Table 9. Practice Guidelines for Diagnosis and Colon Surveillance of Lynch Syndrome continued...
Genetic studies have demonstrated a common autosomal dominant inheritance pattern for colon tumors, adenomas, and cancers in familial CRC families, with a gene frequency of 0.19 for adenomas and colorectal adenocarcinomas. A subset of families with MSI-negative familial colorectal neoplasia was found to link to chromosome 9q22.2-31.2. A more recent study has linked three potential loci in familial CRC families on chromosomes 11, 14, and 22.
Familial CRC type X
Families meeting Amsterdam-I criteria for LS who do not show evidence of defective MMR by MSI testing do not appear to have the same risk of colorectal or other cancers as those families with classic LS and clear evidence of defective MMR. These Amsterdam-I criteria families with intact MMR systems have been described as familial CRC type X,[388,389,390,391,392] and it has been suggested that these families be classified as a distinct group.
Age of CRC onset in LS ranges from 44 years (registry series) to a mean of 52 years (population-based series).[206,207,208] There are no corresponding population-based data for familial CRC type X, as familial CRC type X by definition requires at least one early-onset case and is not likely to lend itself to any population-based figures in the foreseeable future. Studies that have directly compared age of onset between familial CRC type X and LS have suggested that the age of onset is slightly older in familial CRC type X,[388,389,391] but the lifetime risk of cancer is substantially lower. The SIR for CRC among families with intact MMR (type X families) was 2.3 (95% CI, 1.7–3.0) in one large study, compared with 6.1 (95% CI, 5.7–7.2) in families with defective MMR (LS families). The risk of extracolonic tumors was also not found to be elevated for the type X families, suggesting that enhanced surveillance for CRC was sufficient. Although further studies are required, tumors arising within type X families also appear to have a different pathologic phenotype, with fewer tumor-infiltrating lymphocytes than those from families with LS.
Interventions/family history of CRC
There are no controlled comparisons of screening in people with a mild or modest family history of CRC. Most experts, if they accept that average-risk people should be screened starting at age 50 years, suggest that screening should begin earlier in life (e.g., at age 35 to 40 years) when the magnitude of risk is comparable to that of a 50-year-old. Because the risk increases with the extent of family history, there is room for clinical judgment in favor of even earlier screening, depending on the details of the family history. Some experts suggest shortening the frequency of the screening interval to every 5 years, rather than every 10 years.