Resources for YOU!

Here is a list of available resources that discuss the APC gene, FAP, genetic counseling, and the J pouch surgery.  Each short explanation links out to the site I've described.

Resources for FAP:

Genetics Home Reference provides a great starting point for learning more about FAP and has a very user-friendly site.  The site also provides information about the genes responsible for the conditions they discuss (the APC gene site is given a little ways down this list).

Genetic Health is another great resource for a multitude of conditions, and their colon cancer page is great!  They also link out to other informative sites including information about genetic testing, ethical issues surrounding testing, current research, other resources, and most importantly (in my opinion), they provide links that discuss basic principles surrounding genetics to teach those who don't know as much about these diseases as the scientists that study them.  Check this out if you find yourself confused about inheritance, mutation, or personalized medicine.

This link takes you to the National Cancer Institute's Introduction page for Genetics of Colorectal Cancer.  This site provides information on cancer statistics, research and funding, current clinical trials for treatment methods, among additional information about the genetics of colon cancer, including FAP.

This is a short review of FAP done in 2007.  It is not nearly as informative as some of the above sites, but some information can still be gleaned here.

This article about hereditary and familial colon cancers is not for the faint of heart.  It covers multiple types of cancer including FAP, Lynch syndrome, and others.  Some nitty gritty details are discussed that may not be easily understood by the layman.

Resources for APC: 

This is the link to Genetics Home Reference's APC page that I told you about a little earlier.  It's very easy to understand, but doesn't give a terribly large amount of information.

This links to Gene Cards, a part of the Human Gene Compendium.  It gives a very detailed explanation of various aspects of APC including information about the protein including its domains/families, function, pathways and interactions, expression, etc.  It may be more difficult to understand the the Genetics Home Reference page on APC, but much more information about APC can be retrieved here. Plus, GeneCards links out to a TON of other sources!

This is OMIM's APC gene entry.  It's an intermediate in difficulty and material between the Genetics Home Reference and Gene Cards.

Resources for Genetic Counseling:

Another resource from Genetic Health.  It's easy to understand and provides information on how to go about finding a genetic counselor.

Resources for the J-pouch surgery (Ileoanal Anastomosis):

A great starting point for learning about the J pouch surgery.  Breaks down the surgery into steps and is very easy to understand.

An illustrated walk-through of the J pouch surgery.  Very informative and easy to understand (plus, there are pictures!)

The Importance of Animal Models for Experimentation

Almost all of today's medical knowledge has been gleaned from animal experimentation, especially via model organisms.  The APC gene is a highly evolutionarily conserved protein, i.e. over the past hundreds of thousands of years, the APC gene has not changed very much among animal taxa.  Mice are likely the most common model organisms to be used for APC research--recall the picture that demonstrated adnomatous polyp formation from my earlier post "Adenomatous Polyp Formation."  In fact, lines of mutant mice are available for a wide variety of gene losses and APC knockout mice are no exception.  "Knockout" simply refers to a genetically engineered organism whose gene of interest has been inactivated.  By studying what happens in the absence of a particular protein, scientists are often able to discern that protein's role by comparing what occurs in a healthy organism versus a knockout organism.  Sure, humans aren't mice, but believe it or not, our DNA isn't too terribly different--our proteins are so similar that most of them can be identified as homologs, or evolutionary relatives across species!  Mice are relatively easy to maintain in a laboratory, the mouse genome has been sequenced, and much is known about mouse genetics.  These three reasons make mice great candidates for APC gene study.

Below, I've compiled a phylogenetic tree of the APC gene across a few different species.

From Top to Bottom: Bos taurus (domestic cow), Homo sapiens (human), Pan troglodytes (chimpanzee), Mus musculus (mouse), Rattus norvegicus (rat), Gallus gallus (chicken), Xenopus laevis (African clawed frog), Danio rerio (zebrafish), Drosophila melanogaster (fruit fly), and Canis lupus familiaris (domestic dog).  Courtesy of Protein Information Resource.  ClustalW Multiple Sequence Analysis.

While the chimpanzee has the closest homolog to the human APC gene, chimpanzees are not ideal model organisms for genetic engineering because they are large, expensive to maintain, and have a long life cycle.  This same reasoning applies to cows.  However, the next closest related homologs belong to the mouse and rat, making them the most ideal animal models for APC gene study in terms of gene relatedness.

Testing and Screening, Prevention, and Treatment

Fortunately, in today's day and age, genetics counseling is becoming a more common practice and is available for whole genomes or individual genes, depending on the needs of a patient.  Initial screening for FAP involves an upper GI (gastrointestinal tract) endoscopy that discerns the approximate number of polyps present in the colon.  If the number of adenomatous polyps is above average, then genetics screening can take place.


The three major types of screening for genes are Protein Truncation Assays (PTA), Denaturing Gradient Gel Electrophoresis (DGGE), and gene sequencing.  When familial history of FAP is unknown for a patient, PTA is the most common method for APC gene screening.  This test uses the latest in protein formation technologies to determine whether or not the patient's APC protein product is functional.  DGGE and gene sequencing, on the other hand, rely on previously identified cases of FAP within a family before their use can take place, thus they are far less common screening methods at this point in time.  DGGE uses an identified truncation from an FAP family member to sequence that same region in a patient.  Gene sequencing is only used when a concrete history of FAP has been identified within a family.  Regions surrounding the gene have been identified as genetic markers for sequencing machines to use to single out the APC gene alone for screening.  The truncating mutations of the family's APC genes are compared to the same regions within the patient's APC gene to identify similar mutations within the genes.


FAP cancer development really cannot be prevented.  Of course, there are certain steps that can be taken to postpone or prevent cancer progression.  Diet is considered an important component of cancer formation because oxidative stress can quicken the process.  Oxidative stress occurs as a result of eating foods that are difficult to digest, i.e. red meat, excess dietary fat, etc.  Also, annual exams should be attended to maintain up-to-date and current statuses of a patient's colonic tissues.  These exams include flexible sigmoidoscopies, colonoscopies and upper GI endoscopies.  Each of the exams inspects a different aspect of intestinal tissues and should be attended annually beginning in children 10 to 12 years old in the case that family medical history points to FAP.  If no polyps are found in a patient by the age of 25, exams can be attended on a less-regular basis.  If large numbers of polyps are found, it is imperative that the patient continue annual examination and consider more serious treatment options.


Currently, the most common and effective treatment option for FAP and other colon cancer patients is a colectomy (removal of the large intestine/colon).  Years ago, this surgery resulted in a patient's loss of the ability to naturally remove waste from the body; instead, waste was collected in a bag attached to the abdomen, where a hole was made for digestive emptying.  Recently, a new colectomy development was made--the J pouch.  Ileoanal Anastomosis surgery involves the removal of the colon/large intestine and the implementation of a pouch that attaches the small intestine to the anus for continued natural waste removal.


The Ileoanal Anastomosis (J-pouch) surgery is a two step process.  During the first surgery, the infected portion of (or the entire) colon is removed.  Once the colon is removed, a small portion at the end of the small intestine is brought up to form a J-loop, and once the loop is formed, the tissue in the middle of the loop is removed to create a reservoir.  Special care is taken to suture the loop such that the end of the small intestine is now closed off.  The lining of the rectum is then removed, but the sphincters muscles of the anus are retained.  A hole is made in the bottom of the loop/reservoir to which the top of the anal canal is connected.  Finally, a temporary ileostomy is performed, where the ileum tissue is cut and a path is made to divert digested materials through the abdomen for waste release while the newly formed reservoir and its connecting channels heal.  During this time, a bag will be attached to the abdominal hole for waste retrieval.  After a few months time, the second surgery is performed.  The second surgery solely involves the reconnection of the ileum, which finally allows for food to travel from the stomach, through the small intestine into the fully healed J pouch reservoir to the anus for waste relief.  While a small amount of training and practice is involved in learning to recover continence (control over one's own bodily functions), recovery from the second surgery is usually quite quick with few to no complications.  Over time, a patient retains full bodily control and maintains continence through a proper diet and relaxation.

Adenomatous Polyp Formation

Healthy intestinal epithelium (colon) tissue is comprised of crypt cells connecting microscopic villi that are responsible for the final uptake of nutrients of digested material before it is removed from the body as waste.  The characteristic polyps that form in the gut lumen of FAP patients are a result of tissue build-up within the villi due to proliferative DNA replication; remember the stem cell-like replication I was talking about earlier?  The tissue build-up begins to puff out from the base of the villi and, over time, fills up the individual villi.  Eventually, the outpocketing tissues cannot be contained within a single villi and begin to spread to neighboring villi causing eruption of villus tissues.  The photo on the right demonstrates adenomatous polyp formation in mice whose APC gene has been experimentally inactivated.


Loss of APC function in FAP patients is a lifelong phenotype.  Thus, at a young age, FAP can be suspected as the cause of the formation of large numbers of polyps in these people.  Hundreds to thousands of polyps form in these people before they reach the age of 20.  Proliferative replication continues to take place throughout a lifetime and, over time, mutations accumulate in other genes.  It is this process of mutation accumulation that ends in cancer formation before the age of 50 in FAP patients.

FAP - a result of non-functional APC

So, we now realize that FAP is a result of a non-functional APC product, but how exactly does a protein become non-functional?  The answer is simply mutations.  Mutations are typically random changes to the nucleotides of a DNA sequence--in our case, the APC gene.  There are many different types of mutations, but for simplicity, let's only consider mutations that change the overall shape of the final protein product in a way that is detrimental to the protein's proper functionality.  In APC, mutations that occur in the promoter regions, the 5' CCAAT box, and a region known as the mutation cluster region (MCR) often result in non-functional protein products.  It is thought that the number of devastating mutations in the APC gene correlates with the number of adenomatous polyps that develop in the colon, where more mutations result in greater numbers of polyps.

When a person gets his or her whole genome sequenced, all of that individual's SNPs (Single Nucleotide Polymorphisms, or single-base changes) are identified.  These SNPs can be studied and compared to the reference human genome to determine whether or not the nucleotide change is detrimental to the protein product.  After studying the SNPs of two great scientists, James Waston and J. Craig Venter, I was able to determine that neither of them are likely to have been diagnosed with FAP.  The two men's genomes are both available for public viewing online and serve as a great resource for the beginnings of whole genome sequencing for the public.

Haplotypes and GWAS both involve identifying the interaction and inheritance of sets of genes that work together to produce a specific genotype/phenotype.  Haplotype information and GWAS studying have not yet shed too much light on FAP, especially since the disease is believed to be attributed primarily to the function of a single gene (APC), rather than a set of genes.

APC Gene Function

FAP, or Familial Adenomatous Polyposis, is a genetically inherited form of colon cancer that results from a non-functional protein product of the APC (Adenomatous Polyposis Coli) gene.  This gene functions within many facets of cell biology including cell adhesion and cellular structure, as well as various aspects of cell meiosis (division) such as spindle formation and chromosome segregation.  However, these functions are not critical for understanding APC's function in FAP disease development.

3-D Representation of APC protein from Protein Workshop

You see, APC has been long-identified as a "tumor-suppressor gene," but, in reality, is acts as a suppressor of an early-initiating event of tumorigenesis (the beginnings of tumor formation) by maintaining low levels of a molecule called beta-catenin in the cell's nucleus.  The functional APC protein product interacts with Axin and GSK3 to form what biologists call a "destruction complex."  When these three proteins oligomerize, or loosely bind to one another, a site forms where interactions between Axin and GSK3 (plus an input of cellular energy, or ATP) mark beta-catenin for degradation by the proteosome.  This action leaves nuclear levels of beta-catenin very low, which keeps the Wnt signaling pathway suppressed.  It is suspected that stabilized levels of beta-catenin in the nucleus acts as an early event during, and may even initiate, tumorigenesis of adenomatous polyps in the intestinal epithelium.  When beta-catenin levels are stable in the cytoplasm, there is plenty of opportunity for its translocation into the cell's nucleus where it interacts with TCF (T-cell factor) and LEF (lymphoid-enhancer factor) to activate transcription within the nucleus.  This TCF and LEF-induced transcription has been described to have stem cell-like properties, where the DNA is rapidly and repetitively replicated.  These events are currently thought to be involved in the earliest steps of cancerous tumor formation (tumorigenesis).

Since APC is such a critical protein that functions in nearly all bodily tissues, it has no repressor domains.  However, two promoters have been identified within the APC gene; they are known as promoters 1A and 1B.  The addition of methyl groups to DNA nucleotides within these promoter regions results in decreased expression of the APC gene, thus fewer APC proteins are made.  There is also a site, called a 5' CCAAT box, which is recognized by a CCAAT Binding Factor (CBF), and the recognition of this site by a CBF results in a great increase in the amount of APC protein product produced. Conversely, when the region surrounding the CCAAT box is methylated, CBFs cannot recognize their binding region and smaller amounts of the protein product are made (usually, in genetics, methylation of genes results in less expression).

An Introduction to FAP

Familial Adenomatous Polyposis, FAP, has been studied for over a century, but it wasn't until after the 1980's that anything about the disease's genetics was known.  In 1987, researchers narrowed down the location of the gene responsible for FAP to the long arm of chromosome 5.  This information was very helpful in the identification of the entire gene, which occurred in 1992 by a group from King's College School of Medicine. The gene was eventually named APC, Adenomatous Polyposis Coli, and became a poster-gene for cancer genetics.

The APC gene is comprised of roughly 139,000 base-pairs, and its translated protein product contains 2,843 amino acids.  It's 15 exons can be alternatively spliced into 30 different mRNAs of roughly similar shape and function.  There are 40 distinct introns that are cleaved from the mRNA product before the 15 exons are pasted together to form the final protein product.

FAP is identified in patients via genetic tests, as well as by identifying abnormally large numbers of polyps in intestinal tissues, especially the large intestine/colon.  A patient with FAP has a near-100% chance of developing colon cancer by the age of 40 or 50 years old.  There is no way to prevent the formation of these polyps or their progression to tumors.  The only protection against FAP colon cancer is regular colonoscopies or a serious surgery that removes the entire colon but maintains rectal function for natural waste removal.


FAP is inherited in dominant fashion.  That means, that where a parent with FAP has a 50% chance of passing the disease along to each of his or her children.  When a child does not inherit a mutant allele from an affected parent, that child has no chance of passing along the disease to his or her progeny.  This tells us that two dysfunctional APC alleles are necessary for the manifestation of this disease.