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. About 5% of all colorectal cancer cases are due to inherited mutations in cancer predisposing genes.

Colorectal cancer is the fourth most common type of cancer diagnosed in the United States and the second leading cause of cancer-related deaths in the country.

Are you at high risk for colorectal cancer?

You could have an inherited risk if:

  • You have a personal or family (mother’s or father’s side) history of early onset colorectal or endometrial cancer (<50 yrs)
  • History of ≥10 adenomas or polyps
  • History of two or more associated cancers
  • You have two or more relatives with associated cancers and one was diagnosed <50yrs
  • 3 or more relatives with associated cancers at any age
  • Abnormal Microsatellite Instability (MSI) and Immunohistochemistry (IHC) tumor test results

What are the possible benefits of genetic testing for Colorectal Cancer Risk?

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 ColoDx ClearTM?

ColoDx ClearTM is a multi-gene test focused on hereditary colon cancer syndromes. This assay analyses point mutations, gross deletions and duplications in the following genes associated with inherited colorectal and some other types of cancer: APC, BMPR1A, EPCAM (CNV only), MLH1, MSH2, MSH6, MUTYH, PMS2, POLD1, POLE, PTEN, SMAD4, STK11 and TP53. We use next-generation sequencing (NGS) technology to identify variants in the coding regions of these genes. The identified variants 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.

Colorectal Cancer Risk Panel genes

Pathogenic variants (mutations) in high-risk colorectal cancer genes are associated with several hereditary cancer syndromes and increase the risk of cancer in many organs.


GENE LIST
APC BMPR1A EPCAM MLH1 MSH2 MSH6 MUTYH PMS2 POLD1 POLE PTEN SMAD4 STK11 TP53
Click on any gene to view its definition

APC - This gene provides instructions for making the APC protein, which plays a critical role in several cellular processes. The APC protein acts as a tumor suppressor, which means that it keeps cells from growing and dividing too fast or in an uncontrolled way. It helps control how often a cell divides, how it attaches to other cells within a tissue, and whether a cell moves within or away from a tissue. This protein also helps ensure that the number of chromosomes in a cell is correct following cell division. The APC protein accomplishes these tasks mainly through association with other proteins, especially those that are involved in cell attachment and signaling.

One protein with which APC associates is beta-catenin. Beta-catenin helps control the activity (expression) of particular genes and promotes the growth and division (proliferation) of cells and the process by which cells mature to carry out specific functions (differentiation). Beta-catenin also helps cells attach to one another and is important for tissue formation. Association of APC with beta-catenin signals for beta-catenin to be broken down when it is no longer needed.

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.

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.

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 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.

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.

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.

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."