INTRODUCTION — MUTYH-associated polyposis is an autosomal recessive polyposis syndrome. Affected patients have multiple colorectal adenomas and an increased risk for developing colorectal cancer. This topic will review the clinical manifestations, diagnosis, and management of MUTYH-associated polyposis. The clinical manifestations, diagnosis, and management of familial adenomatous polyposis, Lynch syndrome, and hamartomatous polyposis syndromes are discussed elsewhere. (See "Clinical manifestations and diagnosis of familial adenomatous polyposis" and "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Cancer screening and management" and "Juvenile polyposis syndrome".)
GENETICS — MUTYH-associated polyposis is an autosomal recessive polyposis syndrome caused by biallelic pathogenic germline variants in the MUTYH gene [1]. MUTYH is a base excision repair gene whose protein repairs oxidative damage to the DNA. Oxidation of guanine leads to the formation of 8-oxo-6, 7, 8-dihydroxy-2 deoxyguanosine. Failure of base excision repair results in mispairing of this nucleotide with adenine and resultant somatic CG–AT transversions in multiple genes, including the APC and KRAS genes. The target genes that are mutated as a consequence of oxidative damage strongly influence the polyposis phenotype [2].
The two most common MUTYH gene pathogenic variants in Western Europeans and North Americans are Y179C and G396D (previously referred to as Y165C and G382D, respectively) [3]. However, pathogenic germline variants have been reported at other loci, and the prevalence of specific variants differs by ethnicity of the population [4-8]. Patients with MUTYH-associated polyposis may be homozygous or compound heterozygous for pathogenic germline variants in the MUTYH gene.
EPIDEMIOLOGY — Approximately 1 to 2 percent of the general population carry a single (monoallelic) germline MUTYH pathogenic variant, with two (biallelic) pathogenic variants identified in <1 percent of individuals diagnosed with colorectal cancer [9]. Among individuals with multiple colorectal adenomas in whom an APC mutation has been excluded, biallelic MUTYH pathogenic variants are found in 7 to 13 percent of patients with >100 adenomas and in 14 to 40 percent of patients with 10 to 99 adenomas [1,10-13].
CLINICAL MANIFESTATIONS — MUTYH-associated polyposis is typically characterized by the presence of multiple colorectal adenomas; however, the phenotype can vary based on the genotype. In addition, environmental and epigenetic factors may also affect the MUTYH-associated polyposis phenotype [14]. A number of extracolonic manifestations have also been associated with MUTYH-associated polyposis. (See 'Genotype phenotype correlation' below.)
Colonic manifestations — Individuals with MUTYH-associated polyposis usually develop between 10 to 100 colorectal polyps by the fifth or sixth decade [1,15]. However, the clinical presentation can vary, and biallelic MUTYH pathogenic variants have been identified in individuals with colorectal cancer (CRC) in the setting of few (<10) or no colorectal polyps [16-18]. Although adenomas are the predominant polyp type in patients with MUTYH-associated polyposis, multiple hyperplastic and/or sessile serrated polyps have been reported in some patients. In a study that included 17 patients with MUTYH-associated polyposis, eight (47 percent) had at least one hyperplastic and/or sessile serrated polyp [2]. In addition, three (18 percent) met criteria for serrated polyposis syndrome, and of these, one patient had over 100 hyperplastic and sessile serrated polyps. (See "Overview of colon polyps", section on 'Sessile serrated polyps and traditional serrated adenomas'.)
Individuals with biallelic MUTYH pathogenic variants and MUTYH-associated polyposis are at high risk for developing CRC, and approximately 60 percent of patients have CRC at presentation [19-25]. In contrast, the risk of CRC in monoallelic MUTYH carriers appears to be only marginally increased with an estimated lifetime risk of 5 to 7 percent [5,17,20-23,26,27]. In a meta-analysis of eight studies that included 20,565 CRC cases and 15,524 controls, there was no significant increase in CRC risk in individuals with monoallelic G396D variants, while individuals with a monoallelic Y179C variant had a 1.3-fold (95% CI 1.01-1.77) increased risk of CRC [20].
Extracolonic manifestations — Data on the extraintestinal manifestations of MUTYH-associated polyposis continue to emerge. Individuals with MUTYH-associated polyposis are at increased risk of upper gastrointestinal polyps and appear to have an increased risk for developing cancers of the duodenum [28,29].
However, as compared with patients with familial adenomatous polyposis, patients with MUTYH-associated polyposis appear to have a lower burden of adenomas. In a cohort study of 394 patients with MUTYH-associated polyposis, 21 percent had duodenal adenomas; median number of adenomas was three (range 1 to 20) and the majority were <10 mm in size [30]. Although Spigelman stage IV duodenal polyposis was rare, four individuals developed duodenal cancers, none of which occurred in the setting of stage IV duodenal polyposis (table 1). High-grade dysplasia was noted in small adenomas and two of the duodenal cancers developed within one year of a prior normal upper endoscopy, reinforcing the importance of upper endoscopic surveillance.
The incidence of extraintestinal malignancies in individuals with MUTYH-associated polyposis has not been well-defined. Rare extracolonic features that have been reported in patients with MUTYH-associated polyposis include osteomas, congenital hypertrophy of the retinal pigment epithelium, dental cysts, desmoids, sebaceous hyperplasia, and Muir-Torre phenotype with sebaceous gland tumors [27].
The risk for thyroid cancer also appears to be moderately increased [31]. (See 'Management' below.)
The tumor spectrum associated with biallelic MUTYH pathogenic variants continues to evolve. An early report suggested overall cancer incidence was almost twice that of the general population (standardized incidence ratio 1.9; 95% CI 1.4-2.5), with risks of cancers of the duodenum, ovaries, bladder, and skin significantly higher as compared with the general population (4, 10, 6, and 17 percent, respectively) [28]. Another study evaluated the risk of extracolonic cancer in 266 probands with MUTYH pathogenic germline variants (41 biallelic and 225 monoallelic) and 5158 first- and second-degree relatives from the Colon Cancer Family registry [32] and found the cumulative risk of bladder cancer by age 70 years was 25 percent for males and 8 percent for females. In that analysis, females with biallelic MUTYH pathogenic germline variants had an elevated risk of ovarian cancer; however, this has not been consistently observed. In addition, while some studies have suggested risks of breast cancer and endometrial cancer may be increased in individuals with MUTYH-associated polyposis, this has not been consistently demonstrated [33-35]. (See "Muir-Torre syndrome".)
Some reports have suggested that prevalence of Barrett's esophagus may be higher in individuals with MUTYH-associated polyposis compared with the general population; however, additional studies are needed to confirm these findings [36].
Genotype phenotype correlation — The clinical phenotype in patients with MUTYH-associated polyposis who carry biallelic G396D pathogenic germline variants appears to be less severe than for Y179C homozygotes [19]. In one study that evaluated the phenotype of 257 patients with MUTYH-associated polyposis, patients with a homozygous G396D variant or compound heterozygous G396D/Y179C variants presented at a later age and had a lower risk of developing CRC as compared with patients with a homozygous Y179C variant. The mean ages of CRC diagnosis for individuals who were homozygous G396D, compound heterozygous G396D/Y179C, and homozygous Y179C were 58, 52, and 46 years, respectively. However, long-term prospective studies are needed to validate these findings.
DIAGNOSIS — The diagnosis of MUTYH-associated polyposis should be suspected in individuals with 10 or more cumulative colorectal adenomas or a history of multiple adenomas in combination with extracolonic features associated with MUTYH-associated polyposis (eg, duodenal/ampullary adenomas, desmoid tumors, thyroid cancer, congenital hypertrophy of the retinal pigment epithelium, epidermal cysts, or osteomas). Biallelic pathogenic germline variants in the MUTYH gene are required to establish the diagnosis [37-40].
When an individual is diagnosed with biallelic germline variants in MUTYH that are classified as pathogenic or likely pathogenic, genetic testing should be offered to at-risk relatives of the index case. Siblings of the index case with biallelic germline MUTYH variants have a 25 percent chance of having inherited both MUTYH variants and a 50 percent chance of being carriers of a monoallelic MUTYH variant. Since MUTYH pathogenic germline variants are carried by 1 to 2 percent of individuals in the general population, children of mono- or biallelic MUTYH carriers have a 0.5 to 1.0 percent chance of inheriting two MUTYH variants because the other parent might also be a MUTYH heterozygote. A cost-effectiveness analysis of Dutch MUTYH-associated polyposis patients estimated that MUTYH testing in spouses of MUTYH-associated polyposis patients, and spouses of MUTYH heterozygotes, may be cost-effective [41]. Genetic counseling should be offered prior to genetic testing [42]. (See "Genetic testing".)
DIFFERENTIAL DIAGNOSIS
Familial adenomatous polyposis (FAP) — FAP is an autosomal dominant polyposis syndrome, in which carriers of germline pathogenic variants in the APC gene develop multiple (ie, 10 to >1000) colorectal adenomas. Unlike MUTYH-associated polyposis (which is associated with autosomal recessive inheritance), most families with FAP exhibit a vertical (parent-to-child) transmission of polyposis. However, approximately one-third of individuals with FAP have de novo APC mutation and thus have no family history of FAP [43]. FAP is characterized by germline pathogenic variants in the APC gene and can be differentiated from MUTYH-associated polyposis by genetic testing. (See "Clinical manifestations and diagnosis of familial adenomatous polyposis", section on 'Clinical manifestations'.)
Lynch syndrome — Lynch syndrome (previously known as hereditary nonpolyposis colorectal cancer) is an autosomal dominant hereditary cancer syndrome characterized by an increased risk for colorectal cancer (CRC), endometrial cancer, and several other malignancies, including cancers of the ovary, renal pelvis, ureter, stomach, small bowel, bile duct, skin (sebaceous neoplasms), and brain (gliomas). Lynch syndrome is caused by a germline pathogenic variant in one of several DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2) or loss of expression of MSH2 due to deletion in the EPCAM gene. While most individuals with monoallelic pathogenic germline variants in DNA mismatch repair genes develop relatively few colorectal adenomas, individuals who harbor biallelic pathogenic germline variants in DNA mismatch repair genes (known as Biallelic/ Constitutional Mismatch Repair Deficiency) often develop multiple colorectal adenomas in childhood [44]. Individuals with MUTYH-associated polyposis who have few colorectal adenomas (oligo-polyposis) may be difficult to distinguish clinically from Lynch syndrome, but the diagnosis can be confirmed by genetic testing. (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis", section on 'Clinical features'.)
Polymerase proofreading-associated polyposis — Polymerase proofreading-associated polyposis is an autosomal dominant hereditary cancer syndrome caused by germline pathogenic variants in DNA polymerase ε (POLE) and δ (POLD1). Affected individuals develop adenomatous polyposis (classic or oligo-polyposis) and are at risk for developing CRC and endometrial cancer at an early age. Polymerase proofreading-associated polyposis appears to be rare compared with the prevalence of MUTYH-associated polyposis, FAP, and Lynch Syndrome, and only a few families have been characterized [45]. In one study of 858 familial/early-onset CRC cases and polyposis patients, one POLE germline pathogenic variant and one POLD1 pathogenic variant were identified [46]. Given the potential overlap among the adenomatous polyposis syndromes, germline genetic testing of patients with multiple (20 or more) adenomatous polyps should include a multigene panel to evaluate for variants in APC, MUTYH, and other genes associated with predisposition to polyposis and/or CRC [47].
MANAGEMENT
Colorectal cancer surveillance — For individuals with MUTYH-associated polyposis, we suggest colorectal cancer (CRC) screening with a colonoscopy every one to two years, starting at 25 to 30 years of age. Our recommendations are consistent with the American College of Gastroenterology guidelines, which are based on expert consensus [31]. However, other guidelines recommend colonoscopy annually starting at age 18 to 20 for biallelic carriers [48,49].
Surgical resection (eg, partial, subtotal, or total colectomy) is reserved for patients with documented or suspected CRC, or significant polyp burden that cannot be effectively managed with colonoscopic polypectomy. For patients with subtotal colectomy with ileorectal anastomosis, we perform sigmoidoscopy six months after surgery and annually thereafter [31].
Monoallelic MUTYH pathogenic variants may be associated with a small increase in risk (1.5 to 2-fold) for CRC; we therefore suggest that these individuals be managed based on their family history. Colonoscopic surveillance at five-year intervals should begin 10 years earlier than the earliest CRC diagnosis in the family or at age 40 years, whichever is earlier [49-51]. (See "Screening for colorectal cancer in patients with a family history of colorectal cancer or advanced polyp".)
Extracolonic surveillance
●We suggest that patients with MUTYH-associated polyposis undergo an upper endoscopy with duodenoscopy at baseline or the age of 30 to 35 years [31,49]. Examination of the stomach should include random sampling of fundic gland polyps. It is important to note that low-grade dysplasia is common in fundic gland polyps. Fundic gland polyps >1 cm should be resected for evaluation of high-grade dysplasia and malignant transformation [49]. In addition, polyps in the gastric antrum and duodenum should be endoscopically resected given the high probability of adenomas in this location. Surgery is reserved for high-grade dysplasia or cancer.
If endoscopic evaluation demonstrates an ampulla with mucosal abnormality or enlargement (>10 mm), we obtain biopsies of the ampulla. In patients with duodenal polyps, the surveillance interval should be based on the extent of duodenal polyposis. (See "Familial adenomatous polyposis: Screening and management of patients and families", section on 'Duodenal polyps'.)
While studies suggest that the use of chromoendoscopy may increase the diagnostic yield of upper endoscopy in patients with MUTYH-associated polyposis, further studies are needed to determine if this improves patient outcomes [52].
●We suggest annual thyroid screening by physical examination and/or ultrasound since individuals with MUTYH-associated polyposis appear to have a moderate increase in risk for thyroid cancer [31]; however, data to support the effectiveness of thyroid surveillance in this population are lacking.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hereditary colorectal cancer syndromes".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Colon and rectal cancer screening (The Basics)" and "Patient education: Colonoscopy (The Basics)" and "Patient education: Familial adenomatous polyposis (The Basics)")
●Beyond the Basics topics (see "Patient education: Screening for colorectal cancer (Beyond the Basics)" and "Patient education: Colonoscopy (Beyond the Basics)" and "Patient education: Flexible sigmoidoscopy (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Genetics – MUTYH-associated polyposis is an autosomal recessive polyposis syndrome caused by biallelic pathogenic variants in the base excision repair gene MUTYH. (See 'Genetics' above.)
●Epidemiology – Among individuals with multiple colorectal adenomas in whom an APC pathogenic germline variant has been excluded, biallelic MUTYH pathogenic variants are found in 7 to 13 percent of patients with >100 adenomas and in 14 to 40 percent of patients with 10 to 99 adenomas. MUTYH-associated polyposis is estimated to account for less than 1 percent of all colorectal cancers (CRCs). Monoallelic MUTYH pathogenic variants are found in 1 to 2 percent of the general population. (See 'Epidemiology' above.)
●Colonic manifestations – Individuals with MUTYH-associated polyposis usually develop between 10 to 100 colorectal polyps. However, the clinical presentation can vary, and biallelic MUTYH pathogenic variants have been identified in individuals who develop CRC in the absence of colorectal polyps.
The lifetime risk of CRC is increased for individuals with biallelic MUTYH pathogenic variants; however, the risk for monoallelic carriers of a single pathogenic variant is only marginally increased. (See 'Colonic manifestations' above.)
●Extracolonic manifestations – Individuals with MUTYH-associated polyposis are at increased risk of gastric and duodenal polyps. Other rare extracolonic features may include osteomas, congenital hypertrophy of the retinal pigment epithelium, dental cysts, desmoids, sebaceous hyperplasia, and Muir-Torre phenotype with sebaceous gland tumors. The risk of developing thyroid cancer is increased, whereas the risk for other extraintestinal cancers such as breast and gynecologic cancers have not been consistently demonstrated. (See 'Extracolonic manifestations' above.)
●Diagnosis – The diagnosis of MUTYH-associated polyposis should be suspected in individuals with 10 or more cumulative colorectal adenomas or a history of adenomas in combination with extracolonic features associated with MUTYH-associated polyposis. Biallelic germline pathogenic variants in the MUTYH gene are required to establish the diagnosis. (See 'Extracolonic manifestations' above and 'Diagnosis' above.)
●Management – For patients with MUTYH-associated polyposis, we initiate CRC screening with a colonoscopy every one to two years, starting at 25 to 30 years of age. We reserve colectomy for patients with documented or suspected cancer, or significant polyp burden that cannot be effectively managed with colonoscopic polypectomy. (See 'Colorectal cancer surveillance' above.)
For patients with MUTYH-associated polyposis, we perform upper endoscopy with duodenoscopy at baseline or the age of 30 to 35 years. Examination of the stomach should include random sampling of fundic gland polyps. (See 'Extracolonic surveillance' above.)
As monoallelic MUTYH pathogenic germline variants are associated with a small increase in risk for CRC, these individuals are managed based on their family history, with colonoscopic surveillance every five years, beginning 10 years earlier than the earliest CRC diagnosis in the family or at age 40 years, whichever is earlier. (See 'Colorectal cancer surveillance' above.)
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