Clinical Diagnosis And Genetic Testing

Diagnosis of this syndrome requires evaluating a combination of clinical criteria including a thorough family history, histological tumor characteristics, and consideration of genetic testing. The International Collaborative group for HNPCC initially developed the Amsterdam Criteria to help identify potential HNPCC patients.[9] However, 60% of families with a known germline mutation do not meet the criteria for the disease,[10] and only 40-80% of patients meeting the criteria have an identified germline mutation.'11- The revised Amsterdam criteria were developed to include extracolonic malignan-cy.'12] These criteria increased sensitivity by 12%,'13] but the identified MMR mutations were found in only 5-50%.'11] Subsequently, the Bethesda guidelines (Table 2) were developed to help identify patients who should undergo microsatelite instability analysis.'15]

Strategy for molecular testing for HNPCC varies among clinical centers, but generally is performed as a multistep process. At some centers, MSI testing and immunohistochemistry for MLH1 and MSH2 proteins are performed on colorectal tumor tissue from an individual putatively affected with HNPCC prior to consideration of germline MLH1 and MSH2 testing, as it may help more accurately target individuals who are likely to carry germline mutations.'16-1 This strategy has been endorsed by the American Gastroenterological Association in its position statement on genetic testing for hereditary colorectal cancer.'17] Tumors are considered to have high MSI when two or more of a panel of two mononucleotide (Bat 25 and Bat 26) and three dinucleotide repeats (D5S346, D2S123, and D17S250) show differences between the length of the microsatellite repeat regions amplified in tumor and normal DNA. Once high level of MSI is detected in tumor DNA, germline testing (typically performed on peripheral lymphocytes) by sequencing, conformational-sensitive gel electrophoresis (CSGE), or single-strand conformation polymorphism (SSCP) analysis for mutations in MLH1 and MSH2 is considered. Loss of MLH1 or MSH2 protein

Table 2 Bethesda guidelines for testing of colorectal tumors for MSI

- Individuals with cancer in families that meet the Amsterdam criteria

- Individuals with two HNPCC-related cancers, including synchronous and metachronous colorectal cancers or associated extracolonic cancers

- Individuals with colorectal cancer and a first-degree relative with colorectal cancer and/or HNPCC-related extracolonic cancer and/or a colorectal adenoma; one of the cancers diagnosed at age less than 45 years, and the adenoma diagnosed at age less than 40 years

- Individuals with colorectal cancer or endometrial cancer diagnosed at age less than 45 years

- Individuals with right-sided colorectal cancer with an undifferentiated pattern (solid/cribriform) on histopathology diagnosed at age less than 45 years

- Individuals with signet-ring-cell-type colorectal cancer diagnosed at age less than 45 years

- Individuals with adenomas diagnosed at age less than 40 years

staining by immunohistochemistry may direct which gene to target for germline analysis. Individuals with low or absent levels of MSI in tumor DNA are unlikely to harbor germline MMR gene mutations, and germline testing is usually not pursued. If germline testing reveals a mutation in a putatively affected family member, the HNPCC diagnosis is confirmed, and genetic testing of at-risk family members will provide true positive or negative results. If no mutation is detected, or if a variant of unknown clinical significance is detected, further genetic studies for large genomic rearrangements may be pursued, or segregation analysis in families carrying the same variant may be initiated. Ultimately, if a mutation cannot be identified, further testing of at-risk relatives should not be pursued, because testing will not be conclusive; a negative result could be a false negative because current testing may not be capable of detecting a mutation even if present. If MSI testing is not possible in the affected individual because of the absence or condition of the tumor specimen, or if the first three conditions of the modified Bethesda criteria are met, AGA guidelines support consideration of initial germline testing in the affected individual. Although it is possible to initiate germline testing with an at-risk family member when an affected family member is not available for testing, this strategy can only yield positive or inconclusive results. In this situation, only the identification of a mutation in a family member can enable a true negative result.

Genetic testing should be offered when results could influence the medical management of that patient or the patient's family members. It should always be done in the setting of pre- and posttest genetic counseling, as endorsed by the American Society of Clinical Oncology in its position statement on genetic testing for hereditary cancer.[18] The process of genetic counseling includes providing risk assessment, educating patients about testing options, discussing the implications for medical management, and providing supportive counseling to the individual and their family.

stage shift toward earlier stages and a probable reduction in colorectal cancer mortality among screen-detected cancers. In HNPCC, current recommendation for surveillance includes full colonoscopy starting at age 20-25 years (or 5 years younger than the youngest age at diagnosis in the family) and repeated every 1-2 years.[19] Annual colonoscopy should ensue at age 40. Rectal stump surveillance with annual sigmoidoscopy should continue in patients after subtotal colectomy. This level of screening has been shown to decrease the risk of colorectal cancer by greater than 50% and 65% fewer colorectal cancer deaths.[20,21] Screening for extracolonic malignancy in Lynch II syndrome has not proven as beneficial as that for colorectal cancer because of lack of sensitivity for the available screening modalities. Nevertheless, recommendations exist. For endometrial and ovarian cancer, annual transvaginal ultrasound with endometrial aspirate cytology and CA-125 is recommended starting at age 25-35 and repeated every 1-2 years.[19] While upper GI endoscopy and genitourinary ultrasound with urinalysis and cytology are not recommended in the entire HNPCC population, they may be helpful and are recommended in pedigrees that show a propensity toward malignancy at those sites.

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