Ten percent to 15% of persons with CRC and/or colorectal adenomas have other affected family members,[326,327,329,330,331,335,336,337,338,339,340] but their findings do not fit the criteria for FAP, and their family histories may or may not meet clinical criteria for LS. Such families are categorized as having familial CRC, which is currently a diagnosis of exclusion (of known hereditary CRC disorders). The presence of CRC in more than one family member may be caused by hereditary factors, shared environmental risk factors, or even chance. Because of this etiologic heterogeneity, understanding the basis of familial CRC remains a research challenge.
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,[344,345,346,347,348] 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).[203,204,205] 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,[344,345,347] 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.