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

Table 8. Clinical Practice Guidelines for Diagnosis and Colon Surveillance of Familial Adenomatous Polyposis (FAP) continued...

Revised Bethesda Guidelines for Testing of Colorectal Tumors for MSI:

  1. CRC diagnosed in an individual younger than 50 years.
  2. Presence of synchronous, metachronous colorectal, or other LS-associated tumors.*
  3. CRC with MSI-high (MSI-H) pathologic associated features diagnosed in an individual younger than 60 years. Presence of tumor-infiltrating lymphocytes, Crohn-like lymphocytic reaction, mucinous/signet-ring differentiation, or medullary growth pattern.
  4. CRC or LS-associated tumor* diagnosed in at least one first-degree relative younger than 50 years.
  5. CRC or LS-associated tumor* diagnosed at any age in two first-degree or second-degree relatives.

*LS-associated tumors include colorectal, endometrial, stomach, ovarian, pancreatic, ureter and renal pelvis, biliary tract, and brain tumors; sebaceous gland adenomas and keratoacanthomas in Muir-Torre syndrome; and carcinoma of the small bowel.[244,245] Data from the Cancer Family Registry suggest that breast and prostate cancer may also be considered in the spectrum of LS-associated tumors.[233]

Research has included CRC families who do not meet Amsterdam criteria for LS and/or in whom the colorectal tumors are microsatellite stable (MSS). A number of these families have been found to have mutations in MSH6.[246,247,248,249,250] While the clinical significance and implications of these findings are not clear, these observations suggest that germline mutations in MSH6 may predispose to late-onset familial CRCs that do not meet Amsterdam criteria for LS and tumors that might not necessarily display MSI.

Genetic/Molecular testing for LS

Genetic risk assessment of LS generally considers the cancer family history and age at diagnosis of CRC and/or other LS-associated cancers in the patient. Studies of gene testing using DNA sequencing in suspected LS probands from a cancer risk assessment clinical setting found that approximately 25% test positive for an informative MSH2 or MLH1 mutation, allowing genetically informed management strategies to be developed for the family.[251,252] Computer models analogous to BRCAPro predict the probability of a MMR gene mutation. PREMM1, PREMM2, PREMM6, and the MMRPro models are easy to use and have been validated.[253,254,255,256] Although these models can predict mutation even in the absence of MSI or IHC information, they can incorporate those data as available. All three computer prediction models take family history of endometrial cancer into account. The mutation detection rate is higher for patients with more striking family histories or with informative tumor testing.

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