Major Genetic Syndromes
The constellation of CRC and brain tumors has been referred to as Turcot syndrome; however, Turcot syndrome is molecularly heterogeneous. Molecular studies have demonstrated that colon polyposis and medulloblastoma are associated with mutations in APC, while colon cancer and glioblastoma are associated with mutations in MMR genes.
There are several reports of other extracolonic tumors associated with FAP, but whether these are simply coincidence or actually share a common molecular genetic origin with the colonic tumors is not always evident. Some of these reports have demonstrated LOH or a mutation of the wild-type APC allele in extracolonic tumors in FAP patients, which strengthens the argument for their inclusion in the FAP syndrome.
Genetic testing for FAP
APC gene testing is now commercially available and has led to changes in management guidelines, particularly for those whose tests indicate they are not mutation carriers. Presymptomatic genetic diagnosis of FAP in at-risk individuals has been feasible with linkage  and direct detection  of APC mutations. These tests require a small sample (<10 cc) of blood in which the lymphocyte DNA is tested. If one were to use linkage analysis to identify gene carriers, ancillary family members, including more than one affected individual, would need to be studied. With direct detection, fewer family members' blood samples are required than for linkage analysis, but the specific mutation must be identified in at least one affected person by DNA mutation analysis or sequencing. The detection rate is approximately 80% using sequencing alone.
Studies have reported whole exon deletions in 12% of FAP patients with previously negative APC testing.[122,123] For this reason, deletion testing has been added as an optional adjunct to sequencing of APC. Furthermore, mutation detection assays that use MLPA are being developed and appear to be accurate for detecting intragenic deletions.MYH gene testing may be considered in APC mutation-negative affected individuals. (Refer to the Colon Cancer Genes section of this summary for more information.)
Patients who develop fewer than 100 colorectal adenomatous polyps are a diagnostic challenge. The differential diagnosis should include AFAP and MYH-associated colorectal neoplasia (also reported as MYH-associated polyposis or MAP). AFAP can be diagnosed by testing for germlineAPC gene mutations. (Refer to the Attenuated Familial Adenomatous Polyposis (AFAP) section in the Major Genetic Syndromes section of this summary for more information.) MYH-associated neoplasia is caused by germline homozygous recessive mutations in the MYH gene.
Presymptomatic genetic testing removes the necessity of annual screening of those at-risk individuals who do not have the gene mutation. For at-risk individuals who have been found to be definitively mutation-negative by genetic testing, there is no clear consensus on the need for or frequency of colon screening, though all experts agree that at least one flexible sigmoidoscopy or colonoscopy examination should be performed in early adulthood (by age 18-25 years).[20,21] Colon adenomas will develop in nearly 100% of persons who are APC gene mutation positive; risk-reducing surgery comprises the standard of care to prevent colon cancer after polyps have appeared.