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...
AFAP is found at the other end of the oligopolyposis spectrum. Most cases will have more than 100 adenomas, albeit at a later age and often with a predominance of microadenomas of the right colon and with fewer, larger polyps in the left colon. Cases with a positive family history and an APC mutation are clearly variant cases of FAP, as the term AFAP implies. However, patients with no immediate family history and a lesser adenoma burden may not be found to have an APC mutation. The lower the polyp count the lower the probability of APC mutation. Some of these cases are now known to carry biallelic MYH mutations, although even here, the lower the adenoma count the lower the mutation likelihood.
Another study evaluated 152 patients with 3 to 100 adenomas and another 107 APC mutation-negative patients with a "classic" FAP polyp burden for evidence of MYH mutations. Six patients with multiple adenomas and eight with a classic FAP burden had biallelic MYH mutations. The authors concluded that a cut-point of about 15 adenomas was a threshold above which MYH testing was reasonable, and many insurance companies in the United States have adopted a policy based on this cumulative adenoma count. Similar mutation rates for MYH biallelic mutations were found by others using 20 adenomas as the threshold for considering testing.
Mutations in related DNA polymerase genes POLE and POLD1 have been described in families with oligopolyposis and endometrial cancer.[209,210] An elegant approach was employed using whole-genome sequencing in 15 selected patients with more than ten adenomas before age 60 years. Several had a close relative with at least five adenomas who could also have whole-genome sequencing performed. All tested patients had CRC or a first-degree relative with CRC. All had negative APC, MYH, and MMR gene mutation test results. No variants were found to be in common among the evaluated families. In one family, however, linkage had established shared regions, in which one shared variant was found (POLE p.Leu424Val; c.1270C>G), with a predicted major derangement in protein structure and function. In a validation phase, nearly 4,000 affected cases enriched for the presence of multiple adenomas were tested for this variant and compared with nearly 7,000 controls. In this exercise, 12 additional unrelated cases were found to have the L424V variant, with none of the controls having the variant. In the affected families, inheritance of multiple-adenoma risk appeared to be autosomal dominant. Somatic mutations in tumors were generally consistent with the otherwise typical chromosome instability (CIN) pathway, as opposed to MSI or CIMP. No extracolonic manifestations were seen. A similar approach, whole-genome testing for shared variants, with further "filtering" by linkage analysis identified a variant in the POLD1 gene, p.Ser478Asn alteration, c.1433G>A). This S478N variant was identified in two of the originally evaluated families, suggesting evidence of common ancestry. The validation exercise showed one patient with polyps with the variant but no controls with the variant. Somatic mutation patterns were similar to the POLE variant. Several cases of early-onset endometrial cancer were seen. The mechanism underlying adenoma and carcinoma formation resulting from the POLE L424V variant appeared to be a decrease in the fidelity of replication-associated polymerase proofreading. This in turn appeared to lead to mutations related to base substitution.