Mark is a 52-year-old male recently diagnosed with colorectal cancer (CRC). He has 2 children—a 25-year-old son and a 30-year-old daughter. Additionally, he has a 5-year-old grandson and 2 sisters in their late 40s. His father is aged 76, and his mother died at age 72 of metastatic breast cancer (diagnosed at age 70). He has 2 paternal aunts, 2 paternal uncles, and 3 maternal aunts. All of these individuals have children. Both his maternal and paternal grandparents were older than 75 when they died. No other malignancies are reported, and Mark is unaware of any risk-reducing surgeries, such as hysterectomies, in the family. He states his ethnic background is western European and denies consanguinity. Should genetic consultation be considered? What else would you want to know?
The majority of CRC cases are sporadic and not associated with family history. An individual is considered average risk for developing CRC if he or she has no personal history of cancer, adenoma, or inflammatory bowel disease and a family history negative for CRC or cancers related to Lynch syndrome (cancers associated with Lynch syndrome include endometrial, ovarian, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and sebaceous). However, up to 25% of CRC cases are associated with a family history, and approximately 5% of cases are linked to a hereditary CRC syndrome. According to the NCCN guidelines (2011),1 an individual should be evaluated for a CRC syndrome when he or she:
- Meets the Revised Bethesda Guidelines (used to diagnose Lynch syndrome)
- Meets the Amsterdam Criteria (used to diagnose Lynch syndrome)
- Has greater than 10 cumulative adenomas in his or her lifetime
- Has multiple gastrointestinal hamartomatous polyps or hyperplastic polyps
- Is from a family with a known hereditary cancer syndrome associated with CRC
Distinguishing among the different inherited CRC syndromes is important because each has its own inheritance pattern and cancer risks. Thus, medical management for the patient and at-risk family members varies significantly based on the syndrome. Among the inherited CRC syndromes are Lynch syndrome (also called hereditary nonpolyposis CRC syndrome), familial adenomatous polyposis (FAP), attenuated FAP (AFAP), MYH-associated polyposis (MAP), Peutz-Jeghers syndrome, juvenile polyposis syndrome, serrated polyposis/ hyperplastic polyposis syndrome, and PTEN hamartoma tumor syndrome.
Knowledge Applied to Mark
At first glance, Mark’s personal and family history is unremarkable. Mark has multiple family members, and the only reported cancer is his mother’s breast cancer at age 70. Breast cancer is not highly associated with Lynch syndrome. Based on these characteristics, a referral to genetics would not be indicated. However, you would also want to know if other family members had colonoscopies, as well as obtain more information about Mark’s personal history.
Upon inquiry, you learn that Mark’s father had his first colonoscopy about 8 years ago and was told he didn’t need another one until age 78. Based on this information you can infer that it is unlikely Mark’s father had adenomatous colon polyps. Mark is not sure if other family members have had colonoscopies. Additionally, you learn Mark was diagnosed with colon cancer during his first routine screening colonoscopy, and 42 adenomatous polyps were removed. As Mark has had more than 10 adenomas in his lifetime, you recognize he is a candidate for genetic services.
Depending on age of onset and family history, an individual with 42 cumulative adenomatous polyps is at risk for FAP, AFAP, and MAP. All 3 syndromes are associated with adenomatous polyps and a high risk for CRC. FAP and AFAP are associated with mutations in the APC gene and are inherited in an autosomal dominant pattern, while MAP is associated with mutations in the MYH gene and is inherited in an autosomal recessive pattern. Additionally, approximately 30% of the time FAP/AFAP is caused by a new mutation. Thus, neither parent has FAP/AFAP; however, the patient’s children would be at risk for inheriting the mutation.
The typical age of onset for adenomatous colonic polyps in FAP is between 7 and 36 years.2 The syndrome is characterized by hundreds to thousands of polyps. Without treatment, the risk for CRC is nearly 100%. A clinical diagnosis of FAP is made when an individual has >100 colorectal adenomatous polyps or <100 colorectal adenomatous polyps and a relative with FAP.3 It is important to note that >100 colonic polyps can also be associated with MAP or a syndrome yet to be identified. Sometimes polyps are also found in the small intestine and stomach. Other cancers associated with FAP confer a ≤2% lifetime risk and include papillary thyroid, pancreatic, gastric, hepatoblastoma, and medulloblastoma. Individuals with FAP may also have osteomas, supernumerary teeth, odontomas, congenital hypertrophy of the retinal pigment epithelium (CHRPE), desmoids, and epidermoid cysts. In the 1950s, Gardner and Richards proposed that the association of multiple colonic polyps with “soft tumors” was due to a single pleiotropic gene.4 As a result, the term “Gardner syndrome” is sometimes used to describe individuals with colonic polyps, osteomas, and soft tissue tumors. Testing for mutations in the APC gene became commercially available in the 1990s.
At present, there is no consensus on the criteria for a clinical diagnosis of AFAP.3 Individuals with AFAP typically have <100 cumulative adenomatous polyps and/or present at a later age. Additionally, the polyps tend to be right-sided. The lifetime risk for CRC is estimated to be 70%.5 Similar to FAP, individuals are at risk for thyroid cancer and other upper gastrointestinal findings. However, unlike classical FAP, other extracolonic findings such as desmoid tumors and CHRPEs are rare. Genotype-phenotype correlations do exist. Therefore, molecular testing can sometimes help distinguish between AFAP and FAP. For example, mutations in the 5-prime and 3-prime section of the APC gene tend to be associated with AFAP.
MAP was first described in 2002.6 Individuals typically present between the ages of 40 and 60 years. The colonic burden is often similar to that of AFAP. However, individuals with MAP have also been found to have few colonic polyps. Some authors suggest that relying solely on colonic burden to diagnose MAP will miss cases and propose that testing should also be considered in individuals with early-onset CRC whose tumors do not exhibit microsatellite instability and/or an autosomal recessive inheritance pattern.7,8 Duodenal adenomas are uncommon. As MAP is a relatively new syndrome, clinical data are limited. Therefore, the absolute risk for CRC and medical management for adenomas are not well characterized. Medical management tends to be similar to that for AFAP unless duodenal adenomatous polyps are identified.
The Importance of Genetic Diagnosis for Mark
As Mark presented at age 52 with CRC and 42 adenomas, the most likely differentials are AFAP or MAP. Since his family history is negative for CRC and colonic polyps, either syndrome is possible. Approximately 30% of the time an individual with an APC mutation is the first in the family to have the syndrome. Therefore, a family history is often not present. Similarly, as MAP is autosomal recessive, a family history is also rarely seen. A molecular diagnosis can help determine risk to family members. If the diagnosis is AFAP, Mark’s children would have a 50% chance of carrying the same mutation. The risk to his sisters and other family members would depend on whether either of his parents carried the APC mutation. If the diagnosis is MAP, all of his children would be carriers, and their risk of having MAP would depend on maternal family history. However, Mark’s sisters would have a 25% chance of having the syndrome.
Determining the syndrome is also important for Mark’s medical management. If Mark has AFAP, he would need annual thyroid examinations and a baseline upper endoscopy. The frequency of upper endoscopy would depend on whether polyposis was present. If Mark has MAP, upper endoscopy and side-viewing duodenoscopy would be recommended every 3 to 5 years.1 For either AFAP or MAP, medical management for colonic polyps would depend on the surgery pursued based on the location and prognosis of his CRC. However, if Mark did not have a diagnosis of CRC, medical management would depend on whether the adenoma burden was manageable by colonoscopy and polypectomy. If it wasn’t, then risk-reducing surgery for prevention of CRC would be considered. In the case of AFAP, colectomy and ileorectal anastomosis is often the surgery of choice, followed by endoscopic evaluation of the rectum every 6 to 12 months. With MAP, the typical choice is subtotal colectomy or proctocolectomy.1 However, because of limited data on MAP, the roles of surgery and endoscopically manageable adenomas are not clearly defined.
- When assessing a CRC survivor for referral to genetics, consider his or her history of colonic polyps. Indicators for referral for polyposis syndromes include having more than 10 adenomas in a lifetime or a history of a hamartomatous polyp. Additionally, individuals with a family member known to have a hereditary cancer syndrome should be referred
- As FAP, AFAP, and MAP have overlapping phenotypes, genetic testing may be useful in clarifying the syndrome. Identifying the syndrome can help determine the most appropriate screening and surgical options for the patient and his or her at-risk family members. Additionally, since the inheritance patterns differ, it will help determine which family members need presymptomatic genetic testing
- Keep in mind that because of a 30% de novo rate for FAP/AFAP and the autosomal recessive inheritance pattern of MAP, a patient with a polyposis syndrome may not have a family history
- NCCN Guidelines Version 2.2011. Colorectal Cancer Screening. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed January 16, 2012.
- Petersen GM, Slack J, Nakamura Y. Screening guidelines and premorbid diagnosis of familial adenomatous polyposis using linkage. Gastroenterology. 1991;100: 1658-1664.
- Jasperson KW, Burt RW; GeneReviews. APC-associated polyposis conditions. http://www.ncbi.nlm.nih.gov/books/NBK1345/. Updated October 27, 2011. Accessed January 16, 2012.
- Gardner EJ, Richards RC. Multiple cutaneous and subcutaneous lesions occurring simultaneously with hereditary polyposis and osteomatosis. Am J Hum Genet. 1953;5:139-147.
- Neklason DW, Stevens J, Boucher KM, et al. American founder mutation for attenuated familial adenomatous polyposis. Clin Gastroenterol Hepatol. 2008;6:46-52.
- Al-Tassan N, Chmiel NH, Maynard J, et al. Inherited variants of MYH associated with G:C→T:A mutations in colorectal tumors. Nat Genet. 2002;30:227-232.
- Wang L, Baudhuin LM, Boardman LA, et al. MYH mutations in patients with attenuated and classic polyposis and with young-onset colorectal cancer without polyps. Gastroenterology. 2004;127:9-16.
- Jo WS, Bandipalliam P, Shannon KM, et al. Correlation of polyp number and family history of colon cancer with germline MYH mutations. Clin Gastroenterol Hepatol. 2005;10:1022-1028.