The methods of recognizing and assigning familial risk

CN14-02

Methods of Recognizing and Assigning Familial Risk
 Randall W. Burt, M.D., Professor of Medicine and Senior Director of Prevention and Outreach, Huntsman Cancer Institute, University of Utah
 Familial risk is common in colorectal cancer [1]. Almost one third of cases exhibit familial risk, probably from inheritance, as part of their pathogenesis [2]. In a large portion of these genetic-environmental factors are likely important. About 10% of persons in the general population have a first-degree relative with colon cancer, while 20% of those with colorectal cancer have an affected first-degree relative.
 Approximately 3% to 5% of colorectal cancer cases occur in the setting of one of the known inherited syndromes of colon cancer. The genes mutated in these conditions are known and genetic testing is available for clinical diagnosis. Both common and syndromic categories will be covered in this presentation.
 Common Familial Risk
 Common familial risk is determined by assessing which relatives have colon cancer as well as the age of cancer occurrence and the degree of relationship of each relative [1, 3]. The population risk for colon cancer in the U.S. is 6%. Having a first-degree relative with colon cancer >50 years increases that risk two- to three-fold. An affected second-degree relative or third-degree relative increases the risk about 50%. If a person has a first-degree relative with an adenomatous polyp, particularly a high risk polyp (≥1cm, villous histology or advanced dsyplasia), the risk of colon cancer approximately doubles. A person with a first-degree relative with colon cancer at an age ≤50 years, or two or more affected first-degree relatives has a three- to four-fold increased risk [1].
 Screening for persons with an affected first-degree relative >50 years should be the same as for average risk persons, but should start at age 40 years or ten years earlier than the earliest diagnosis in the family and be repeated every 5 years. In the higher risk setting, as outlined above, colonoscopy should be used, and should begin at age 40 or ten years younger than the earliest case in the family. An extended family history should also be done to see if one of the inherited syndromes should be considered.
 Inherited Syndromes of Colorectal Cancer
 Familial adenomatous polyposis (FAP)
 FAP is autosomal dominant, arises from mutations of the APC gene and occurs in about 1 in 10,000 individuals. The phenotype is that of hundreds to thousands of colorectal adenomatous polyps with an average age of appearance of 16 years, and a virtually 100% risk of colon cancer without colectomy. The average age of colon cancer diagnosis is 39 years [4]. Polyps also occur in the stomach, duodenum and small bowel, with a 5% lifetime risk of peri-ampullary cancer. Subtypes of FAP also arise from mutations of the APC gene and include Gardner syndrome, in which osteomas and benign soft tissue tumors occur in addition to the GI phenotype, attenuated FAP that averages 30 colonic polyps which appear about 10 years later than in typical FAP [5], and Turcot syndrome, that includes CNS tumors.
 FAP or attenuated FAP should be considered in any person who develops 10 to 20 or more adenomatous polyps or in all close relatives of an affected individual. Deleterious APC mutations are found in 70% to 90% of persons with the typical clinical phenotype [6]. Once the disease causing mutation is found in the index case, relatives can be tested for the presence or absence of that mutation with virtually 100% accuracy.
 Screening includes colon examination beginning at age 10 to 12 years in those who are found to have the mutated gene or in at risk persons where genetic testing is not possible or is uninformative. An appropriately timed colectomy is planned once polyps occur, but can often wait until after high school. Screening can be delayed until the late teens in families with attenuated FAP and surgery may note always be necessary.
 MYH associated polyposis (MAP)
 MAP is an autosomal recessive disease, arising from biallelic mutations of the MYH gene [7]. It is characterized by multiple colonic adenomas, usually less than 100, and an increased risk of colon cancer. MAP has been found in 5% to 40% of persons with 15 to 100 adenomas, and in approximately 1% of colon cancer cases. It should be suspected when multiple adenomas occur in a recessive pattern or an APC gene mutation could not be found in a polyposis patient. Genetic testing is done looking for biallelic MYH gene mutations. Colonoscopy screening should be done every one to three years, probably beginning in the mid 20’s. Colectomy is sometimes necessary.
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 Hereditary Nonpolyposis Colorectal Cancer (HNPCC), or Lynch Syndrome
 HNPCC is caused by autosomal dominant inheritance of mutations of any one of the four mismatch repair genes, MLH1, MSH2, MSH6 and PMS2 [8]. It may account for up to 5% of colon cancer cases. HNPCC is clinically defined by the Amsterdam I criteria (Am), which are: 1) three relatives with colorectal cancer, two of them being first-degree relative of the third; 2) at least two affected generations; and, 3) at least one case having a diagnosis at an age <50 years. The average age of colon cancer diagnosis is 45 years, but may be older, and frequent syndronous and metachronous cancers are found. Adenomatous polyps precede the cancer, but only one or several are usually found. Other cancers that occur as part of the syndrome include uterine (40%), and 5% to 10% ovarian, gastric, biliary, renal, CNS, ureter and renal pelvis, and duodenum and small bowel. Amsterdam II criteria are similar to those listed above, but include colon or any of these other cancers. Am II criteria are more sensitive but less specific than Am I.
 Germline genetic testing for mismatch repair gene mutations should be done on an index case, preferably the youngest colon cancer case in the family if the Am I or II criteria are met [6]. DNA is usually obtained from lymphocytes through peripheral blood sampling. As this approach misses about 50% of cases, Bethesda guidelines should be applied to families with a strong family history of colon cancer who do not meet Am I or II [6]. If one of the guidelines are positive, colon cancer tissue should undergo microsatellite instability (MSI) or immunohistochemistry (IHC) testing, both of which indicate mutation of one of the mismatch repair genes [6]. If MSI or IHC is positive, then germline genetic testing should be done. Disease causing mutations are found in 50% to 70% of people meeting Am I or II, and 50% of those meeting Bethesda guidelines whose tumor is found to be MSI or IHC positive.
 Another approach to finding HNPCC patients and families is to perform IHC testing on all colon cancers and then genetic testing if IHC is positive and then genetic testing if positive. Whether this approach is sufficiently cost and disease efficient remains to be determined.
 Patients with HNPCC, determined either clinically or genetically should undergo colonoscopy beginning at age 25 years, or ten years younger than the earliest case in the family, whichever comes first. This should be repeated every 2 years. Screening for certain other tumors is also indicated [8]. High risk families where the tumor MSI testing is negative, do not have HNPCC, and should have colonoscopy as outlined above under common familial risk [9].
 Hamartomatous polyposis syndromes
 These include Peutz-Jeghers syndrome (PJS), juvenile polyposis (JP) and Cowden’s syndrome (CS), arising respectively from the STK11 gene; the BMPR1A, SMAD4, or ENG genes; and, the PTEN gene [10]. All are extremely rare but all exhibit varying risks for colon and other cancers. PJS should be suspected anytime histologically characteristic polyps are found in the GI tract, JP when three or more juvenile polyps are found, and CS when any of the characteristic findings of this disease are present. Germline genetic testing is available for each of these diseases. It is advised that any person with one of these conditions should have at least one consultation at a center that deals with inherited colon cancer syndromes.
 References: 
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 5. Burt, R.W., et al., Genetic testing and phenotype in a large kindred with attenuated familial adenomatous polyposis. Gastroenterology, 2004. 127(2): p. 444-51.
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 8. Vasen, H.F., et al., Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer). J Med Genet, 2007. 44(6): p. 353-62.
 9. Lindor, N.M., et al., Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X. Jama, 2005. 293(16): p. 1979-85.
 10. Schreibman, I.R., et al., The hamartomatous polyposis syndromes: a clinical and molecular review. Am J Gastroenterol, 2005. 100(2): p. 476-90.