Genetic+Factors+of+Adenocarcinoma+of+the+Colon

__Genetic Factors of Hereditary Adenocarcinoma of the Colon. __

__ 1. Introduction __

1.1. Colorectal Cancer
Colorectal cancer is one of the leading causes of cancer mortality within the United States. Among cancers that effect both men and women, it is the second most deadly. Overall, colorectal cancers are the third most common type of cancer in the United States as well as the third most common cause of cancer death. In 2007 alone, more than 142,000 people were diagnosed with colorectal cancer. That same year, over 53,000 death were attributed to colorectal cancer. [1][2][3][4]

=1.2 Adenocarcinoma of the Colon= Adenocarcinoma of the colon is the most type of colorectal cancer to appear in humans. It accounts for greater than 95% of colorectal cancer. On average, adenocarcinoma of the colon effects 5-6% of the human population in their lifetime. It's characterized by the initial formation of adenomatous ployps within the colon. An adenomatous polyp, or adenoma, is a benign abnormal growth stemming from the epithelial mucous layer of an organ, in this case the colon. A carcinoma is a malignant cancerous growth stemming from the epithelial layer of an organ. An adenomas will not necessarily become carcinomas, but every adenoma runs the risk of becoming carcinomatous. [3][4]



1.3 Hereditary Adenocarcinoma of the Colon
Hereditary adenocarcinoma of the colon is a class of hereditary disease characterized by a germ-line mutation resulting in a significantly greater than average risk of developing abnormal tissue growths within the epithelial mucous layer of the colon. While these heritable genetic disorders also result in adenocarcinoma within other organs of the gastrointestinal tract or otherwise, adenocarcinoma of the colon is generally the type of cancer that most often presents itself. Of diagnosed cases of adenocarcinoma of the colon, 25% have any apparent risk factors as characterized by family history and symptomatic polyp density. Only 5% of diagnosed patients can be diagnosed with a specific genetic mutation. Currently, there are 4 hereditary diseases that present a significantly greater than average risk of polyposis; Familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (AFAP), MYH-associated polyposis (MAP), and Lynch Syndrome. [3][4]


 * ==Table of Contents== ||
 * # Introduction
 * 1) Colorectal Cancer
 * 2) Adenocarcinoma of the Colon
 * 3) Hereditary Adenocarcinoma of the Colon
 * 4) Symptoms
 * 5) Genetic Disorders
 * 6) Familial Adenomatous Polyposis (FAP)
 * 7) Clinical Profile
 * 8) Mutations
 * 9) Attenuated Familial Adenomatous Polyposis (AFAP)
 * 10) Clinical Frofile
 * 11) Mutations
 * 12) MYH-Associated Polyposis (MAP)
 * 13) Clinical Profile
 * 14) Mutations
 * 15) Lynch Syndrome
 * 16) Clinical Profile
 * 17) Mutation
 * 18) MLH1
 * 19) MSH2
 * 20) MSH6
 * 21) PMS2
 * 22) EPCAM
 * 23) Molecular Mechanisms
 * 24) Adenomatous Polyposis Coli (APC)
 * 25) Mismatch Repair (MMR)
 * 26) MYH
 * 27) c-MYC
 * 28) Diagnosis
 * 29) Adenocarcinoma of the Colon
 * 30) Screening
 * 31) Family History
 * 32) Staging
 * 33) Stage 1
 * 34) Stage 2
 * 35) Stage 3
 * 36) Stage 4
 * 37) Genetic Disorders
 * 38) Familial Adenomatous Polyposis (FAP)
 * 39) Attenuated Adenomatous Polyposis (AFAP)
 * 40) MYH-Associated Polyposis (MAP)
 * 41) Lynch Syndrome
 * 42) Treatment
 * 43) Invasive Treatment
 * 44) Colonoscopy
 * 45) Polypectomy
 * 46) Surgery
 * 47) Colectomy
 * 48) Chemotherapy
 * 49) Medication ||

__ 2. Symptoms __
The most common distinctive symptoms associated with adenocarcinoma of the colon are rectal bleeding and anemia. Other non-specific symptoms include diarrhea, constipation, abdominal pain, nausea, vomiting and weight loss. [3][5]

=__ 3. Genetic Disorders __= Familial adenomatous polyposis (FAP) is a hereditary autosomal dominant genetic disorder characterized by the formation of hundreds to thousands of adenomatous polyps in the colon within a carrier's lifetime. It has a birth incidence of 1 in 8300. [6][7]
 * ==3.1. Familial Adenomatous Polyposis (FAP)== ||
 * ===3.1.1. Clinical Profile===

The onset of adenomas can begin as soon as early childhood. By 10 years of age, 15% of familial adenomatous polyposis (FAP) have developed adenomas. By 15 years of age, 50% have developed adenomas. By 20 years of age, 75% have developed adenomas. By 35 years of age, 95% have developed adenomas. Over the course of a lifetime, the probability of a familial adenomatous polyposis (FAP) developing one or more adenomas is functionally 100% [4][6][7].



The onset of carcinoma is less rapid, but none the less highly prevalent. By the 21 years of age, 7% of familial adenomatous polyposis (FAP) carriers develop adenocarcinoma of the colon. Left untreated, familial adenomatous polyposis (FAP) carriers have a virtually 100% chance of developing adenocarcinoma of the colon in their lifetime. [7] || FAP is caused by a non-synonymous mutation within the adenomatous polyposis coli (APC) gene on human chromosome 5 that results in a loss of function. There are various different mutations to APC that result in FAP. The most common mutation to the APC gene that results in FAP is a 5 nucleotide deletion that causes a premature stop codon to appear in the gene sequence, resulting in a shortened, non-functional APC protein.[8][J]
 * ===3.1.2. Mutations===

For the molecular effect of these muations, please see 4.1. Adenomatous Polyposis Coli (APC) Inactivation. ||

Attenuated familial adenomatous polyposis (AFAP) is a hereditary autosomal dominant genetic disorder that is clinically and genetically similar to familial adenomatous polyposis (FAP). Carriers of attenuated familial adenomatous polyposis (AFAP) develop hundreds of adenomas in their lifetime, but rarely to the extent seen in familial adenomatous polyposis (FAP). Furthermore, the age of polyp onset is significantly later than in familial adenomatous polyposis (FAP). Due to the symptoms being less prevalent, the average age of polyp onset is difficult to deduce, however, the average age of polyp diagnosis is 44 years of age. The average age of adenocarcinoma diagnosis is 56 years of age. Despite later onset, attenuated familial adenomatous polyposis (AFAP) carriers have a lifetime risk of vitually 100% of developing adenocarcinoma of the colon. [5][7] || Attenuated familial adenomatous polyposis (AFAP) is caused by a non-synonymous deleterious mutation within the adenomatous polyposis coli (APC) gene on human chromosome 5 that results in reduced function. There are various different mutations to adenomatous polyposis coli (APC) that result in attenuated familial adenomatous polyposis (AFAP). In general these muatations are clustered near the far 5′ end or at the 3′ end of the APC gene. [9]
 * ==3.2. Attenuated Familial Adenomatous Polyposis (AFAP)== ||
 * ===3.2.1. Clinical Profile===
 * ===3.2.2. Mutations===

For the molecular effect of these muations, please see 4.1. Adenomatous Polyposis Coli (APC) Inactivation. ||

MYH-associated polyposis (MAP) is an autosomal recessive genetic disorder that results in increased risk of adenocarcinoma of the colon in homozygous individuals. MAP has a birth incidence of 1:5000, though about 2% of the population are MAP carriers [10]. The average age of diagnosis for MAP is 45-50 years of age [K]. MAP is caused by a mutation in the MYH gene. ||
 * ==3.3. MYH-Associated Polyposis== ||
 * ===3.3.1. Clinical Profile===
 * ===3.3.2. Known Mutations=== ||
 * MYH-associated polyposis (MAP) results from a mutation within the MYH gene, also known as the MUTYH gene. MYh is located on the short arm of human chromosome 1, in between positions 32.1 and 34.1, from base pairs 45,464,007 to 45,475,152. In Caucasian Americans, the two most common know mutations are SNP's at position 165, resulting in cysteine instead of a tyrosine, and position 382, resulting in an asparic acid instead of a glycine [10].

For the molecular effects of these muations, please see 4.2. Base-Excision Repair (BER) Inactivation. ||

Lynch Syndrome, formerly known as Hereditary Nonpolyposis Colorectal Cancer (HNPCC), is an autosomal dominant genetic disorder characterized by increased risk of adenocarcinoma of the colon as well as other cancers. Lynch Syndrome has a birth incidence rate of 1 in 350 and accounts for 3-5% of Adenocarcinoma of the colon. Carriers of Lynch Syndrome have an 80% chance of developing colorectal cancer in their lifetime. It's most often caused by a deleterious deletion to one of the mismatch repair (MMR) genes; MLH1, MSH2, MSH6, PMS2. The MLH1, MSH2, MSH6 and PMS2 bind to create the MMR complex. This complex is responsible for repairing mismatched nucleotides during DNA replication. [11]
 * ==3.4. Lynch Syndrome== ||
 * ===3.4.1. Clinical Profile===

Lynch Syndrome has also been shown to result from mutations to the epithelial cell adhesion molecule (EPCAM) gene. While not directly involved in the Mismatch pathway, the epithelial cell adhesion molecule (EPCAM) gene sits just upstream of the MSH2 genes. Certain mutations of the epithelial cell adhesion molecule (EPCAM) gene can disturb the transcription of its neighboring gene MSH2. || Mutations responsible for the onset of Lynch Syndrome have been located in 5 different genes; MLH1, MSH2, MSH6, PMS2, MLH3 and EPCAM.
 * ===3.4.2. Mutations===

The MLH1 gene is located on human chromosome 3 from base pairs 37,034,840 to 37,092,336. Mutations to MLH1 are responsible for more than half of all identified Lynch Syndrome cases. Of these MLH1 mutations, one third were SNP's resulted in an amino acid exchange.[Q]
 * 3.4.2.1. MLH1**



The MSH2 gene is located on human chromosome 2 from base pairs 47,630,262 to 47,710,359. Mutations to MSH2 pose a greater lifetime risk of developing cancer MLH1. [P] There are over 300 identified mutations to MSH2 that result in Lynch Syndrome. Of these, the majority are frameshift mutations that cause a stop codon to appear in the sequence early, truncating the protein product. [Q]
 * 3.4.2.2. MSH2**



The MSH6 is located on human chromosome 2 from base pairs 48,010,220 to 48,034,091. Mutations to MSH6 account for 10-20% of all Lynch Syndrome cases. All identified mutations to MSH6 linked to Lynch Syndrome are insertions/deletions resulting in a truncated protein product. [12]
 * 3.4.2.3. MSH6**



The PMS2 gene is located on human chromosome 7 from base pairs 6,012,869 to 6,048,736. Mutations to PMS2 account for about 2% of Lynch Syndrome cases. All identified mutations linked to Lynch Syndrome are insertion/deletions resulting in a truncated protein product.[S]
 * 3.4.2.4. PMS2**



The epithelial cell adhesion molecule (EPCAM) gene is located on human chromosome 2 from base pairs 47,596,286 to 47,614,166. All of the mutations to EPCAM that result in Lynch Syndrome are either large scale deletions of most of the EPCAM gene or deletions near the 3' end of the gene near the neighboring MSH2 gene's promoters. These deletions cause a read-through of the MSH2 gene, effectively silencing it. For the effects of these mutations, please see 4.3. Mismatch Repair (MMR) Inactivation. ||
 * 3.4.2.5. EPCAM**

=**__ 4. Molecular Mechanisms __**= Genes involved: APC
 * ==4.1. Adenomatous Polyposis Coli (APC) Deactivation==

Adenomatous polyposis coli (APC) is the most common gene through which the WNT pathway is modified to over-express the c-MYC gene and cause tumorigenesis. All know mutations that cause familial adenomatous polyposis (FAP) lie within the adenomatous polyposis coli (APC) gene. These mutations result in loss of function by the adenomatous polyposis coli (APC) protein. The formation of adenomatous polyps coincides with a loss of function by the adenomatous polyposis coli (APC) protein in the WNT signalling pathways of the cell. Under normal circumstances, the adenomatous polyposis coli (APC) protein carries several functional domains and acts on numerous biochemical pathways. In respect to the WNT signalling pathway, the adenomatous polyposis coli (APC) protein acts as a tumor suppressor protein. Functionally, it forms a protein complex with axin and glycogen synthase kinase 3 beta (GSK3-B), which activates a phosphorylation domain on the glycogen synthase kinase 3 beta (GSK3-B). When active, glycogen synthase kinase 3 beta (GSK3-B) phosphorylates beta-catenin causing beta-catenin to be targeted for ubiquitin-mediated proteasomal degradation.[C,N]

When the WNT pathway is activated, it binds to the frizzled cell-surface receptor and to lipoprotein-related protein co-receptor. Upon binding to frizzled and the lipoprotein-related protein co-receptor, this complex activates the dishevelled cytoplasmic phosphoprotein (DSH) [O]. The now activated dishevelled (DSH) protein recruits the protein complex composed of adenomatous polyposis coli (APC), glycogen synthase kinase 3 beta, and axin to the cell membrane. As a result, the ability of the glycogen synthase kinase 3 beta (GSK3-B) to phosphorilate beta-catenin is inhibited. With beta-catenin no longer being for ubiquitin-mediated proteasomal degradation, its concentration begins to rise within the cell. Beta-catenin forms a protein complex with T-cell factor (TCF). This beta-catenin and T-cell factor protein complex acts as a promoter for the WNT signalling pathway's target genes.

When the adenomatous polyposis coli (APC) gene carries a mutation the results in the protein product being nonfunctional in the WNT pathway of the Most notably, it promotes the expression of the oncogene c-MYC. The gene c-MYC acts as a central oncogenic switch. It's target genes promote movement of the cellular cycle towards cell replication. Activation of m-MYCleads to the synthesis of Cyclin A and Cyclin E, the activation of CDK2 and CDK4, and the suppression of the P21 and P27 tumor suppressors. When over-expressed, c-MYC leads to tumorigenesis. When this occurs in the epithelial layer of the colon, colonic polyps form that act as precursors to adenocarcinoma of the colon. [8][J][N] || Involved genes: MYH (aka. MUTYH)
 * ==4.2. Base Excision Repair (BER) Deactivation==

Under normal circumstances, the base excision repair (BER) pathway recognizes and fixes oxidative damage done to individual nucleotides throughout the cell cycle.

Whe n MYH gene, whcih is key to the Base-excision repair (BER) pathway, is mutated and experiences a resulting loss of function, the base-excision repair (BER) pathway cannot be completed properly and numerous numerous damaged nucleotides make it to DNA replication where they can easily be misread, leading the DNA polymerase to code a mutation into the resultant daughter cell. Over time, more and more of these mutations accumulate. When one such mutation occurs in the adenomatous polyposis coli (APC) or gycogen synthase kinase 3 beta (GSK3-B) genes, it can result in a loss of function in the resultant protein product. In these cases, a novel incidence of familial adenomatous polyposis (FAP) or attenuated familial adenomatous polyposis (AFAP) occurs within the cell. The mutation can also take place within the c-MYC promoter in such a way that it promotes over-expression of the c-MYC gene.

|| Involved genes: MLH1, MSH2, MSH6, PMS2 and EPCAM
 * ==4.3. Mismatch Repair (MMR) Deactivation==

Under normal circumstances, the Mismatch Repair (MMR) proteins complex together to form a Mismatch Repair (MMR) complex. This Mismatch Repair (MMR) system recognizes and repairs erronious insertion, deletions, and nucleotide mismatches during DNA replication and recombination. The system is also capable of repairing certain forms of DNA damage. When a deleterious mutation occurs within one of the Mismatch repair genes, MLH1, MSH2, MSH6 and PMS2, the resulting protein product experiences a loss of function. If any one of the genes cannot produce a functional protein product, then Mismatch Repair (MMR) complex will not have the necessary components to remain stable and will be incapable performing its function properly. As a result, numerous insertion, deletion, and mismatching errors occurring during DNA replication will go unfixed and become novel mutations in the resulting daughter cell. Over time, more and more of these mutations accumulate. When one such mutation occurs in the adenomatous polyposis coli (APC) or gycogen synthase kinase 3 beta (GSK3-B) genes, it can result in a loss of function in the resultant protein product. In these cases, a novel incidence of familial adenomatous polyposis (FAP) or attenuated familial adenomatous polyposis (AFAP) occurs within the cell. The mutation can also take place within the c-MYC promoter in such a way that it promotes over-expression of the c-MYC gene. ||

5.1.1. Screening
Actual adenocarcinoma of the colon can only be diagnosed through physical screening. This screening take the form of a colonoscopy. For the majority of the population, its encouraged that adult undergo their first colonoscopy at age 50. Patients may encouraged to undergo a colonoscopy sooner if they show a family history of familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (AFAP), MYH-associated polyposis (MAP), or Lynch Syndrome or are displaying physical symptoms of colon polyps, including rectal bleeding and anemia. In the context of the colonoscopy, asymptomatic patients display no colonic polyps of any kind. Symptomatic patients display one or more colonic polyp with polyp density corresponding to the degree to which they are symptomatic.

For those that come up asymptomatic for adenocarcinoma and show no prevalent family history of adenocarcinoma of the colon, they are advised to get re-screened in 10 years. For those that are asymptomatic, but show a family history of the disease, they are advised to get re-screened in 5-10 years, depending on the prevalence of adenocarcinoma of the colon in their family history. For those that are symptomatic, an appropriate treatment is administered and they are advised to get re-screened in 1-5 years depending on the severty of their symptoms and the prevalence of adenocarcinoma in their family history. After the identification and removal of 10 or more polyps within a person's lifetime, they are advised to get genetic testing done for the any Syndrome that lead to adenocarcinoma of the colon.

5.1.2. Family History
Studies repeatedly show that first degree relatives of patients with adenocarcinoma of the colon have a two to fourfold increased risk of developing adenocarcinoma of the colon in their lifetime (See Table 1).[V]

//CRC = colorectal cancer. CI = confidence interval.//
 * Table 1. Relative risk of developing colorectal cancer based on family history.**
 * Family History || **Relative Risk for CRC [W] ** || 95% CI ||
 * No family history || 1.0 ||  ||
 * One first-degree relative with CRC || 2.3 || 2.0-2.5 ||
 * More than one first-degree relative with CRC || 4.3 || <span style="display: block; font-family: Arial,Helvetica,sans-serif; text-align: center;">3.0-6.1 ||
 * <span style="display: block; font-family: Arial,Helvetica,sans-serif; text-align: center;">One affected first-degree relative diagnosed with CRC before 45 || <span style="display: block; font-family: Arial,Helvetica,sans-serif; text-align: center;">3.9 || <span style="display: block; font-family: Arial,Helvetica,sans-serif; text-align: center;">2.4-6.2 ||
 * <span style="display: block; font-family: Arial,Helvetica,sans-serif; text-align: center;">One first-degree relative with colorectal adenoma || <span style="display: block; font-family: Arial,Helvetica,sans-serif; text-align: center;">2.0 || <span style="display: block; font-family: Arial,Helvetica,sans-serif; text-align: center;">1.6-2.6 ||

The above table is a summary of a systematic review of the risk of developing colorectal cancer, most prevalently adenocarcinoma of the colon. There were 24 studies included within the meta-analysis, of which 23 reported a significant increase in the risk of developing colorectal cancer if there was an affect first-degree relative. Overall proportion of affected family members and their ages of diagnosis correlated strongly with risk of colorectal cancer development. Presence of a family history, provides at least a twofold increase in risk. When more than one family member has been diagnosed with colorectal cancer, the risk nearly doubles again. [W]

Unfortunately, while family history can be a useful tool and determining relative risk of developing adenocarcinoma of the colon or other colorectal cancers, family pedigrees can often be inaccurate or incomplete. More often than not, family history is self reported and the reporting patient may not know their family history of colorectal cancer accurately enough to provide a useful pedigree. Furthermore, due to premature deaths, small family sizes, and possible recessive inheritence, patients and doctors may not have enough information to form an accurate pedigree.[X]

5.1.3. Staging
The AJCC (TNM) system for staging cancers can be utilized on colorectal cancers. Under this system, T is a measure of the tumor size, N is a count of the number of nearby lymph nodes the cancer has spread to, and M is an indication of whether the cancer has metstasized. In the context of the colon, T, N, and M are graded as follows.

__T Categorty:__ <span style="font-family: Arial,Helvetica,sans-serif;">This category is used to provide a description of the extent to which an adenocarcinoma has grown and spread through the layers of the colon. These layers include the following from inside, out;


 * 1) <span style="font-family: Arial,Helvetica,sans-serif;">The muscular mucosa - a thin layer of smooth muscle
 * 2) <span style="font-family: Arial,Helvetica,sans-serif;">The submucosa - a layer of fibrous connective tissue
 * 3) <span style="font-family: Arial,Helvetica,sans-serif;">The muscularis propria - the main body of smooth muscle within the colon
 * 4) <span style="font-family: Arial,Helvetica,sans-serif;">The subserosa - a thin layer of connective tissue
 * 5) <span style="font-family: Arial,Helvetica,sans-serif;">The serosa - a smooth outer membrane

<span style="font-family: Arial,Helvetica,sans-serif;">Based on this, the following values may be awarded in the T category:
 * <span style="font-family: Arial,Helvetica,sans-serif;">Tx: No description available.
 * <span style="font-family: Arial,Helvetica,sans-serif;">Tis: The tumor has not broken from the muscularis mucosa.
 * <span style="font-family: Arial,Helvetica,sans-serif;">T1: The tumor has moved through the muscularis mucosa, now extending into the submucosa.
 * <span style="font-family: Arial,Helvetica,sans-serif;">T2: The tumor has moved through the submucosa, now extending into the muscularis propria.
 * <span style="font-family: Arial,Helvetica,sans-serif;">T3: The tumor has moved through the muscularis propria, now extending into the outermost layers of the colon, but not yet through them.
 * <span style="font-family: Arial,Helvetica,sans-serif;">T4A: The tumor has moved through the serosa, the outermost lining of the intestines.
 * <span style="font-family: Arial,Helvetica,sans-serif;">T4B: The tumor has moved through the outermost wall of the colon and has now attached to or invaded into a nearby tissue or organ.

__N Category:__ Th<span style="font-family: Arial,Helvetica,sans-serif;">is category indicates whether or not the tumor has spread to nearby lymph nodes and, if so, how many have been infected. <span style="font-family: Arial,Helvetica,sans-serif;">Based on this, the following values may be awarded in the N category:
 * <span style="font-family: Arial,Helvetica,sans-serif;">Nx: No description of lymph node involvement is available.
 * <span style="font-family: Arial,Helvetica,sans-serif;">N0: Tumor has not yet spread to nearby lymph nodes.
 * <span style="font-family: Arial,Helvetica,sans-serif;">N1: Tumor has spread to, or near to, 1 to 3 nearby lymph nodes
 * <span style="font-family: Arial,Helvetica,sans-serif;">N2: Tumor has spread to, or near to, 4 or more nearby lymph nodes

__M Category:__ This category indicates whether or not the tumor has metastasized and, if so, how severely.<span style="font-family: Arial,Helvetica,sans-serif;">Based on this, the following values may be awarded in the M category:
 * <span style="font-family: Arial,Helvetica,sans-serif;">M0: No apparent metastasis
 * <span style="font-family: Arial,Helvetica,sans-serif;">M1a: The tumor has metastasized to either one distant organ or set of lymph nodes.
 * <span style="font-family: Arial,Helvetica,sans-serif;">M1b: The tumor has metastasized to more than one distant organ or set of lymph nodes. Alternatively, the tumor may also have spread to distant parts of the peritoneum.

5.2.1. Screening
DNA testing is currently available for familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (AFAP), MYH-associated polyposis (MAP), and Lynch Syndrome. Due to the costs associated with the test and the low birth incidence of adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (AFAP), and MYH-associated polyposis (MAP), DNA testing is usually forgone unless a patient is notably symptomatic or has a family history of any of the diseases. As the specific mutations that cause hereditary adenocarcinoma of the colon have been identified in 5% of CRC cases whereas 25% show some apparent genetic risk factors, the genetic tests for these syndromes simply aren't yet comprehensive enough to properly diagnose the majority of patients with hereditary adenocarcinoma of the colon [4].

Testing for Lynch Syndrome is the most commonly asvised test as it's birth incidence rate is 1 in 350. However, the test for Lynch Syndrome is also the most expensive of the DNA tests because it must test for mutations in all 5 genes associated with Lynch Syndrome. A patient is advised to seek testing for Lynch Syndrome after having 10 or more total polyps located in and removed from their gastrointestinal tract.

Adenomatous polyposis (FAP) and Lynch Syndrome are both autosomal dominant diseases that tend to show clear family history. As such, family history is often the most efficient way to diagnose a patient's risk towards developing these diseases. Due to the rapid onset of familial adenomatous polyposis (FAP), affected patients can potentially be diagnosed as soon ad early-to-mid childhood by physical symptoms alone. However, this same rapid onset makes early risk management vastly more important. By the time an affected familial adenomatous polyposis (FAP) patient becomes symptomatic, they would already have greatly benefitted from preventative care. While not precise, family history at least provides the general chance of being a carrier of any of the diseases.
 * 5.2.2. Family History**

Attenuated familial adenomatous polyposis (AFAP) is also inherited in a autosomal dominant fashion. However, attenuated familial adenomatous polyposis (AFAP) has been shown to appear de novo in patients whose family history contained exclusively member afflicted by the more aggressive familial adenomatous polyposis (FAP).

MYH-associated polyposis (MAP) stands out from the other syndromes in that it is autosomal recessive. As a result, MYH-associated polyposis will often be diagnosed in people who have no apparent family history of the disease.

6.1.1. Adenocarcinoma of the Colon
Treating individual polyps, adenomas, and adenocarcinomas is generally a simply and easy process. Over 95% of polyps can be removed with a polypectomy during a colonoscopy. A polypectomy is a procedure to remove polyps from the gastrointestinal lining. For a quick example of a polypectomy, [|click here]. In regards to adenocarcinoma of the colon, a long, specialized, flexible scope is inserted into the patient's rectum. Using the camera on the scope, the gastroenterologist working the procedure can identify any polyps in the colon. When a polyp is found, a metal wire loop is extended and wrapped around the stalk of the polyp. An electrical current is sent through the wire as it is tightened around the stalk. This current helps to cauterize the wound as the tightening wire cuts through the stalk and cuts the polyp free of the gastrointestinal lining, so that it can be removed.
 * 6.1.1.1. Colonoscopies and Polypectomies**

While surgery is always an option for polyp removal, it is generally reserved for more severe case that are complicated by the sheer quantity of polyps, or its size and location. In extreme cases, a colectomy, the partial or complete removal of the colon my be necessary. Unfortunately, this is almost always found to be eventually necessary in patients with familial adenomatous polyposis (FAP) and in many patients with attenuated familial adenomatous polyposis. [3]
 * 6.1.1.2. Surgery**

As adenomas are fairly safely and easily treated when caught early, medications and chemotherapy are generally reserved for the most severe cases of adenocarcinoma of the colon. When utilized, they are almost always being used in adjuncture with invasive surgery, either before or after.
 * 6.1.1.3. Medication & Chemotherapy**

**6.1.2. Genetic Disorders**
At this time there are no invasive treatments available for curing any genetic disorder itself. All invasive treatments are geared towards treatment of the polyps that form as a result of the genetic disorders. Though potentially deadly, all adenomas, adenocarcinoma and polyps are in fact simply a symptom of the genetic disorder.

The most promising possible treatment for the many of the genetic disorders is a medication that will regulate the WNT pathway as mutations resulting in over-expression of the WNT signalling pathway are most often responsible for the formations of adenocarcinomas of the colon in those affected by familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (AFAP), MYH-associated polyposis (MAP) and Lynch Syndrome. [Z]

__**Sources**__
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<span style="font-family: Arial,Helvetica,sans-serif;">2. Kaz, AM; Brentnall, TA (2006). [|Genetic testing for colon cancer]. //<span style="font-family: Arial,Helvetica,sans-serif;">Nature Clinical Practice Gastroenterology & Hepatology //<span style="font-family: Arial,Helvetica,sans-serif;">, 3:670-9.

<span style="font-family: Arial,Helvetica,sans-serif;">3. Auld, Richard MD. Personal Interview. 2012 May 29.

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<span style="font-family: Arial,Helvetica,sans-serif;">5. Astin, M; Griffin, T; Neal, RD; et. al. (2011).[|The diagnostic value of symptoms for colorectal cancer in primary care: a systematic review]. The British Journal of General Practice, 61(586):231–43.

<span style="font-family: Arial,Helvetica,sans-serif;">6. Reed, TE; Neel, JV (1955). [|A genetic study of multiple polyposis of the colon with an appendix deriving a method of estimating relative fitness]. //<span style="font-family: Arial,Helvetica,sans-serif;">American Journal of Human Genetics //<span style="font-family: Arial,Helvetica,sans-serif;">, 7:236-263.

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