Squaring Genetic vs Clinical Findings in Familial Polyposis
Prevalence and Phenotypes of APC and MUTYH Mutations in Patients With Multiple Colorectal AdenomasGrover S, Kastrinos F, Steyerberg EW, et al
SummaryFamilial adenomatous polyposis (FAP) is caused by mutations in the APC gene and 2 different, or biallelic mutations, in the MUTYH gene. However, not all patients with colorectal polyposis are found to carry mutations on these genes. In addition, it is unclear how the extent of polyp burden or the age at development of the first adenoma corresponds to the likelihood of finding mutations in either of these 2 genes.
In an effort to better characterize the mutation frequency in patients with multiple colorectal adenomas, this study tested for APC and MUTYH mutations in 8676 individuals over 8 years. Each person's cancer history, adenoma count, and family history of cancer or colorectal adenomas was reported by clinicians ordering the genetic testing.
The study found that patients with classic polyposis were very likely to carry an APC mutation: 80% of those with ≥ 1000 colorectal adenomas and 56% of those with 100-999 adenomas carried an APC mutation. APC mutations were prevalent even in individuals with fewer than 100 adenomas, with mutations seen in 10% of those with 20-99 adenomas and in 5% of those with 10-19 adenomas.
With regard to MUTYH mutations, the frequency was low in individuals with≥ 1000 adenomas (2%) but was fairly consistent in those with < 1000 adenomas (7% of persons with 100-999 adenomas, 7% of those with 20-99 adenomas, and 4% of those with 10-19 adenomas). The odds of finding a mutation on either gene increased with progressively younger age at diagnosis of polyposis, but family history of colorectal cancer did not consistently correspond with mutation status.
ViewpointCurrently, individuals with more than 10 adenomas are recommended for genetic evaluation for hereditary cancer predisposition syndromes, including those caused by mutations on the APC and MUTYH genes. Knowing mutation status is important for determining appropriate colonoscopy intervals and tolerance for conservative management, surveillance for other mutation-associated manifestations, and predictive genetic testing for other family members.
Clinically, FAP can present with a wide range of clinical manifestations, which directly affects treatment protocols. Besides causing gastrointestinal polyposis and high risk for colorectal cancer, classic FAP, which is clinically characterized by ≥ 100 adenomas, increases the risk for desmoid tumors; cancers of the small intestine, thyroid, brain, ampulla, pancreas, and stomach; and hepatoblastoma. Attenuated FAP, with 20-99 adenomas, has lower cancer risk and fewer extraintestinal manifestations.
Typically, genetic testing for APC and MUTYH mutations is pursued in individuals with > 10 colonic adenomas, those who present with multiple adenomas at an unusually young age, or those who have a family history consistent with FAP. The findings of the current study support testing in these individuals and demonstrate that the greater the number of polyps, the greater the likelihood of identifying a mutation.
However, multiple factors can complicate the value of genetic testing in clinical practice. The clinical phenotype of biallelic MUTYH mutations is quite varied; reports show that some mutation carriers can have hundreds of polyps, whereas others with colon cancer have no reported polyps. Also, overlap among the clinical phenotypes of Lynch syndrome, MUTYH-associated disease, and attenuated FAP or other polyposis conditions may require clinical expertise for appropriate diagnosis and management. Finally, some controversy remains with regard to risk (if any) for colon cancer in persons with only 1 MUTYH mutation, and management in these patients is uncertain.
At the same time, not all individuals manifesting colonic polyposis harbor a mutation in APC or MUTYH, and management is not straightforward in patients with polyposis but no identified mutation. Clearly, there are cases of unknown etiology, and there are probably as-yet unidentified genes that may predispose to adenomatosis. But changing technologies and testing standards can also affect interpretation of genetic test results. For example, polyposis testing was once only pursued in persons with > 20 polyps, whereas guidelines now recommend that testing be done in all patients who have ≥ 10 adenomas, so historically "negative" tests may need to be revisited in the future.
Similarly, individuals tested before the availability of APC deletion/duplication analysis and MUTYH testing must be reassessed. Indeed, in the past few months, new and more efficient molecular testing modalities, so-called next-generation sequencing, have allowed the commercial launch of several cost-efficient gene panels that can test multiple genes at once for polyposis and nonpolyposis mutations. This may prove particularly helpful in evaluating patients with low polyp counts.
Current recommendations note that individuals with multiple adenomas or a family history of colon cancer be referred for genetic counseling. However, a lack of family history does not exclude the possibility of FAP, because an individual can harbor a de novo mutation; genetic testing for a hereditary cancer syndrome can thus be pursued on the basis of age, polyp count, and family history. In the absence of an identified mutation, family history as well as clinical presentation can be used to determine whether the individual may be at increased risk for other syndromes, and an empiric screening and prevention protocol can be established