Colorectal Cancer (CRC) is the second most prevalent cancer worldwide [1
]. In 35% of CRC patients, statistically significant effects of hereditary factors have been found [2
]. For some of these patients the genetic background is known; major CRC syndromes being: Lynch Syndrome, Familial Adenomatous Polyposis (FAP) and MUTYH
Associated Polyposis (MAP), which will be focused on in this review. Fig. (
) shows a delimitation of the groups of patients, which are referred to in this paper.
Delimitation of the groups of patients.
Lynch Syndrome is characterized by the development of particularly CRC and endometrial cancer at a young age. Lynch Syndrome is an autosomal dominant disease often caused by germline mutations in one of the Mismatch Repair (MMR) genes [3
]. The clinical and genetic features of the syndrome have previously been thoroughly reviewed in [5
Another autosomal dominant disease, Familial Adenomatous Polyposis (FAP), is caused by a germline mutation in the APC
gene, and confers a near 100% risk of developing CRC. FAP has been shown to account for less than 0.1% of all CRC cases [10
]. The characterization of the APC
gene and protein-product has been repeatedly reviewed, among others in [11
] and [12
]. Phenotypic characteristics of FAP include: early development of more than 100 and up to thousands of colorectal adenomas, as well as extracolonic manifestations such as gastric and duodenal adenomas, desmoid tumors and congenital hypertrophy of the retinal pigment epithelium (reviewed in [8
]). In FAP, genotype-phenotype correlations have been identified, specific APC
gene mutations being associated with particular manifestations reviewed in [11
] and [17
]. Of particular clinical interest is the milder phenotypical FAP variant, Attenuated Familial Adenomatous Polyposis (AFAP), which is associated with APC
mutations in the extreme ends of, or in the alternatively spliced region of exon 9 [11
]. AFAP is distinguished from FAP by the development of less than 100 colorectal adenomas, fewer extracolonic manifestations and the later development of CRC [11
]. One study showed that about 8% of registered FAP families present with an AFAP phenotype [19
Prophylactic screening of Lynch Syndrome patients, FAP patients and their families is shown to reduce the development of CRC and CRC-associated mortality markedly [5
]. For Lynch Syndrome patients, the recommendation is colonoscopy from about 20-25 years of age, in intervals of 1-3 years [5
]. The benefit of screening for endometrial cancer and other cancers associated with Lynch Syndrome is still controversial, and recommendations should be adjusted according to the individual patient’s wishes, family history and possibly genotype [7
Recommendations for FAP surveillance was recently reviewed in [13
] and [16
]. Sigmoidoscopy is advised to FAP patients commencing in the early teens, typically in intervals of 1-3 years, according to the clinical manifestations [13
]. Furthermore, individual assessment is especially necessary in FAP families displaying a more severe phenotype [16
]. Additionally, FAP patients should be offered endoscopy of the upper gastrointestinal tract from the age of about 25-30 years, in intervals of 1-5 years, according to the severity of duodenal Polyposis [16
]. Moreover, prophylactic colectomy is often advisable for FAP patients. Especially in patients with an early first appearance of the disease, the surgical procedure recommended varies between the individual FAP patients [13
]. For AFAP patients, coloscopy in intervals of 2 years is advised starting from 18-20 years of age, due to the later CRC development and the typically more distal location of adenomas in AFAP patients compared to FAP patients [16
In as many as 30% of patients with a FAP-like phenotype, no germline mutations in the APC
gene can be found [15
]. Similarly, one study of patients with an AFAP-like phenotype (3-100 adenomas), found that merely about 10% of these patients had inherited germline APC
]. However, another study (N=59) showed that almost 70% of patients with an AFAP-like phenotype (10-100 adenomas) had a germline APC
In 2002, the significance of mutations in the MUTYH
gene regarding the development of the Polyposis predisposition syndrome MUTYH
Associated Polyposis (MAP) was discovered [21
]. Since then, many aspects of MAP have been investigated, and the important question of how, these new discoveries can be used in the genetic counseling and screening of individuals at risk of developing MAP, now stands to be answered.
Here we review the main genetic aspects of MAP, including analysis of functional consequences and the outlining of specific ethnic allelic frequencies of MUTYH variants. In addition, we review the clinical aspects of the syndrome and introduce a new nomenclature for MUTYH germline mutations, which is likely to replace the nomenclature, which is currently used.
We believe that this review provides a broad, up-to-date overview of existing findings regarding MAP. We hope to provide perspective of the significance of MUTYH, as well as of which issues regarding MAP call for future investigation.