which can block the cell cycle, causing cell cycle arrest-if the DNA is damaged and requires repair, and p27, another tumor suppressor that binds cyclin and cdk proteins and can block entry into S phase. (source: the biology project.cell biology: “The cell cycle and Mitosis Tutorial”; Wikipedia;).
Cell Cycle Arrest-
During the cell cycle in normal cells, there exist a series of checkpoints to insure that all is proceeding correctly before a cell actually goes through with cell division. At these points in the process of cell replication, there are checkpoints built into the system so that if there are problems, cells can either go into cell cycle arrest until the problem detected can be corrected, or undergo apoptosis, which is programmed cell death. There are both exogenous and endogenous components determining a cell’s arrest or apoptosis. Toxic substances or UV or other damage to the DNA can initiate cell damage or stress. Cell Cycle Checkpoints are biochemical pathways that restrain cell cycle progression and or induce cell death. The tumor suppressor P53 is a key regulator of cell cycle arrest at the G1 checkpoint, or apoptosis following cellular stress. P53 performs this role primarily through regulating the transcription of genes that mediate these processes. There is a G1 “restriction” checkpoint, a G2-M” DNA damage” Checkpoint, an M phase “spindle checkpoint”, each providing the cell opportunities for detecting problems and ceasing the process of cell division. (source: ScienceDirect: Cell cycle checkpont signaling: Cell cycle arrest vs. Apoptosis)
CHK-Check Point Kinases-
The DNA inside a cell is constantly monitored for problems during the normal cell cycle. There are “checkpoints” for sensing errors or problems that occur during the G1/S phase of the cell cycle, and again at the G2/M phase of the cell cycle. If the DNA is damaged by one of several mechanisms, these checkpoints inhibit the cell cycle, causing cell cycle arrest until the DNA can be repaired. The protein kinase ATM along with its’ partner NBS1 detect double strand breaks (DSB’s) in the DNA, and modify mediator proteins which act to amplify the response to DNA damage to downstream proteins in the signal cascade. CHK is one of these downstream proteins which plays an important role in delaying the cell cycle after DNA damage, enhancing the role of P53 in acting as a tumor suppressor by arresting the cell cycle in response to DNA damage. CHK’s are known to play a major role in facilitating DNA repair upon radiation exposure, including activity following radiation treatment of cancers. Inhibitors of CHK’s therefore enhance cancer cell radiosensitivity through reducing the inhibition of DNA repair, and induction of mitotic catastrophy, leading to cancer cell death. (sources: Investigational New Drugs PMID 20024691; Wikipedia; )
Circulating Tumor Cells (CTCs)-
These are cancer cells that break away from the tumor, enter the vasculature and bloodstream, and with the correct techniques, can therefore be isolated from a patient’s blood sample. By detecting the number of circulating tumor cells (CTCs) in the bloodstream, doctors can gain important information about a patient’s prognosis and how well they are responding to treatment. This allows the team of cancer doctors to better guide treatment decisions. While there are a number of reasons for CTCs to be found in the blood, at least a portion of them may represent metastatic cells that will ultimately be responsible for spreading the cancer to other parts of the body, a process called metastasis. The CTCs isolated from a patients’ blood sometimes have different genetic alterations from the cells found in the primary tumor. Therefore, genetic analysis of CTCs sometimes yields information that can be used to tailor more effective treatment strategies for some patients. New methods for capturing and analyzing CTCs are being developed in order to facilitate their incorporation into routine cancer care.
Circulating Tumor DNA
-As tumor cells die, either as a result of normal cellular processes or in response to cancer treatment, small and degraded fragments of DNA are sometimes released into the patients’ blood stream. Many new methods are being developed to isolate circulating tumor DNA from routine patient blood samples. This may eventually offer a less invasive method than taking a tumor biopsy for monitoring very early responses to cancer treatment, and for predicting with better accuracy the likelihood of developing drug resistance in cancer patients.
A general category of cancer treatment that is usually given as part of a standard treatment regimen. This type of cancer treatment uses either naturally occurring compounds or synthetic agents that selectively kill actively dividing cells.
The compact set of structures in the nucleus that contains all the DNA of an organism. Humans have 46 chromosome pairs, and except for ovum and sperm, the nucleus of every cell in the body contains a full set of the chromosomal material.
A research study that has been reviewed and approved by an Institution’s Scientific Advisory Committee and Institutional Review Board (IRB), that tests a new therapy for patients with the appropriate diagnosis. Patients who enroll in such a study must first learn about the study in detail, and give their informed consent to be treated using the new clinical trial protocol. Clinical Trial studies can involve any of the following: a new drug, combinations of drugs, surgical procedure, radiation treatment, something that may prevent a disease from occurring, use of a new device, or examining a behavioral change as it relates to a disease (eg. exercise while undergoing cancer treatment). Clinical Trials can involve one or a combination of the above types of treatments. All Clinical Trials are strictly regulated and overseen, both by the Institution conducting the studies, and by the Federal Government.
DNA-the genetic material (Deoxyribonucleic Acid or nucleic acid) found in the nucleus of cells that contains all of the genetic instructions. DNA is composed of four different nucleotides: guanine (G), adenine (A), thymine (T), or cystosine (C). Each nucleotide (G, A, T or C) also has a sugar (deoxyribose) and a phosphate group attached. The nucleotides bind to each other, with the sugar of one nucleotide covalently binding to the phosphate of the next, forming a backbone. Nucleotide bases pair specifically, an A binds to a T, and a C to a G, aligning two chains that form a double helix. The sequence of these nucleotides is highly conserved, and contain segments of DNA that make up genes, or the code to make proteins. Genes in the DNA get transcribed into messenger RNA, which then is translated into the amino acids that make up proteins. Changes in the nucleic acid sequence of a gene are called mutations and are more recently referred to as variants, and can cause functional changes in the proteins they encode. DNA is organized into long compacted structures in the nucleus of cells called chromosomes.
DNA Damage-Any of a number of mechanisms can damage the normal structure of DNA, including cross-linking agents, agents that insert themselves between bases in the DNA double helix (intercalating agents), radiation, or other agents that cause breaks in the DNA. In normal cells, many types of DNA damage can be repaired, usually through cell cycle arrest giving the cells time to conduct this repair. In many cancer cells, normal cell cycle controls are mutated, and damaged DNA is incorporated into daughter cells which can lead to cancers.
DNA Sequencing-The process of determining the nucleotide sequence that makes up the code for proteins either in normal tissue, or in tumor tissue. Often when DNA sequencing is performed on cancer patients’ tumor DNA, oncologists are looking for mutations in the DNA sequence of genes that are known to contribute to the development of cancers, and that can potentially be treated with targeted therapies.
Driver Mutations-Genetic alterations in tumor DNA that are thought to play a key role in tumor growth, or that are essential for tumor survival.
Duplication-a specific type of insertion mutation in the DNA in which an inserted sequence of DNA is a repeat of the adjacent DNA. Duplications may be just a few nucleotides in length, or can be long stretches of nucleotides repeated in the DNA.
E2F1, E2F2, and E2F3-E2F’s are a family of transcription factors, several of which are involved in cell growth, and active in transcribing genes that are responsive to E2F from the DNA to produce proteins. The E2F family of transcription factors play key roles in regulating the cell cycle, and in affecting proteins that enhance the ability of the tumor suppressor p53 to control the cell cycle. (source: Wikipedia)
Enzymes-proteins that catalyze reactions in the cell, from energy transfer, to regulatory reactions that activate or inactive various cellular processes, to modifications that cause proteins to be degraded.
Epigenetic Alterations- Some genetic alterations in cells lead to changes in the way DNA is packaged in the cell nucleus. These changes in the packaging of DNA are collectively called epigenetic changes, and some of these contribute to the development of cancer. DNA is tightly compacted in the nucleus of cells in chromosomes. The chromosomes are made up of chromatin, DNA that is wound around spindle shaped proteins called nucleosomes. Some genetic alterations that have been found in cancer have been found to epigenetically alter the packaging of the DNA in the nucleus. Changes in the way the DNA is packaged in the nucleus alters which genes are expressed. Some of these changes in gene expression have been shown to contribute to the development of cancer.
Exosomes (Tumor Derived)-Exosomes are tiny vesicles (microscopic balloons) released by cells that contain protein, RNA and micro-RNA. These vesicles provide a means of transmitting information between different cells. Exosomes released from cancer cells have been shown experimentally to alter the programming of surrounding cells. Changing the behavior of cells in the area immediately around the tumor, called the tumor microenvironment, can contribute to tumor growth and metastasis, immune escape, and therapy resistance.
FISH-A genetic test performed in the MGH Center for Integrated Diagnostics (CID) and other Genetics labs. FISH stands for “Fluorescence in situ hybridization”. FISH is performed on tumor cells to examine chromosome structure, and look for abnormalities in the chromosomes that have been found in some cancers. FISH can identify chromosomal translocations as well as amplifications in tumors, some of which lead to specific treatments.
Functional Domain-Proteins are often schematically divided into different regions based on their structure or their function. A functional domain is that part of a protein sequence that has a distinct role, for example, a kinase enzyme might have a mutation found in it’s catalytic domain, the domain that binds ATP and is instrumental in transferring a phosphate group to another protein.
Fusion Gene (also see Gene Tranlocation/Fusion)-One of a group of genetic alterations that happen in tumors. A gene fusion occurs when there is a break in the DNA, and a portion of one gene joins a portion of another gene, creating an abnormal gene that has a piece of two different genes. Gene fusions can occur as the result of several different mechanisms in DNA, including translocations, deletions, or inversions.
Fusion Protein-A protein that results from a gene fusion, where the coding region of two different genes have rejoined abnormally and become contiguous. This abnormal gene made up of two segments of two different genes is then transcribed, and the resulting protein is made up of a portion of each. Fusion proteins are found in some cancers, and are the result of chromosomal breakage and/or recombination.
Gain-of-Function-When a genetic mutation occurs in the DNA of a gene that gives the resulting protein new capabilities, we call this a “gain-of-function mutation”. In cancer, such gain of function mutations lead to oncogenesis (tumor development), atypical survival of cells, or uncharacteristic cell proliferation.
Gene-a region of DNA that encodes the sequence to make a protein-A gene usually contains a promotor region, where regulatory proteins bind and direct transcription. Genes are transcribed into messenger RNA, which is then translated into a string of precise amino acids that fold into a functioning protein. Mutations in the DNA can cause changes in the amino acid sequence, altering the function of the protein. Some of these changes are tumorigenic, thereby contributing directly to tumor formation.
Genetic Alterations- Genetic alterations are any of a number of changes in the DNA that occur that can alter the normal proteins or the regulation of proteins in cells, and therefore can contribute to the development, maintenance, or spread of cancer. Genetic alterations include mutations, gene translocations, gene fusions, gene amplifications, and epigenetic changes in DNA. For definition of each, see each term in this glossary.
Gene Amplification- A specific type of genetic alteration in which instead of one copy of a gene per cell, specific genes are copied multiple times in the DNA (amplified). The amplified genes result in many more RNA transcripts of the DNA, which are then translated into the protein at a much higher level than is found in normal cells. This overexpression of amplified proteins has been shown to contribute to the development of some cancers.
Gene Duplication- A specific type of genetic alteration in which an inserted sequence of DNA is a repeat of an adjacent sequence of DNA. Genetic Duplications may consist of a sequence that is only a few nucleotides in length, or genetic duplications can be long stretches of nucleotide sequences repeated one or more times in the DNA. Each novel gene duplication that is discovered in tumor tissue must be studied in the laboratory to determine whether or not it contributes to the development or propagation of cancer.
Gene Expression- In normal cells, a highly regulated process involving the transcription of mRNA from segments of DNA that encode a gene; In normal cells the mRNA is then translated into the accurate sequence of amino acids, and folded correctly to produce the protein encoded by the gene. Various genetic alterations can affect the carefully regulated expression of genes, sometimes contributing to cancer.
Gene Fusion- A specific type of genetic alterations that occurs when there is a break in the DNA, and a gene or a portion of a gene moves to a new location and joins (fuses) with another gene or portion of a gene. This event creates an abnormal gene that is made up of pieces of two different genes. The resulting protein is therefore a fused portion of two different proteins. Gene fusions can occur as a result of genetic translocations, genetic deletions, or genetic inversions. Each novel gene fusion that is discovered in tumor tissue must be studied in the laboratory to determine whether or not it contributes to the development or propagation of cancer.
Genome- The complete genetic code of DNA that makes up an organism.
Genomic Testing- A type of medical test that examines the DNA of a patient to identify abnormalities in chromosomes, genes, or proteins. Genomic testing can be performed to look for one specific alteration in DNA, or can be more extensive looking at long lengths of DNA. Genomic testing can be performed on DNA from normal cells in a patient to look for inherited mutations. Genomic testing is also performed on cancer cells to determine what genetic changes may be driving tumor growth, to assist oncologists in finding the right treatment for a patient if a specific genetic alteration is found.
Gene Translocation- A genetic alteration involving a break in the DNA, and the subsequent change of a gene or a portion of a gene to a new location in the DNA. In the new location, the gene or portion of a gene may fuse to another gene, and therefore is not regulated as it would normally be in its’ usual location. Some of these gene translocations have been found to contribute to the development of cancer. Novel gene translocations that are discovered in tumors must be studied in the laboratory to determine whether or not each contributes to the development or propagation of cancer.
Growth Arrest-Interruption of the cell cycle by the activities of tumor suppressor proteins such as p53 due to DNA damage, or induced by a lack of nutrients in the cellular environment.
Growth Factor- Molecules made by the body that regulate cell growth, division, and survival. Usually external to the cell, growth factors are one of a variety of signal molecules that bind to specific receptors on the cell surface. The binding of growth factors to cell surface growth factor receptors triggers an activation of the receptor, causing changes in the expression of genes in the cell that promote growth.
Growth Factor Receptor- Usually located on the outer membrane of cells, growth factor receptors are proteins that characteristically have three domains; An external growth factor (ligand) binding domain; A trans-membrane domain that connects the external ligand-binding domain to an interior cytoplasmic domain; and the intracellular Cytoplasmic domain. Following binding of a growth factor to the external ligand-binding domain, the receptor is activated, causing amino acids in the cytoplasmic domain to have a phosphate group added to specific amino acids in a process called phosphorylation. Phosphorylation of these sites on the cytoplasmic domain of the receptor initiate a series of changes in a cascade of proteins called signal molecules in the cell. These result in altered gene expression in the nucleus of the cell that promotes growth.
Hormone- A special type of growth factor that is a signal for altered gene expression in the cell nucleus.
Hormone Receptor- a protein that binds to hormone signaling molecules, and in doing so is activated, and transported to the nucleus where it initiates expression of specific genes that are responsive to the hormone.
Hormone Therapy- Drug treatments that are used to alter the level or activity of one or more hormones in a patient. In cancer patients, these drugs work by various means to decrease the level of hormones that may be stimulating growth of the tumor. Hormones themselves may be used in cancer treatment, analogues or “mimics” of naturally occurring hormones may be used, or hormone antagonists may be used to slow or stop the growth of certain cancers, for example prostate or breast cancer. Synthetic hormones or other drugs may also be used to block the body’s production of hormones.
IHC (Immuno-Histo-Chemistry Staining)-A test method used by pathologists on tumor sections or biopsies to stage and analyze a tumor pathologically, or to assess biomarkers of the tumor that may help clinicians make better treatment decisions for patients. Tissue is treated with antibodies that bind to specific molecules if they are present in the tumor. This antibody staining is visible under the microscope using fluorescent dyes or radioisotopic labels. Experienced experts read the IHC tests to determine positivity. At MGH, we have an extensive IHC testing program in a lab that is CLIA certified (meets rigorous professional standards for validating and performing clinical tests). In our Center for Integrated Diagnostics (CID), we have sophisticated IHC methodologies in place to test for specific tumor biomarkers that may indicate which therapy would be most effective for a given tumor. Our CID also develops and validates new tests not available in other Hospitals or laboratories.
Immuno-Therapy-An exciting new field in cancer treatment is the development of a series of new therapeutic modalities that stimulate the immune system to destroy tumors. Drugs utilized in immuno-oncology include agents called “checkpoint inhibitors” or monoclonal antibodies. Normally, the immune system has a series of inhibitors that act as “brakes” to prevent the immune system from attacking tissue that is “self”, and enabling it to attack infectious bacterial or viral pathogens. However, in cancer, the tumor tissue is a genetically altered version of “self”. Check-point inhibitors involve using agents that prevent the immune system inhibitors from holding the immune system back. This stimulates the immune system to become more active, and attack the tumor. Other immune therapies involve use of the patient’s own T-cells being removed and programmed to attack the tumor before being re-infused back into the patient, specific growth factors, or vaccines that stimulate immune cell attack of tumors.
Kinase-A type of enzyme that transfers phosphate from a high energy phosphate-donating molecule such as ATP to a substrate that accepts the phosphate at specific sites in a process called phosphorylation. Kinases are important in many reactions related to growth, metabolism, cell signaling, the regulation of proteins, cellular transport, and secretion. Many of the genetic mutations in DNA that are associated with cancer are found in kinase enzymes, or in the proteins involved in regulating kinase enzymes.
MDM2-MDM2 is a key negative regulator of the P53 tumor suppressor protein. Initially discovered in mice, it has a parallel gene in humans, called HDM2. H/MDM2 is part of the ubiquitin proteolytic pathway, a set of proteins that target specific proteins for degradation within the cell. By binding to one end of the P53 protein, H/MDM2 inhibits the activation of P53, preventing P53 from performing its’ important role in cell cycle arrest and controlling cell growth. Genetic alterations in H/MDM2 have been found in several human cancers. (source: GeneCards, Human Gene Database)
Metastasis-Tumors start in localized regions of an organ in the body. If undetected, they grow and can spread through several mechanisms. Tumors can grow to invade adjacent tissues and organs; they can shed cancer cells into the lymphatic or circulatory system and spread to distant sites in the body. Cancers that have spread are said to be metastatic.
Monoclonal Antibody-Immune cells that have been exposed to specific parts of a protein, called an antigen, are stimulated to produce antibodies directed against that specific part of the protein, called an epitope. Once antibody producing cells are exposed to the antigen of choice, they are replicated, so that all the cells produce the identical antibody directed against that antigen. When used in patients, monoclonal antibodies bind to very specific epitopes of a protein, for example in a tumor. Now used frequently in cancer treatment and other medical applications, monoclonal antibodies are useful in targeting antigens that are specifically found on the tumor cells but not on normal cells, or to inhibit proteins that are driving tumor growth.
Next Generation Sequencing (NGS)-A diagnostic testing method involving determining the sequence of DNA from tumor tissue or tumor biopsy of patients, and analyzing it for genetic alterations that may be contributing to tumor growth. At MGH, we have one of the most extensive NGS testing platforms in use anywhere in the U.S. Our Center for Integrated Diagnostics (CID), a CLIA certified laboratory (recognized for its’ sophisticated and accurate testing methodologies and its’ ability to develop and validate new tests), routinely tests tumor tissue for hundreds of genetic alterations known to contribute to the development and propagation of tumors. Results from our NGS testing directly contribute to treatment decisions for our patients by our clinicians based on the specific genetic alterations found in our patient tumors through NGS testing.
Nucleotide-the building blocks of DNA, which is made up of deoxyribonucleic acid. There are four different nucleotides that make up DNA. They are guanine (G), adenine (A), thymine (T), or cystosine (C). Each nucleotide (G, A, T or C) also has a monosaccharide sugar component (deoxyribose), as well as a phosphate group. Nucleotides are joined to each other in a chain by covalent bonds between the sugar component of one nucleotide and the phosphate of the next. Base pairing occurs between A and T, or between C and G nucleotides. Two complementary strands of nucleotides are drawn together to form the classic double helix that is DNA. Genetic mutations in the DNA are changes in the sequence of the nucleotides such that the code for making a protein is altered, sometimes resulting in changes in the function or regulation of that protein, which can contribute to the development of cancer.
Oncoprotein-proteins that promote growth and cell division. In normal cells, these proteins are tightly regulated to prevent uncontrolled cell growth. However, in many cancers, oncoproteins are mutated or otherwise genetically altered, losing their normal regulation and resulting in uncontrolled growth.
Oxidative Stress-A circumstance that can occur in cells when antioxidant levels are lower than normal, which leaves cells vulnerable to DNA damage by oxygen radicals through their chemical reaction with DNA. (source: what is oxidative stress? Metabolism, 2000)
P19(ARF)-A cellular tumor suppressor gene, found to be genetically altered in several cancers. P19(ARF) protein protects the tumor suppressor P53 from being broken down. The accumulation of P53 leads to cell cycle arrest, regulating cell division and growth, and pausing cells to enable DNA repair to take place. By preventing the degradation of P53, P19(ARF) helps prevent cancer. (source: Cell: the regulation of ink4/ARF in Cancer and Aging, 2006)
P16(INK4A)-A cellular tumor suppressor gene, found to be genetically altered in several cancers. P16(INK4a) acts as a cell-cycle regulatory protein that interacts with cell-cycle progression proteins CDK4 and CDK6. When bound by P16(INK4a), CDK4 or CDK6 are held in check, blocking their ability to promote cell division. (source: Cell: the regulation of ink4/ARF in Cancer and Aging, 2006)
Peptide-A segment of a protein made up of amino acids in a specific sequence.
Protein-a molecule that is made up of a specific sequence of amino acids encoded by DNA, and transcribed into mRNA before being folded in the cell cytoplasm into a three dimensional, functional protein. Different proteins carry out specific functions within the cell; they can be structural or regulatory, or they can be enzymes that are involved in specific biochemical reactions within the cell.
Protein Kinase Inhibitor-protein kinases are enzymes that catalyze the transfer of a phosphate group from one protein to another, in a reaction called phosphorylation. Phosphorylation often results in activation of the protein recipient of the phosphate transfer. Many of the growth signal pathways in cells involve a cascade of phosphorylation reactions starting from a growth factor receptor on the cell surface being activated through binding a growth factor, and subsequently phosphorylation of a series of signal molecules that ultimately lead to changes in protein expression in the nucleus that stimulates growth. In many cancers, protein kinases are found to be genetically altered, causing them to be hyperactive and to stimulate tumor growth. Protein kinase inhibitors are substances that interfere or stop the phosphorylation reaction of a given kinase. Protein kinase inhibitors are often peptides or monoclonal antibodies that bind to the catalytic domain of the kinase, preventing the phosphate-donating ATP molecule from binding, thereby blocking the transfer of a phosphate to the next protein in the cascade to inhibit the growth signal.
Reactive Oxygen Species-An unstable molecule that contains oxygen that readily reacts with other molecules such as DNA, RNA, and proteins in the cell. A high level of reactive oxygen species in cells may cause cell death through these reactions. Reactive oxygen species are also called “free radicals” or “oxygen radicals”. (source: BioTek:An introduction to reactive oxygen species; 2014)
Receptor Tyrosine Kinase-A class of proteins that are located on the outer cell membrane that are activated upon binding growth factors, or by interacting with specific receptors on the outer membrane of other signaling cells. In addition to the domain of the receptor located on the outer cell membrane, receptor tyrosine kinases (RTK’s) often have a transmembrane domain that traverses the outer membrane and is connected to a third domain, the intracellular domain in the cell cytoplasm. When activated, RTK’s cytoplasmic domain interacts with other RTK cytoplasmic domains, and become phosphorylated on tyrosine residues. This activation initiates a cascade of phosphorylation events involving intracellular kinase signal molecules, eventually conveying a signal to the nucleus that results in changes in gene expression in the nucleus that cause growth and cell division. In many cancers, RTK’s are mutated or otherwise genetically altered such that no growth factor is required for their activation. They are constitutively active, constantly sending “grow” signals to the cell and contributing to tumor growth.
RNA-messenger RNA (ribonucleic acid) is the transcript readout from DNA (deoxyribonucleic acid) that is an intermediate message for translation into the amino acid sequence that is then folded in the cell into a functional, three-dimensional protein. Both DNA and RNA are composed of nucleotides, however, the building blocks of RNA are guanine (G), adenine (A), uracil (U), and cytosine (C). Unlike DNA, messenger RNA (mRNA) exists as a single strand, not as a double helix. In addition to messenger RNA (mRNA), there are other kinds of RNA molecules that play various roles in the cell, including regulating gene expression and protein synthesis.
Senescence-The process of deterioration in cells with age, and in cellular terms defined as an inability to proceed through the cell cycle. Senescent cells remain alive, but are arrested in a senescent instead of in an actively dividing state. (source: Annu Rev Physiol 2012, Aging, Cellular Senescence, and Cancer)
Serine Kinase-A family of enzymes that catalyze the transfer of phosphate from a phosphate donor molecule such as ATP to another protein. For the serine kinases, the phosphorylation reaction specifically occurs on serine residues on the target proteins.
SNP (single nucleotide polymorphism)-a nucleotide substitution in the DNA in a specific part of the genome. Many SNP’s have been identified in tumors, and shown to contribute to the development of cancers. At MGH, we have extensive testing for SNP’s that are known cancer-associated genetic changes in the DNA. Novel SNP’s that are discovered from tumor DNA must be studied in the laboratory to determine whether or not they contribute to the development or propagation of cancer.
Somatic Mutation-a change in the DNA of a gene that is the code for a protein in a single cell, or a group of cells such as a tumor. Somatic mutations are not inherited from the parents of a person, but rather arise spontaneously in cells due to exposure to UV sunlight, to chemicals that cause mutations, or for other reasons not always understood.
Stem Cells-Noteworthy for their ability to develop into multiple different cell types, stem cells are somewhat undifferentiated cells in complex organisms such as humans. Stem cells can renew themselves through cell division, unlike fully differentiated cells like skin cells, for example. In addition, under the appropriate conditions, stem cells can become several types of tissue or organ specific cells that carry out highly specialized functions. Sources of stem cells for study previously have been either embryonic stem cells or adult stem cells. Several years ago, researchers discovered that under some circumstances, differentiated cells could be reprogrammed to have some of the characteristics of stem cells. Research is currently underway to find methods for using stem cells in cell-based therapies in cancer and other diseases.
Targeted Therapy-Unlike chemotherapy, which involves the administration of drugs that are toxic to all dividing cells whether they are tumor cells or normal cells in the body, targeted therapy aims to be toxic only to specific cancer cells without directly impacting normal cells. With advanced genomic testing techniques, specific features of an individual patients’ tumor can be identified. Knowing what the exact genetic alterations in a particular individuals’ tumor are can enable clinicians to select targeted therapies that are predicted to specifically reduce or eliminate the tumor with the genotype identified through tumor testing. This selects the appropriate patients for the best therapeutic option available, and reduces the unnecessary treatment of cancer patients with therapies that are unlikely to work on their cancer.
Tumor-Abnormal growth of tissue in the body, whether benign or malignant. A collection of cells that divide and grow excessively, eventually creating a lump or swelling.
Tumor Metastasis-See Metastasis
Tumor Suppressor Gene-A gene that encodes a protein that protects cells from unregulated growth such as cancer. Mutations or genetic alterations in tumor suppressor genes prevent the protein from performing its’ normal function, and contribute to the development of cancer.