Hereditary Nonpolyposis Colorectal Cancer

Features and Cancer Risks

Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, was first identified in families with a significant history of young-onset colorectal cancer. The lifetime risk of this malignancy ranges from 25% to 75%, with an average age at diagnosis of colorectal cancer of 44 years. Almost 75% of HNPCC-associated colorectal cancers present in the ascending (right) colon, and the risk of a metachronous colorectal cancer ranges from 1% to 4% per year.

Although colorectal cancer is the predominant feature in HNPCC, this syndrome is associated with an increased risk of other malignancies as well. The second most common cancer is endometrial or uterine, with a lifetime risk of 30% to 60%, followed by ovarian cancer with a lifetime risk of 10%. Other associated cancers, with a lifetime risk generally of less than 10%, are stomach, small bowel, urinary tract, and biliary tract cancers. Synchronous primary endometrial and ovarian cancers are suggestive of HNPCC if the woman also has a personal history of colorectal cancer or a family history suggestive of HNPCC.53

As with hereditary breast and ovarian cancer, the precise factors that determine which mutation-positive individuals will and will not develop which cancers are unknown. It is suspected that cancer development is due to a combination of the specific mutation location along one of four DNA mismatch repair genes, other coinherited genetic factors, and environmental interactions. Therefore, it is not currently possible to provide personalized risk estimates to a specific person.

Genetic Testing

The Bethesda and Amsterdam criteria are used to identify affected persons who are most likely to benefit from additional genetic evaluation (Boxes 3-2 and 3-3). Diagnostic testing of the tumor is conducted in those who meet one or more of these criteria. Compared with most hereditary cancer syndromes, genetic testing for HNPCC is generally a two-step process. The first step is to analyze the tumor itself. Two analyses are performed, the first of which is microsatellite instability (MSI)

Box 3-2. The Revised Bethesda Guidelines for Testing Colorectal Tumors for Microsatellite Instability (MSI)

Tumors 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 tumor infiltrating lymphocytes, Crohn's-like lymphocytic reaction, mucinous/signet-ring differentiation, or medullary growth pattern 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.

*Hereditary nonpolyposis colorectal cancer (HNPCC)-related tumors Include colorectal, endometrial, stomach, ovarian, pancreas, ureter and renal pelvis, biliary tract, and brain (usually glioblastoma as seen in Turcot syndrome) tumors, sebaceous gland adenomas and keratoacanthomas in Muir-Torre syndrome, and carcinoma of the small bowel. Data from Umar A, Boland CR, Terdiman JP, et al: Revised Bethesda Guidelines for Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome) and Microsatellite Instability. JNCIJ Nat Cancer Inst 96(4):261-268, 2004.

Box 3-3. Amsterdam-I and Amsterdam-II Criteria for Clinical Diagnosis of Hereditary Nonpolyposis Colorectal Cancer (HNPCC)

Amsterdam-I Criteria

• Three relatives with colorectal cancer (one must be a first-degree relative of the other two)

• Two or more generations of colorectal cancer

• One or more relatives diagnosed with colorectal cancer before age 50 years

• Exclude Familial Adenomatous Polyposis (FAP)

Amsterdam-II Criteria

• Three relatives with an HNPCC-associated* cancer (one must be a first-degree relative of the other two)

• Two or more generations of HNPCC-associated* cancer

• One or more relatives diagnosed with HNPCC-associated* cancer before age 50 years

* HNPCC-associated cancers include colorectal, endometrial, small bowel, ureter or renal pelvis.

Data from Vasen HF, Mecklin JP, Khan PM, Lynch HT: The International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer (ICG-HNPCC). Dis Colon Rectum 34:424-425, 1991; Vasen HF, Watson P, Mecklin JP, Lynch HT: New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative Group on HNPCC. Gastroenterology 116:1453-1456, 1999.

testing. Microsatellite instability testing evaluates numbers of repeats within specific DNA markers in the tumor and is performed in specific situations suggestive of HNPCC. Because the HNPCC-associated genes are involved in DNA mismatch repair, instability within the microsatellite repeats is suggestive of an underlying problem within the DNA repair process. Although microsatellite instability is detected in 90% to 95% of HNPCC-associated colorectal tumors, it is also present in 10% to 20% of sporadic colorectal tumors, generally due to acquired changes in the MLH1 gene. Thus, microsatellite instability testing is not diagnostic of HNPCC, but increases the probability of having a DNA mismatch-repair germline mutation.

In addition to microsatellite instability testing, immunohistochemistry (IHC) analysis of the HNPCC-associated proteins is also performed. Immunohistochemis-try currently assesses production of four mismatch repair proteins: MLH1, MSH2, MSH6, and PMS2. Absence of expression of any of these proteins, along with microsatellite instability, is strongly suggestive of HNPCC, and indicates that germline testing is warranted. By comparison, lack of instability and normal production of all HNPCC-associated gene products suggest that HNPCC is less likely, and germline testing is apt to be inconclusive.

Germline testing is available for all four of the HNPCC-associated genes, and as with BRCA1 and BRCA2 testing, peripheral blood is the preferred specimen.

Several different laboratories perform the testing, but the cost is still over $1000 per gene. The results of the immunohistochemistry help to guide the germline testing. Analysis generally begins with the gene whose protein product was absent on immunohistochemistry analysis, since it is the most likely site of mutation. Of all mutations detected, thus far approximately 90% have been found in MLH1 and MSH2.

If a woman with ovarian cancer and a family history suggestive of HNPCC undergoes germline testing and a mutation is identified, the mutation likely genetically explains her cancer. It also indicates that she has an increased risk of colorectal cancer and other HNPCC-associated malignancies, including endometrial carcinoma, and her risk is modestly increased for cancer of the stomach, urinary tract, hepatobiliary tract, brain, and small intestine and for certain skin neoplasms.54 Depending on her prognosis, increased screening or consideration of cancer risk-reducing options may be indicated. In addition, it is possible to offer predictive genetic testing to other interested family members to identify those who are also at increased risk for HNPCC-associated cancers.

If no mutations are identified, and the woman does not have a BRCA1 or BRCA2 mutation or does not have the classic features of HNPCC, then her ovarian cancer is genetically unexplained. Possible explanations are that (1) there is a mutation in an HNPCC-associated gene that is not identifiable using current technology, (2) there is a mutation in an undiscovered gene, or (3) the ovarian cancer is due to a combination of many genetic and environmental factors. The woman's risk for a future malignancy—and cancer risk to her relatives—is based on her family history.

A third possible result is a variant of uncertain significance, which is a change in the DNA sequence whose role in cancer development is not known. Through research, some variants are ultimately determined to be polymorphisms (normal genetic variation between individuals and populations), whereas others are ultimately classified as deleterious (cancer-causing). Until the significance of the variant is determined, genetic testing is generally not offered to unaffected relatives. Uncertain variants are detected in approximately 10% of samples tested from Caucasian individuals. In non-Caucasian populations, the chance of an uncertain variant increases owing to less available genetic data in minority ethnicities.

Once a germline mutation has been identified in a family, most other relatives undergo testing just for that specific mutation. This is due to the rarity of HNPCC-associated mutations, such that one seldom sees a family with more than one mutation.


Individuals with HNPCC should undergo colonoscopy every 1 to 2 years, beginning at age 20 to 25 years, and annually after age 40. HNPCC-associated colorectal cancers tend to be rapid-growing, and annual colonoscopic surveillance allows for removal of polyps before they become malignant. Because of the propensity for rightsided colorectal cancers, flexible sigmoidoscopy is not an adequate substitute for colonoscopy.

Colectomy is also a consideration for some individuals. The preferred surgery is subtotal colectomy with ileorectal anastomosis, which avoids an ostomy bag. It also allows for surveillance of the retained rectum via sigmoidoscope, which does not require the sedation necessary for colonoscopy. Because of the effectiveness of colo-noscopy at reducing the risk of colon cancer, most patients decline prophylactic col-ectomy. However, those with HNPCC who require surgical resection of a recently diagnosed colorectal tumor may opt for removal of the majority of the colon.

Unlike with colorectal cancer, there are no data on the efficacy of screening for gynecologic cancers in women with Lynch syndrome. For mutation-positive women who have not completed their family, however, surveillance is recommended via pelvic examination, transvaginal ultrasound, random endometrial biopsy, and consideration of serum CA-125 (see Chapter 7 for more detail). For those who have completed childbearing, prophylactic hysterectomy with bilateral salpingo-oophorectomy is a strong consideration. This eliminates the risk of uterine cancer and reduces the risk of ovarian cancer by 80% to 90%. In contrast to concerns about hormone therapy in women with a BRCA1 or BRCA2 mutation, there are no specific or exclusive contraindications to hormone replacement therapy related to a diagnosis of Lynch syndrome in women who have undergone prophylactic hysterectomy with bilateral salpingo-oophorectomy,54 because the risk for development of hormone-related cancers in these women is not greater than that of the general population risk.

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