Colon Cancer Awareness Month and the Genetics of Inherited Colorectal Cancer
In 2000, President Clinton signed a White House Proclamation that March be designated Colon Cancer Awareness Month to bring attention to the second leading cause of cancer death in the United States. Each year, those who have been affected by colon cancer, their caregivers, and advocates come together to celebrate and honor people who have battled colon cancer, increase awareness, and educate the wider community about colon cancer screening and prevention. This Friday, March 3rd, 2017, celebrate the kickoff of Colon Cancer Awareness Month by wearing blue to show your support and help spread the word about colon cancer! For more details please visit dressinblueday.org!
Colorectal cancer is the third most common cancer in the U.S., and approximately 5% of all colon cancer cases are caused by an inherited genetic mutation. Lynch syndrome is the most common cause of hereditary colorectal cancers, accounting for approximately 2-3% of inherited colon cancer cases. There are also other genetic syndromes that can cause a significantly increased risk for colon cancer, including Familial Adenomatous Polyposis, which accounts for approximately 1% of all colon cancer cases, and other rarer syndromes including attenuated Familial Adenomatous Polyposis, MUTYH-associated polyposis, Peutz-Jeghers syndrome, Juvenile Polyposis syndrome and Cowden syndrome, which collectively account for approximately 1% of inherited colon cancer cases. Please read on to learn a few important facts about these rarer inherited cancer syndromes
(Nat’l Cancer Inst, 2017)
Familial Adenomatous Polyposis (FAP)
Familial adenomatous polyposis (FAP) is the second most common cause of inherited colorectal cancers (~1% of all cases), and affects approximately 1/8,000-1/32,000 individuals. It is characterized by the development of hundreds to thousands of polyps, which are non-cancerous cell growths, in the lining of the gastrointestinal (GI) tract. The specific type of polyp associated with this condition is called an adenoma. The adenomatous polyps in FAP are usually found in the colon, but can appear anywhere in the GI tract, including the stomach and small intestine. Polyps usually develop by age 16, but can be seen in early childhood (range 7-36). By age 35, 95% of people affected with FAP will have colonic polyps. Without treatment, the uncontrolled overgrowth of polyps will inevitably lead to the development colon cancer. The average age of colon cancer diagnosis in FAP is age 39.
There are several other cancers that FAP patients are at an increased risk for compared to the general population, including duodenal, gastric, periampullar, thyroid, brain (medulloblastoma), and pancreatic cancers. Children with FAP are also at a 1-2% increased risk for hepatoblastoma (liver cancer), which typically presents before age 5 if it is present. There are several other clinical features outside the GI tract that can be associated with FAP, including desmoid tumors (noncancerous growths in the connective tissue), dental anomalies, osteomas (bony growths), and congenital hypertrophy of the retinal pigment epithelium (CHRPE; spots on the back of the eye that do not affect vision).
FAP is due to a genetic mutation in the adenomatous polyposis coli (APC) gene and is inherited in an autosomal dominant manner. This means that one copy of a person’s APC gene has a mutation that renders it nonfunctional, which is enough to cause disease (see diagram below). It can be passed down in a family, and can affect men and women in every generation. The genetic change in APC is inherited from a parent approximately 75-80% of the time, and is seen for the first time in a person without a family history in 20% of cases. Individuals with FAP have a 50% risk of passing on an APC mutation to their children.
People with FAP should begin annual screening for polyps between ages 10-15 with a flexible sigmoidoscopy or colonoscopy, as well as an annual physical exam to evaluate the thyroid in the late teens. Screening for stomach and small intestinal polyps with upper endoscopy typically begins around age 25. As there is currently no curative treatment for FAP, the recommendation to prevent colon cancer is surgical removal of the colon (colectomy). The average age for colectomy is between 15-26. After surgery, colonoscopy or flexible sigmoidoscopy of the remaining rectal and/or intestinal tissue is still required.
Attenuated FAP (AFAP) has historically accounted for approximately 0.5% of all colon cancer cases and is thought to affect 1/7,000-1/31,000 individuals. AFAP is similar to FAP, but people with AFAP typically develop between 10 and 100 polyps (average 30 polyps) on the right side of their colon. There is a 70% lifetime risk for developing colon cancer by age 80 in those affected with AFAP, and people are usually diagnosed with colon cancer around age 50-55. Individuals with AFAP are also at increased risk for duodenal, gastric, thyroid, and stomach cancer. AFAP is also caused by genetic mutations in the APC gene and follows an autosomal dominant inheritance pattern.
Screening and management recommendations are made based on the polyp burden. Colonoscopy to monitor for polyps usually begins in the late teens, and continues every 1-2 years from then on. It may be possible to control polyp growth by removing polyps (polypectomy) during each endoscopic screening procedure. A gastroenterologist will be able to determine if a colectomy should be considered, should the polyp burden become too overwhelming. Screening protocols for the other associated cancer risks (duodenal, gastric, thyroid) is similar to that of FAP.
MUTHY-Associated Polyposis (MAP)
MUTYH-associated polyposis (MAP) is another condition that causes the development of colonic polyps, which usually number less than 100. Aside from adenomas, there are other types of non-cancerous polyps that can be seen in MAP, including serrated adenomas, hyperplastic/serrated sessile polyps, and mixed (hyperplastic and adenomatous) polyps. Individuals affected with MAP have a 43-100% lifetime risk for developing colorectal cancer if they are not monitored closely. Colon cancer typically presents over age 50 after polyps have formed, but there have been cases where colon cancer due to MAP has been diagnosed in an individual who did not have any polyps. There is a 4-5% lifetime risk for duodenal polyps and cancer, as well as some evidence to suggest a slightly increased risk for various other types of late-onset cancer (ovary, bladder, skin; possibly breast and endometrial).
Unlike FAP and AFAP, MAP is due to inherited mutations in the MUTYH gene and is inherited in an autosomal recessive manner. This means that both copies of the MUTYH gene have mutations that render them non-functional (see diagram above). Individuals who only have one mutated copy of MUTYH are called “carriers” because they do not have MAP, but they can pass along the condition to their children if they have children with another carrier. Approximately 1-2% of the general northern European population are carriers for MAP. Because carriers do not experience any of the clinical features of MAP, it is typical for there to be little or no family history of colon polyps and colon cancer when someone is identified as having MAP.
Colonoscopy and polypectomy are recommended for those affected with MAP beginning at age 25-30 and should be continued every 1-2 years if polyps are detected. Colectomy may be considered if the polyp burden becomes too overwhelming. A baseline upper endoscopy to monitor for duodenal polyps and cancer is recommended at age 30-35, and management will be tailored based upon individual findings.
Peutz-Jegher syndrome (PJS)
Peutz-Jegher syndrome (PJS) is a rare inherited cancer syndrome that affects anywhere from 1/20,000 to 1/300,000 individuals. PJS causes specific polyps called hamartomas to develop anywhere in the GI tract, but are most commonly found in the small intestine. These polyps can cause bleeding and anemia, as well as intestinal blockage that leads to intussusception, a telescoping of the small intestine into itself that requires emergency surgery. A hallmark clinical finding in PJS is the presence of mucocutaneous pigmentations (dark blue/brown freckles) on the mouth, eyes, and nostrils at birth. These freckles typically fade by puberty and adulthood, but can be most persistent in the inner lip (see image below).
PJS also comes with significantly increased lifetime risks for a number of cancers. Included below is a table from the 2016 National Comprehensive Cancer Network (NCCN) guidelines that summarizes these risks, the screening recommendations, and the age at which to begin these screenings:
(National Comprehensive Cancer Network Guidelines V2.2016)
PJS is caused by a genetic mutation in the STK11 gene and is inherited in an autosomal dominant manner. This means that one copy of a person’s STK11 gene has a mutation that renders it nonfunctional, which is enough to cause PJS. It can be passed down in a family, and can affect men and women in every generation. Approximately 45% of individuals with PJS do not have a family history of the condition. In those cases, it is still unclear whether their condition is the result of a new genetic mutation in that individual, or if there may be other family members affected with PJS but limited clinical findings. Individuals with PJS have a 50% risk of passing it on to their children.
Juvenile Polyposis Syndrome (JPS)
Juvenile polyposis syndrome (JPS) is an inherited cancer syndrome that is characterized by an increased risk for the development of juvenile polyps within the GI tract, specifically the stomach, small intestine, colon, and rectum. Juvenile polyps are a specific type of hamartoma, and the term ‘juvenile’ does not refer to the age at when they develop. Those affected by JPS typically develop polyps by age 20, and these juvenile polyps can cause bleeding and anemia if left untreated. Included below is a table from the 2016 National Comprehensive Cancer Network (NCCN) guidelines that summarizes the associated cancer risks for JPS, the screening recommendations, and the age at which to begin these screenings:
(National Comprehensive Cancer Network Guidelines V2.2016)
JPS is inherited in an autosomal dominant manner by mutations in either SMAD4 or BMPR1A. This means that one copy of a person’s SMAD4 or BMPR1A gene has a mutation that renders it nonfunctional, which is enough to cause disease. Approximately 20% of JPS patients have a disease-causing genetic mutation identified in the SMAD4 gene and 20% have a genetic mutation identified in the BMPR1A gene. These are the only two genes currently associated with JPS. The remaining 60% of JPS cases do not yet have a genetic cause identified. The genetic change is inherited from a parent approximately 75% of the time, and is seen for the first time in a person without a family history in 25% of cases. Individuals with JPS have a 50% risk of passing on an APC mutation to their children.
For a great and thorough explanation about Cowden syndrome, please refer to the previous blog post by my classmate, Kendra Frome!
Brand, R., Nielsen, M., Lynch, H., & Infante, E. (2012). MUTYH-associated polyposis. GeneReviews. University of Washington: Seattle, WA.
Colon Cancer Awareness Month: How It Got Started. Colon Cancer Alliance. Retrieved March 2, 2017. https://ccalliance.org/blog/colon-cancer-awareness-month-how-it-got-started/
Haidle, J. L., & Howe, J. R. (2015). Juvenile polyposis syndrome. GeneReviews. University of Washington: Seattle, WA.
How March Became Our Month. Colon Cancer Alliance. Retrieved March 2, 2017. https://www.ccalliance.org/awareness-month/
Jasperson, K. W., & Burt, R. W. (2014). APC-associated polyposis conditions. GeneReviews. University of Washington: Seattle, WA.
NCCN Guidelines: Genetic/Familial High Risk Assessment: Colorectal Version 2.2016. Retrieved March 2, 2017 from NCCN.org
Pagon, R. A., Adam, M. P., Ardinger, H. H., Wallace, S. E., Amemiya, A., Bean, L. J. H., … & Stephens, K. (2007). Peutz-Jeghers Syndrome–GeneReviews (®).
Lauren Gima is a second year student in the Master’s Program in Genetic Counseling at Northwestern University. She will graduate in March 2017 with experience in cancer, prenatal, and pediatric genetic counseling.
She has a background in research regarding inflammatory bowel disease and is currently working on her thesis project exploring healthcare providers’ interactions with FAP and Lynch syndrome patients. Originally from Southern California,
Lauren is always looking for the next great restaurant to try and enjoys hiking and swimming with her dog, Riley.
I recently got back from the Lynch syndrome conference in Rockville, MD and attended the Genomics and Population Action Collabarative (GPHAC) Leadership Meeting, in Washington, DC, with Dr. Muin Khoury. Please go to my twitter @ShewithLynch to see slides from the Rockland Lynch syndrome conference.
Please join us for #GenCSM on Twitter with Heather Hampel to discuss Lynch syndrome and other hereditary colon cancer syndromes on Monday, March 27tth.
Georgia M. Hurst
Founder and Executive Director of ihavelynchsyndrome.org