Adenomatous Polyposis gene (APC) and Familial Adenomatous Polyposis

by Inna Pavlyuk, MBS 2019, Geisinger Commonwealth School of Medicine

Mentor: Michael Bordonaro, PhD

Familial adenomatous polyposis (FAP) is a rare form of colorectal cancer characterized by the presence of hundreds to thousands of colorectal benign tumors (called also polyps or adenomas). Colorectal cancer (CRC) is the third most common cancer in women and men in the United States (Herzig et al.,2017). FAP is autosomal dominant syndrome meaning that inheriting one mutant gene is enough to develop FAP. About 20-30% of CRC cases are linked to a family history of colorectal polyps or cancer and 3-5% of the cases are associated with an identifiable inherited colorectal cancer syndrome (Herzig et al.,2017). It is estimated that about 1% of all cases of colorectal cancer are caused by FAP.

Research on FAP is important because, if left untreated, the syndrome will always develop into CRC (Herzig et al.,2017). Patients with FAP also have a higher risk of developing additional colonic manifestations such as upper gastrointestinal polyps and desmoids, which are connective tissue tumors, that are life threatening (Herzig et al.,2017).

The syndrome is caused by mutations in the Adenomatous Polyposis (APC) gene (Grover et al., 2012). APC is a tumor suppressor gene, that when functioning normally, has a role in signal pathways that target β - catenin to be broken down by a proteasome (Grover et al., 2012). Proteasomes are a complex of proteins that degrade not needed or damaged proteins (Grover et al., 2012). 

 β - catenin is involved in the WNT signaling pathway and when the APC gene is not functioning properly it allows the buildup of β - catenin, which is then translocated to the nucleus and acts as a coactivator with the transcription factor family (Grover et al., 2012). The transcription factor family is a group of proteins that regulate genes to make sure they are expressed at the right time and in the right cell (Grover et al., 2012). The proliferative genes that are regulated by the WNT β - catenin signaling pathway are known to contribute to tumor progression (Grover et al., 2012). 

FAP exhibits a strong genotype - phenotype relationship, which means that the location of the mutation influences the outcome and severity of the disease (Bertario et al., 2003). It has been found that the most severe cases of CRC are those with mutations near codon 1300 (Bertario et al., 2003). The codon is a specific sequence of DNA that can be identified along a DNA strand (Bertario et al., 2003). When the APC mutation happens around codon 1,300, it is often associated with the production of over 2,000 polyps (Bertario et al., 2003). For example, in one study, researchers screened 233 colorectal adenomas from 39 FAP patients (Bertario et al., 2003). In patients with mutations before codon 1264, the median polyp number was 800 as opposed to a median of 1,850 in patients with mutations between 1,399 and 1,494 (Bertario et al., 2003).

Genetic analysis of the APC gene is not only important for surveillance of those carrying the mutation but also important to spare other persons who are unaffected by the mutation to prevent unnecessary and potentially harmful interventions (Wu et al.,1998). A person with more severe polyposis, or mutations near the 1,300 codon, are more likely to require removal of the colon, rectum and anus with ileal pouch anal anastomosis (IPAA), which is a procedure that avoids the need for a permanent opening in the abdomen for passing of bowels (Wu et al.,1998). Patients with less severe polyposis would benefit from a with ileorectal anastomosis (IRA), which is a surgical procedure that connects the terminal ileum to the rectum following removal of the colon (Wu et al.,1998). Without prophylactic surgery, which is surgical removal of organs or glands that do not show cancer, most patients with FAP become symptomatic in the third or fourth decade of their life and will usually develop CRC by age 50 (Wu et al.,1998).

Treatment advancements have been made and methods have evolved over time. Until the early 1980’s, IRA was more commonly preferred over a removal of colon, rectum and anus and ileostomy. Later, there has been greater preference to perform an IPAA to reduce the risk of cancer in the otherwise retained rectum (Wu et al.,1998). While IRA is the least invasive and of least disturbance, IPAA which is much more complex and likely to impact the patient’s lifestyle, is generally necessary for high risk patients (Wu et al.,1998).

Medicine today has made it possible for patients with FAP to have a chance at survival. Studies of the APC mutations have shed light on the outcome and severity of the different mutations and how these affect individuals diagnosed with FAP. Clinical guidelines for the management of FAP can be personalized based on the different mutation positions and the interval of screenings can be modified for certain patients to increase survival and quality of life.



























































































































































































































Citations:







Bertario, L. Russo, A. Sala, P. Varesco, L. Giarola, M. Mondini, P. Pierotti, M. Spinelli, P. Radice, P. (2003). Multiple Approach to the Exploration of Genotype-Phenotype Correlations in Familial Adenomatous Polyposis. J Clin Oncol. 21:1698- 1707







Grover, S. Kastrinos, F. Steyerberg, EW. Cook, F. Dewanwala, A. Burbidge, LA. Wenstrup,



RJ. Syngal, S. (2012). Prevalence and Phenotypes of APC and MUTYH Mutations in Patients With Multiple Colorectal Adenomas. JAMA. 308(5): 485- 492











Herzig,D. Hardimann, K. Weiser, M. Yu, N. Paquette, I. Feingold, DL. Steele SR. (2017). Dis Colon Rectum. 60(9): 881-894











Wu,JS.Paul, P. McGannon E,A. Church, JM. (1998). APC Genotype, Polyp Number, and Surgical Options in Familial Adenomatous Polyposis. Ann. Surg. 227: 57-62