Hereditary Colorectal Cancer Syndromes Fap Hnpcc

The adenomatous polyposis coli (APC) gene on chromosome 5q21 encodes a protein that is important in cell adhesion, signal transduction, and transcriptional activation. Germ-line mutations in APC are associated with familial adenomatous polyposis (FAP), a syndrome whose clinical phenotype includes hundreds to thousands of adenomatous polyps in the colon and rectum developing after the first decade of life and a 90% risk of developing colorectal cancer by the fourth decade of life.88 Additional features include extracolonic tumors including thyroid, periampullary, pancreatic, and gastric, hepatoblastoma in children, and congenital hypertrophy of retinal pigment epithelium (CHRPE). In some variants of FAP, the disease presentation may include fewer polyps and later onset of disease. One variant, called Gardner's syndrome, includes osteomas, epidermoid cysts, fibromas, odon-tomas, and desmoid cysts.89 These attenuated forms of FAP are often associated with distinct locations of the mutation on the gene, supporting a genotype-phenotype correlation in this syndrome. For example, a FAP mutation at I1307K, prevalent in 6% of people of Ashkenazi Jewish descent, appears to effect a modest (twofold) increase in colon cancer in that pop-ulation.90 Although highly penetrant, FAP accounts for less than 1% of all colon cancer. Genetic tests for FAP include protein truncation tests and full gene sequencing. The most common use of genetic testing for FAP is to determine if an unaffected relative of a patient with clinical manifestations of FAP has inherited the genetic mutation. Genetic testing is recommended at ages 10 to 12 years. Alternatively, at-risk individuals can pursue endoscopic screening for the pheno-typic features of the syndrome. Annual endoscopic screening usually begins at puberty, with decreasing frequency with increasing decades of life. Some recommend screening for hepatoblastoma with alpha fetoprotein levels in children starting at age 5 years. For primary prevention of FAP, the recommended strategy is colectomy, usually in the second decade of life. Subtotal colectomy with ileorectal anastomosis, total protocolectomy with Brooke ileostomy, or prot-colectomy and ileoanal pull-through are acceptable surgical options. Those who choose subtotal colectomy require frequent endoscopic evaluation of the rectum because of the persistent risk of rectal adenomas and carcinomas. The use of specific or nonspecific cyclooxygenase (COX)-2 inhibitors, such as celecoxib, has been recommended as an adjunct to endoscopic surveillance following subtotal colectomy.91 Upper endoscopic surveillance, as well as thyroid examination, are also recommended by some.

HNPCC is an autosomal dominant condition caused by the germ-line mutation of one of several DNA mismatch repair genes, hMSH2 on chromosome 2p16, hMLH1 on chromosome 3p21, hPMS1 and hPMS2 on chromosomes 2q31 and 7q11, respectively, hMSH6 on chromosome 2p16, and hMSH3 on chromosome 5q11.2-q13.2.92 The function of these genes is to maintain the fidelity of DNA during replication. When mismatch repair is faulty, somatic mutations occur throughout the genome that can ultimately trigger the carcinogenic pathway.89 It is estimated that germ-line mutations in the HNPCC account for 3% to 5% of all colorectal cancers.93

Individuals with HNPCC have a lifetime risk of developing colorectal cancer of 70%, with a mean age at diagnosis of 44 years. Both synchronous and metachronous tumors are common, and both tumors and polyps are often right sided. Extracolonic cancers, including endometrial, ovarian, gastric, urinary tract, kidney, biliary tract, central nervous system, and small bowel, are also increased.89 Criteria for HNPCC, the Amsterdam criteria, were developed by the International Collaborative Group in 1990 and subsequently revised to include other HNPCC-associated cancers, such as endome-trial cancer, small bowel cancers, and ureteral or renal pelvis cancers, whose relative risk ranges from 3 to 25 times that of the general population (Table 25.6).22,94

Because tumor DNA from individuals with HNPCC often have a distinct phenotype with changes in the length of nucleotide repeat sequences, termed MSI, the analysis of MSI in the tumor specimens is often recommended as the first step of evaluation before proceeding to full genetic sequencing for MLH1 or MSH2. Clinical indications for testing a

TABLE 25.6. The Amsterdam criteria for hereditary nonpolyposis colorectal cancer (HNPCC).

The Amsterdam Criteria I:

Histologically confirmed colorectal cancer in at least three relatives, one of whom is a first-degree relative of the other two.

Occurrence of disease in at least two successive generations.

Age at diagnosis below 50 years in at least one individual.

Exclusion of familial adenomatous polyposis.

Amsterdam Criteria II:

Histologically confirmed HNPCC-related cancers (colorectal cancer, or cancer of the endometrium, small bowel, ureter, or renal pelvis) in at least three relatives, one of whom is a first-degree relative of the other two.

Occurrence of disease in at least two successive generations.

Age at diagnosis below 50 years in at least one individual.

Exclusion of familial adenomatous polyposis.

Source: From Vasen et al.,94 by permission of Gastroenterology.

TABLE 25.7. The revised Bethesda guidelines.

Tumors from individuals should be tested for MSI in the following situations:

Colorectal cancer diagnosed in a patient who is less than 50 years of age.

Presence of synchronous, metachronous colorectal, or other HNPCC-associated tumors, regardless of age.

Colorectal cancer with the MSI-H histology diagnosed in a patient who is less than 60 years of age.

Colorectal cancer diagnosed in one or more first-degree relatives with an HNPCC-related tumor, with one of the cancers being diagnosed under age 50 years.

Colorectal cancer diagnosed in two or more first- or second-degree relatives with HNPCC-related tumors, regardless of age.

Source: By permission of A Umar, C Boland, J Terdiman, et al., Journal of the

National Cancer Institute 96:261, 2004.

colonic tumor for MSI are outlined in the Bethesda criteria (Table 25.7) and include early age at onset (less than 50 years), an individual with multiple primary cancers, and a family history of colorectal and/or endometrial cancer.23,89 Of note, tumors that are positive for MSI (MSI high) are characterized by a better clinical outcome compared to tumors with low or no expression of MSI.95 Newer assays include immunohisto-chemistry staining of tumors using antibodies to the MLH1 and MSH2 protein products. Histopathologic features of HNPCC-related colorectal cancer include mucinous or signet-ring types, poor cellular differentiation, and peritu-moral lymphocytic infiltration.96 The polyps that precede cancer are more often villous with areas of high-grade dys-plasia than sporadic polyps.93 Other rare genetic syndromes associated with an increased risk for colon polyps and cancers are Turcot syndrome, Peutz-Jeghers sysndrome, and juvenile polyposis.

Management strategies for HNPCC are based on the observed natural history of the diseases included in the syndrome. Because of the early age of onset of colorectal cancers, it is recommended that annual screening colonoscopy be initiated by age 25, or 5 years younger than the youngest affected individual in the family, and continued at frequent intervals for known mutation carriers. Those relatives who have a 50% chance of being a mutation carrier, but have not undergone genetic testing, are recommended to begin colonoscopy every 1 to 2 years, starting between 20 and 30 years, and annually after age 40. Because of the predominance of right-sided tumors in HNPCC, flexible sigmoidoscopy is not a sufficient screening tool. Because of the significantly increased risk for endometrial cancer in women with an HNPCC mutation, some form of screening of the uterus is recommended starting at age 25, although the optimal screening tool is not clear.93 Current options include annual transvaginal ultrasound or endometrial aspirates.97 Because of the high rate of metachronous tumors seen with HNPCC mutations (25%-40%), subtotal colectomy with ileorectal anastomosis rather than standard colectomy is recommended for individuals at the time of diagnosis of colon cancer.93 As in the case of BRCA1/2, oophorectomy (with hysterectomy) may be presented as an option for women with HNPCC.

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