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Genetics of Colorectal Cancer (PDQ®): Genetics - Health Professional Information [NCI] - Major Genetic Syndromes

Table 10. Clinical Practice Guidelines for Colon Surveillance of BiallelicMYH-Associated Polyposis (MAP) continued...

Even in centers that rely exclusively on IHC testing, there may be a role for subsequent MSI testing in cases in which the clinical picture suggests LS, notwithstanding the results of IHC.

If greatest weight is given to clinical selection considerations (i.e., Bethesda guidelines being met), then IHC combined with MSI may be appropriate. In fact, in a truly high-risk population (Amsterdam criteria being met), any strategy may be acceptable, including germline testing without the benefit of tumor testing first. (Refer to the Genetic/molecular Testing for LS section of this summary for information about models.) However, as more institutions are adopting universal testing using MSI or IHC, perhaps in part based on some of the outlier (older, family history-negative) cases reported [222,301,305] or in part based on prognostic considerations (MSI-H having better prognosis), concerns about cost effectiveness of screening commonly dictate a more truncated approach. Thus, in a relatively low-risk population of patients with CRC, a screen with IHC or MSI alone may be adequate in cases of normal staining or MSS tumor.

(Refer to the Universal MSI/IHC colorectal cancer screening in clinical practice section of this summary for information about issues related to informed consent for MSI and IHC testing.)

Other techniques

In instances in which tumor tissue is not available from individuals to test for MSI and/or MMR protein IHC, germline mutation analysis of MLH1, MSH2, and MSH6 may be considered. This approach is, however, time consuming and expensive. Strategies to screen for mutations using heteroduplex analysis-based techniques have been explored. These techniques are limited by the need to perform DNA sequencing as a subsequent step on all aberrant samples detected in screening. Additionally, such techniques frequently detect numerous variants of uncertain significance. They cannot, therefore, be recommended for routine clinical use at this time.[307]

Genetic testing

Genetic testing for germline mutations in MLH1, MSH2, MSH6, and PMS2 can help formulate appropriate intervention strategies for the affected mutation-positive individual and at-risk family members.

If a mutation is identified in an affected person, then testing for that same mutation could be offered to at-risk family members (referred to as predictive testing). Family members who test negative for the familial mutation are generally not at increased risk of CRC or other LS-associated malignancies and can follow surveillance recommendations applicable to the general population. Family members who carry the familial mutation should follow surveillance and management guidelines for LS. (Refer to the Interventions for LS section of this summary for more information.)

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