ComprehensiveDx Clear^TM

What is hereditary cancer?

There are many genes that control cell growth and division. If certain genes are mutated and do not give cells proper instructions about when to grow and divide, then cancer could develop. Cancer development is a complex process. Environmental factors, such as UV light, tobacco and diet can increase mutation rates. Some of these mutations will be repaired, but some mutations will not. These mutations will be present in some cells in the body and this will increase the risk of cancer development. However in families with hereditary forms of cancer, a mutation is present in a very important gene and is present in all cells in the body. Inheriting a cancer-causing mutation in one of the cancer susceptibility genes does not mean that cancer will definitely occur. It means only that your risk is higher than for someone who does not carry such a mutation in their cells.

Some types of cancer have a significant hereditary component and can develop due to a mutation in one of the hereditary cancer predisposition genes. Breast, ovarian, colorectal, endometrial, melanoma, pancreatic, gastric, and prostate cancers are among those with a significant hereditary component.

Genetic testing using ComprehensiveDx Clear^TM may be appropriate if:

• A family history includes a number of cancer cases of several different types indicating a presence of several hereditary cancer syndromes.
• A family history is suggestive of inherited cancer; however the cancer type(s) do not seem to fit a particular hereditary cancer syndrome.

Are you at high risk for Hereditary Cancer Syndromes?

You could have a hereditary predisposition to cancer if:

• You had cancer diagnosed at a young age (≤50 years, for most cancers)
• Multiple relatives diagnosed with the same or related cancers in multiple generations on the same side of the family, especially when diagnosed younger than average
• You have a history of multiple primary cancers, either of the same origin (such as two separate colon cancers) or of different origins (such as breast cancer and ovarian cancer)
• You were diagnosed with certain rare cancers, such as ovarian or male breast cancer

What are the possible benefits of genetic testing with ComprehensiveDx Clear^TM?

Any hereditary cancer susceptibility testing reduces the uncertainty about the risks of cancer for people and their families. Such testing may be able to explain the cancer history in your family. If a cancer predisposing mutation is identified, it can help your doctor to provide more personalized surgical and ongoing surveillance plans and make more informed treatment decisions.

What is ComprehensiveDx Clear^TM?

ComprehensiveDx Clear^TM is a comprehensive panel for hereditary breast, ovarian, uterine, colorectal, pancreatic, prostate and melanoma cancers. This next-generation sequencing (NGS) assay analyses point mutations, gross deletions and duplications in the following genes associated with various inherited cancers: APC, ATM, BAP1, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A, CHEK2, DICER1, EPCAM (CNV only), FANCC, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, POLD1, POLE, PTEN, RAD50, RAD51C, RAD51D, SDHA, SDHB, SDHC, SDHD, SMAD4, STK11 and TP53. This panel includes emerging genes (such as BARD1, CDK4, DICER1, POLD1) with limited data on their association with hereditary cancer in addition to well-studied cancer predisposing genes. The variants identified by the test are classified according to the guidelines for sequence variant interpretation of the American College of Medical Genetics and Genomics (ACMG). Variant classification categories include pathogenic, likely pathogenic, variant of unknown significance (VUS), likely benign, and benign with likely benign and benign variants excluded from the report.

• Pathogenic variants - Genetic changes with known clinical significance that is associated with an increased risk of hereditary cancer.
• Likely pathogenic variants – Genetic changes that have some preliminary clinical data indicating an association with hereditary cancer but not sufficient to make a definitive determination of pathogenicity.
• Variants of uncertain significance (VUS) – Genetic changes with either conflicting or no supporting data to determine their pathogenicity.
• Negative Result – No variant of clinical or uncertain significance was detected. Negative result does not eliminate the risk of developing cancer. Benign variants that have sufficient evidence to be considered of no clinical significance and likely benign variants that are not likely to increase the risk of cancer will not be shown on the report.

Cancer predisposing genes

Cancer predisposing genes assessed by ComprehensiveDx Clear^TM assay are associated with various hereditary cancer syndromes and increase the risk of cancer in many organs.

GENE LIST

APC

ATM

BAP1

BARD1

BMPR1A

BRCA1

BRCA2

BRIP1

CDH1

CDK4

CDKN2A

CHEK2

DICER1

EPCAM

FANCC

MLH1

MRE11A

MSH2

MSH6

MUTYH

NBN

PALB2

PMS2

POLD1

POLE

PTEN

RAD50

RAD51C

RAD51D

SDHA

SDHB

SDHC

SDHD

SMAD4

STK11

TP53

Click on any gene to view its definition

APC - This gene encodes a protein which interacts with the N-terminal region of BRCA1. In addition to its ability to bind BRCA1 in vivo and in vitro, it shares homology with the 2 most conserved regions of BRCA1: the N-terminal RING motif and the C-terminal BRCT domain. The RING motif is a cysteine-rich sequence found in a variety of proteins that regulate cell growth, including the products of tumor suppressor genes and dominant protooncogenes. This protein also contains 3 tandem ankyrin repeats. The BARD1/BRCA1 interaction is disrupted by tumorigenic amino acid substitutions in BRCA1, implying that the formation of a stable complex between these proteins may be an essential aspect of BRCA1 tumor suppression. This protein may be the target of oncogenic mutations in breast or ovarian cancer. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene.

ATM - The ATM gene provides instructions for making a protein that is located primarily in the nucleus of cells, where it helps control the rate at which cells grow and divide. This protein also plays an important role in the normal development and activity of several body systems, including the nervous system and the immune system. Additionally, the ATM protein assists cells in recognizing damaged or broken DNA strands. DNA can be damaged by agents such as toxic chemicals or radiation. Breaks in DNA strands also occur naturally when chromosomes exchange genetic material during cell division. The ATM protein coordinates DNA repair by activating enzymes that fix the broken strands. Efficient repair of damaged DNA strands helps maintain the stability of the cell's genetic information.

BAP1 - This gene provides instructions for making a protein called ubiquitin carboxyl-terminal hydrolase BAP1 (shortened to BAP1). This protein functions as a deubiquitinase, which means it removes a molecule called ubiquitin from certain proteins. The presence of ubiquitin molecules on a protein can affect the activity of the protein and its interactions with other proteins. The ubiquitin "tag" also promotes breakdown (degradation) of a protein. By removing ubiquitin, BAP1 helps regulate the function of many proteins involved in diverse cellular processes. The BAP1 protein is thought to help control cell growth and division (proliferation) and cell death. Studies suggest that it is involved in the progression of cells through the step-by-step process they take to replicate themselves (called the cell cycle) and that it plays roles in repairing damaged DNA and controlling the activity of genes.

Although the exact mechanism is unclear, the BAP1 protein acts as a tumor suppressor. Tumor suppressor proteins help prevent cells from growing and dividing too rapidly or in an uncontrolled way.

BARD1 - This gene encodes a protein which interacts with the N-terminal region of BRCA1. In addition to its ability to bind BRCA1 in vivo and in vitro, it shares homology with the 2 most conserved regions of BRCA1: the N-terminal RING motif and the C-terminal BRCT domain. The RING motif is a cysteine-rich sequence found in a variety of proteins that regulate cell growth, including the products of tumor suppressor genes and dominant protooncogenes. This protein also contains 3 tandem ankyrin repeats. The BARD1/BRCA1 interaction is disrupted by tumorigenic amino acid substitutions in BRCA1, implying that the formation of a stable complex between these proteins may be an essential aspect of BRCA1 tumor suppression. This protein may be the target of oncogenic mutations in breast or ovarian cancer. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene.

BMPR1A - This gene provides instructions for making a protein called bone morphogenetic protein receptor 1A. This receptor protein has a specific site into which certain other proteins, called ligands, fit like keys into locks. Specifically, the BMPR1A protein attaches (binds) to ligands in the transforming growth factor beta (TGF-β) pathway. This signaling pathway allows the environment outside the cell to affect how the cell produces other proteins. The BMPR1A receptor protein and its ligands are involved in transmitting chemical signals from the cell membrane to the nucleus.

When the BMPR1A protein is bound to a ligand, it turns on (activates) a group of related proteins (a protein complex) called SMAD proteins. The activated SMAD protein complex is then transported into the cell's nucleus, where it regulates cell growth and division (proliferation) and the activity of particular genes.

BRCA1 - This gene provides instructions for making a protein that acts as a tumor suppressor. Tumor suppressor proteins help prevent cells from growing and dividing too rapidly or in an uncontrolled way.

The BRCA1 protein is involved in repairing damaged DNA. In the nucleus of many types of normal cells, the BRCA1 protein interacts with several other proteins to mend breaks in DNA. These breaks can be caused by natural and medical radiation or other environmental exposures, and they also occur when chromosomes exchange genetic material in preparation for cell division. By helping to repair DNA, the BRCA1 protein plays a critical role in maintaining the stability of a cell's genetic information.

Research suggests that the BRCA1 protein also regulates the activity of other genes and plays an essential role in embryonic development. To carry out these functions, the BRCA1 protein interacts with many other proteins, including other tumor suppressors and proteins that regulate cell division.

BRCA2 - This gene provides instructions for making a protein that acts as a tumor suppressor. Tumor suppressor proteins help prevent cells from growing and dividing too rapidly or in an uncontrolled way.

The BRCA2 protein is involved in repairing damaged DNA. In the nucleus of many types of normal cells, the BRCA2 protein interacts with several other proteins to mend breaks in DNA. These breaks can be caused by natural and medical radiation or other environmental exposures, and they also occur when chromosomes exchange genetic material in preparation for cell division. By helping to repair DNA, the BRCA2 protein plays a critical role in maintaining the stability of a cell's genetic information.

Researchers suspect that the BRCA2 protein has additional functions within cells. For example, the protein may help regulate cytokinesis, which is the step in cell division when the fluid surrounding the nucleus (the cytoplasm) divides to form two separate cells. Researchers are investigating the protein's other potential activities.

BRIP1 - The protein encoded by this gene is a member of the RecQ DEAH helicase family and interacts with the BRCT repeats of breast cancer, type 1 (BRCA1). The bound complex is important in the normal double-strand break repair function of breast cancer, type 1 (BRCA1). This gene may be a target of germline cancer-inducing mutations

CDH1 - This gene provides instructions for making a protein called epithelial cadherin or E-cadherin. This protein is found within the membrane that surrounds epithelial cells, which are the cells that line the surfaces and cavities of the body. E-cadherin belongs to a family of proteins called cadherins whose function is to help neighboring cells stick to one another (cell adhesion) to form organized tissues.

E-cadherin is one of the best-understood cadherin proteins. In addition to its role in cell adhesion, E-cadherin is involved in transmitting chemical signals within cells, controlling cell maturation and movement, and regulating the activity of certain genes. E-cadherin also acts as a tumor suppressor protein, which means it prevents cells from growing and dividing too rapidly or in an uncontrolled way.

CDK4 - gene provides instructions for making several proteins. The most well-studied are the p16(INK4a) and the p14(ARF) proteins. Both function as tumor suppressors, which means they keep cells from growing and dividing too rapidly or in an uncontrolled way.

The p16(INK4a) protein attaches (binds) to two other proteins called CDK4 and CDK6. These proteins help regulate the cell cycle, which is the cell's way of replicating itself in an organized, step-by-step fashion. CDK4 and CDK6 normally stimulate the cell to continue through the cycle and divide. However, binding of p16(INK4a) blocks CDK4's or CDK6's ability to stimulate cell cycle progression. In this way, p16(INK4a) controls cell growth and division.

The p14(ARF) protein protects a different protein called p53 from being broken down. The p53 protein is an important tumor suppressor that is essential for regulating cell division and self-destruction (apoptosis). By protecting p53, p14(ARF) also helps prevent tumor formation.

CDKN2A - The protein encoded by this gene is a member of the Ser/Thr protein kinase family. This protein is highly similar to the gene products of S. cerevisiae cdc28 and S. pombe cdc2. It is a catalytic subunit of the protein kinase complex that is important for cell cycle G1 phase progression. The activity of this kinase is restricted to the G1-S phase, which is controlled by the regulatory subunits D-type cyclins and CDK inhibitor p16(INK4a). This kinase was shown to be responsible for the phosphorylation of retinoblastoma gene product (Rb). Mutations in this gene as well as in its related proteins including D-type cyclins, p16(INK4a) and Rb were all found to be associated with tumorigenesis of a variety of cancers. Multiple polyadenylation sites of this gene have been reported.

CHEK2 - The CHEK2 gene provides instructions for making a protein called checkpoint kinase 2 (CHK2). This protein acts as a tumor suppressor, which means that it regulates cell division by keeping cells from growing and dividing too rapidly or in an uncontrolled way.

The CHK2 protein is activated when DNA becomes damaged or when DNA strands break. DNA can be damaged by agents such as toxic chemicals, radiation, or ultraviolet (UV) rays from sunlight, and breaks in DNA strands also occur naturally when chromosomes exchange genetic material.

In response to DNA damage, the CHK2 protein interacts with several other proteins, including tumor protein 53 (which is produced from the TP53 gene). These proteins halt cell division and determine whether a cell will repair the damage or self-destruct in a controlled manner (undergo apoptosis). This process keeps cells with mutated or damaged DNA from dividing, which helps prevent the development of tumors.

DICER1 - This gene provides instructions for making a protein that plays a role in regulating the activity (expression) of other genes. The Dicer protein aids in the production of a molecule called microRNA (miRNA). MicroRNAs are short lengths of RNA, a chemical cousin of DNA. Dicer cuts (cleaves) precursor RNA molecules to produce miRNA.

MicroRNAs control gene expression by blocking the process of protein production. In the first step of making a protein from a gene, another type of RNA called messenger RNA (mRNA) is formed and acts as the blueprint for protein production. MicroRNAs attach to specific mRNA molecules and stop the process by which protein is made. Sometimes, miRNAs break down the mRNA, which also blocks protein production. Through this role in regulating the expression of genes, Dicer is involved in many processes, including cell growth and division (proliferation) and the maturation of cells to take on specialized functions (differentiation).

EPCAM - This gene provides instructions for making a protein known as epithelial cellular adhesion molecule (EpCAM). This protein is found in epithelial cells, which are the cells that line the surfaces and cavities of the body. The EpCAM protein is found spanning the membrane that surrounds epithelial cells, where it helps cells stick to one another (cell adhesion). In addition, the protein in the cell membrane can be cut at a specific location, releasing a piece called the intracellular domain (EpICD), which helps relay signals from outside the cell to the nucleus of the cell. EpICD travels to the nucleus and associates with other proteins, forming a group (complex) that regulates the activity of several genes that are involved in cell growth and division (proliferation), maturation (differentiation), and movement (migration), all of which are important processes for the proper development of cells and tissues.

FANCC - This gene provides instructions for making a protein that is involved in a cell process known as the Fanconi anemia (FA) pathway. The FA pathway is turned on (activated) when the process of making new copies of DNA, called DNA replication, is blocked due to DNA damage. The FA pathway is particularly responsive to a certain type of DNA damage known as interstrand cross-links (ICLs). ICLs occur when two DNA building blocks (nucleotides) on opposite strands of DNA are abnormally attached or linked together, which stops the process of DNA replication. ICLs can be caused by a buildup of toxic substances produced in the body or by treatment with certain cancer therapy drugs.

The FANCC protein is one of a group of proteins known as the FA core complex. The FA core complex is composed of eight FA proteins (including FANCC) and two proteins called Fanconi anemia-associated proteins (FAAPs). This complex activates two proteins, called FANCD2 and FANCI, by attaching a single molecule called ubiquitin to each of them (a process called monoubiquitination). The activation of these two proteins, which attach (bind) together to form the ID protein complex, attract DNA repair proteins to the area of DNA damage so the error can be corrected and DNA replication can continue.

MLH1 This gene provides instructions for making a protein that plays an essential role in DNA repair. This protein helps fix mistakes that are made when DNA is copied (DNA replication) in preparation for cell division. The MLH1 protein joins with another protein called PMS2 (produced from the PMS2 gene), to form a protein complex. This complex coordinates the activities of other proteins that repair mistakes made during DNA replication. The repairs are made by removing a section of DNA that contains mistakes and replacing the section with a corrected DNA sequence. The MLH1 gene is a member of a set of genes known as the mismatch repair (MMR) genes.

MRE11A - This gene encodes a nuclear protein involved in homologous recombination, telomere length maintenance, and DNA double-strand break repair. By itself, the protein has 3' to 5' exonuclease activity and endonuclease activity. The protein forms a complex with the RAD50 homolog; this complex is required for nonhomologous joining of DNA ends and possesses increased single-stranded DNA endonuclease and 3' to 5' exonuclease activities. In conjunction with a DNA ligase, this protein promotes the joining of noncomplementary ends in vitro using short homologies near the ends of the DNA fragments. This gene has a pseudogene on chromosome 3. Alternative splicing of this gene results in two transcript variants encoding different isoforms.

MSH2 - This gene provides instructions for making a protein that plays an essential role in DNA repair. This protein helps fix mistakes that are made when DNA is copied (DNA replication) in preparation for cell division. The MSH2 protein joins with one of two other proteins, MSH6 or MSH3 (each produced from a different gene), to form a protein complex. This complex identifies locations on the DNA where mistakes have been made during DNA replication. Another group of proteins, the MLH1-PMS2 protein complex, then repairs the errors. The MSH2 gene is a member of a set of genes known as the mismatch repair (MMR) genes.

MSH6 - This gene provides instructions for making a protein that plays an essential role in repairing DNA. This protein helps fix mistakes that are made when DNA is copied (DNA replication) in preparation for cell division. The MSH6 protein joins with another protein called MSH2 (produced from the MSH2 gene) to form a protein complex. This complex identifies locations on the DNA where mistakes have been made during DNA replication. Another group of proteins, the MLH1-PMS2 protein complex, then repairs the errors. The MSH6 gene is a member of a set of genes known as the mismatch repair (MMR) genes.

MUTYH - This gene provides instructions for making an enzyme called MYH glycosylase, which is involved in the repair of DNA. This enzyme corrects particular mistakes that are made when DNA is copied (DNA replication) in preparation for cell division. DNA is made up of building blocks called nucleotides, each of which has a specific partner. Normally, adenine pairs with thymine (written as A-T) and guanine pairs with cytosine (written as G-C). During normal cellular activities, guanine sometimes becomes altered by oxygen, which causes it to pair with adenine instead of cytosine. MYH glycosylase fixes this mistake so mutations do not accumulate in the DNA and lead to tumor formation. This type of repair is known as base excision repair.

NBN - This gene provides instructions for making a protein called nibrin. This protein is involved in several critical cellular functions, including the repair of damaged DNA.

Nibrin interacts with two other proteins, produced from the MRE11A and RAD50 genes, as part of a larger protein complex. Nibrin regulates the activity of this complex by carrying the MRE11A and RAD50 proteins into the cell's nucleus and guiding them to sites of DNA damage. The proteins work together to mend broken strands of DNA. DNA can be damaged by agents such as toxic chemicals or radiation, and breaks in DNA strands also occur naturally when chromosomes exchange genetic material in preparation for cell division. Repairing DNA prevents cells from accumulating genetic damage that may cause them to die or to divide uncontrollably.

The MRE11A/RAD50/NBN complex interacts with the protein produced from the ATM gene, which plays an essential role in recognizing broken strands of DNA and coordinating their repair. The MRE11A/RAD50/NBN complex helps maintain the stability of a cell's genetic information through its roles in repairing damaged DNA and regulating cell division. Because these functions are critical for preventing the formation of cancerous tumors, nibrin is described as a tumor suppressor.

PALB2 - This gene encodes a protein that may function in tumor suppression. This protein binds to and colocalizes with the breast cancer 2 early onset protein (BRCA2) in nuclear foci and likely permits the stable intranuclear localization and accumulation of BRCA2.

PMS2 - This gene provides instructions for making a protein that plays an essential role in repairing DNA. This protein helps fix mistakes that are made when DNA is copied (DNA replication) in preparation for cell division. The PMS2 protein joins with another protein called MLH1 (produced from the MLH1 gene) to form a protein complex. This complex coordinates the activities of other proteins that repair mistakes made during DNA replication. Repairs are made by removing the section of DNA that contains mistakes and replacing it with a corrected DNA sequence. The PMS2 gene is a member of a set of genes known as the mismatch repair (MMR) genes.

POLD1 - This gene encodes the 125-kDa catalytic subunit of DNA polymerase delta. DNA polymerase delta possesses both polymerase and 3' to 5' exonuclease activity and plays a critical role in DNA replication and repair. Alternatively spliced transcript variants have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 6.

POLE - This gene encodes the catalytic subunit of DNA polymerase epsilon. The enzyme is involved in DNA repair and chromosomal DNA replication. Mutations in this gene have been associated with colorectal cancer 12 and facial dysmorphism, immunodeficiency, livedo, and short stature.

PTEN - This gene provides instructions for making an enzyme that is found in almost all tissues in the body. The enzyme acts as a tumor suppressor, which means that it helps regulate cell division by keeping cells from growing and dividing too rapidly or in an uncontrolled way. The PTEN enzyme modifies other proteins and fats (lipids) by removing phosphate groups, each of which consists of three oxygen atoms and one phosphorus atom. Enzymes with this function are called phosphatases.

The PTEN enzyme is part of a chemical pathway that signals cells to stop dividing and triggers cells to self-destruct through a process called apoptosis. Evidence suggests that this enzyme also helps control cell movement (migration), the sticking (adhesion) of cells to surrounding tissues, and the formation of new blood vessels (angiogenesis). Additionally, it likely plays a role in maintaining the stability of a cell's genetic information. All of these functions help prevent uncontrolled cell growth that can lead to the formation of tumors.

RAD50 - The protein encoded by this gene is highly similar to Saccharomyces cerevisiae Rad50, a protein involved in DNA double-strand break repair. This protein forms a complex with MRE11 and NBS1. The protein complex binds to DNA and displays numerous enzymatic activities that are required for nonhomologous joining of DNA ends. This protein, cooperating with its partners, is important for DNA double-strand break repair, cell cycle checkpoint activation, telomere maintenance, and meiotic recombination. Knockout studies of the mouse homolog suggest this gene is essential for cell growth and viability. Mutations in this gene are the cause of Nijmegen breakage syndrome-like disorder.

RAD51C - This gene is a member of the RAD51 family. RAD51 family members are highly similar to bacterial RecA and Saccharomyces cerevisiae Rad51 and are known to be involved in the homologous recombination and repair of DNA. This protein can interact with other RAD51 paralogs and is reported to be important for Holliday junction resolution. Mutations in this gene are associated with Fanconi anemia-like syndrome. This gene is one of four localized to a region of chromosome 17q23 where amplification occurs frequently in breast tumors. Overexpression of the four genes during amplification has been observed and suggests a possible role in tumor progression. Alternative splicing results in multiple transcript variants.

RAD51D - The protein encoded by this gene is a member of the RAD51 protein family. RAD51 family members are highly similar to bacterial RecA and Saccharomyces cerevisiae Rad51, which are known to be involved in the homologous recombination and repair of DNA. This protein forms a complex with several other members of the RAD51 family, including RAD51L1, RAD51L2, and XRCC2. The protein complex formed with this protein has been shown to catalyze homologous pairing between single- and double-stranded DNA, and is thought to play a role in the early stage of recombinational repair of DNA. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the downstream ring finger and FYVE-like domain containing 1 (RFFL) gene.

SDHA - This gene provides instructions for making one of four parts (subunits) of the succinate dehydrogenase (SDH) enzyme. The SDH enzyme plays a critical role in mitochondria, which are structures inside cells that convert the energy from food into a form that cells can use.

Within mitochondria, the SDH enzyme links two important pathways in energy conversion: the citric acid cycle (or Krebs cycle) and oxidative phosphorylation. As part of the citric acid cycle, the SDH enzyme converts a compound called succinate to another compound called fumarate. Negatively charged particles called electrons are released during this reaction. The SDHA protein is the active subunit of the enzyme that performs the conversion of succinate, and it also helps transfer electrons to the oxidative phosphorylation pathway. In oxidative phosphorylation, the electrons help create an electrical charge that provides energy for the production of adenosine triphosphate (ATP), the cell's main energy source.

Succinate, the compound on which the SDH enzyme acts, is an oxygen sensor in the cell and can help turn on specific pathways that stimulate cells to grow in a low-oxygen environment (hypoxia). In particular, succinate stabilizes a protein called hypoxia-inducible factor (HIF) by preventing a reaction that would allow HIF to be broken down. HIF controls several important genes involved in cell division and the formation of new blood vessels in a hypoxic environment.

The SDHA gene is a tumor suppressor gene, which means it prevents cells from growing and dividing in an uncontrolled way.

SDHB - This gene provides instructions for making one of four subunits of the succinate dehydrogenase (SDH) enzyme. The SDH enzyme plays a critical role in mitochondria, which are structures inside cells that convert the energy from food into a form that cells can use.

Within mitochondria, the SDH enzyme links two important pathways in energy conversion: the citric acid cycle (or Krebs cycle) and oxidative phosphorylation. As part of the citric acid cycle, the SDH enzyme converts a compound called succinate to another compound called fumarate. Negatively charged particles called electrons are released during this reaction. The SDHB protein provides an attachment site for electrons as they are transferred to the oxidative phosphorylation pathway. In oxidative phosphorylation, the electrons help create an electrical charge that provides energy for the production of adenosine triphosphate (ATP), the cell's main energy source.

Succinate, the compound on which the SDH enzyme acts, is an oxygen sensor in the cell and can help turn on specific pathways that stimulate cells to grow in a low-oxygen environment (hypoxia). In particular, succinate stabilizes a protein called hypoxia-inducible factor (HIF) by preventing a reaction that would allow HIF to be broken down. HIF controls several important genes involved in cell division and the formation of new blood vessels in a hypoxic environment.

The SDHB gene is a tumor suppressor, which means it prevents cells from growing and dividing in an uncontrolled way.

SDHC - This gene provides instructions for making one of four subunits of the succinate dehydrogenase (SDH) enzyme. The SDH enzyme plays a critical role in mitochondria, which are structures inside cells that convert the energy from food into a form that cells can use. The SDHC protein helps anchor the SDH enzyme in the mitochondrial membrane.

Within mitochondria, the SDH enzyme links two important cellular pathways in energy conversion: the citric acid cycle (or Krebs cycle) and oxidative phosphorylation. As part of the citric acid cycle, the SDH enzyme converts a compound called succinate to another compound called fumarate. Negatively charged particles called electrons are released during this reaction. The electrons are transferred through the SDH subunits, including the SDHC protein, to the oxidative phosphorylation pathway. In oxidative phosphorylation, the electrons help create an electrical charge that provides energy for the production of adenosine triphosphate (ATP), the cell's main energy source.

Succinate, the compound on which the SDH enzyme acts, is an oxygen sensor in the cell and can help turn on specific pathways that stimulate cells to grow in a low-oxygen environment (hypoxia). In particular, succinate stabilizes a protein called hypoxia-inducible factor (HIF) by preventing a reaction that would allow HIF to be broken down. HIF controls several important genes involved in cell division and the formation of new blood vessels in a hypoxic environment.

The SDHC gene is a tumor suppressor, which means it prevents cells from growing and dividing in an uncontrolled way.

SDHD - This gene provides instructions for making one of four subunits of the succinate dehydrogenase (SDH) enzyme. The SDH enzyme plays a critical role in mitochondria, which are structures inside cells that convert the energy from food into a form that cells can use. The SDHD protein helps anchor the SDH enzyme in the mitochondrial membrane.

Within mitochondria, the SDH enzyme links two important pathways in energy conversion: the citric acid cycle (or Krebs cycle) and oxidative phosphorylation. As part of the citric acid cycle, the SDH enzyme converts a compound called succinate to another compound called fumarate. Negatively charged particles called electrons are released during this reaction. The electrons are transferred through the SDH subunits, including the SDHD protein, to the oxidative phosphorylation pathway. In oxidative phosphorylation, the electrons create an electrical charge that provides energy for the production of adenosine triphosphate (ATP), the cell's main energy source.

Succinate, the compound on which the SDH enzyme acts, is an oxygen sensor in the cell and can help turn on specific pathways that stimulate cells to grow in a low-oxygen environment (hypoxia). In particular, succinate stabilizes a protein called hypoxia-inducible factor (HIF) by preventing a reaction that would allow HIF to be broken down. HIF controls several important genes involved in cell division and the formation of new blood vessels in a hypoxic environment.

The SDHD gene is a tumor suppressor, which means it prevents cells from growing and dividing in an uncontrolled way.

SMAD4 - This gene provides instructions for making a protein involved in transmitting chemical signals from the cell surface to the nucleus. The SMAD4 protein is part of a signaling pathway, called the transforming growth factor beta (TGF-β) pathway, that allows the environment outside the cell to affect gene activity and protein production within the cell. The signaling process begins when a TGF-β protein attaches (binds) to a receptor protein on the cell surface, which turns on (activates) a group of related SMAD proteins. The SMAD proteins bind to the SMAD4 protein and form a protein complex, which then moves to the cell nucleus. In the nucleus, the SMAD protein complex binds to specific areas of DNA where it controls the activity of particular genes and regulates cell growth and division (proliferation). By controlling these cellular processes, the SMAD4 protein is involved in the development of many body systems.

The SMAD4 protein serves both as a transcription factor and as a tumor suppressor. Transcription factors help control the activity of particular genes, and tumor suppressors keep cells from growing and dividing too fast or in an uncontrolled way.

STK11 - This gene (also called LKB1) provides instructions for making an enzyme called serine/threonine kinase 11. This enzyme is a tumor suppressor, which means that it helps keep cells from growing and dividing too fast or in an uncontrolled way. This enzyme helps certain types of cells correctly orient themselves within tissues (polarization) and assists in determining the amount of energy a cell uses. This kinase also promotes a type of programmed cell death known as apoptosis. In addition to its role as a tumor suppressor, serine/threonine kinase 11 function appears to be required for normal development before birth.

TP53 - This gene provides instructions for making a protein called tumor protein p53 (or p53). This protein acts as a tumor suppressor, which means that it regulates cell division by keeping cells from growing and dividing too fast or in an uncontrolled way.

The p53 protein is located in the nucleus of cells throughout the body, where it attaches (binds) directly to DNA. When the DNA in a cell becomes damaged by agents such as toxic chemicals, radiation, or ultraviolet (UV) rays from sunlight, this protein plays a critical role in determining whether the DNA will be repaired or the damaged cell will self-destruct (undergo apoptosis). If the DNA can be repaired, p53 activates other genes to fix the damage. If the DNA cannot be repaired, this protein prevents the cell from dividing and signals it to undergo apoptosis. By stopping cells with mutated or damaged DNA from dividing, p53 helps prevent the development of tumors.

Because p53 is essential for regulating cell division and preventing tumor formation, it has been nicknamed the "guardian of the genome."