Adenomatous Polyposis

The two most common causes of adenomatous polyposis are mutations in the APC and MUTYH genes. Both are associated with tens to hundreds of adenomatous polyps in the lining of the gastrointestinal tract.

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The two most common causes of adenomatous polyposis are mutations in the APC and MUTYH genes. Both are associated with tens to hundreds of adenomatous polyps in the lining of the gastrointestinal tract.

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Disease Name 
Attenuated FAP (AFAP)
Colorectal cancer
Familial adenomatous polyposis (FAP)
Polyposis
MUTYH-Associated Polyposis (MAP)
Disease Information 

Familial adenomatous polyposis (FAP) is an autosomal dominant colorectal cancer predisposition syndrome caused by mutations in the APC gene and characterized by hundreds to thousands of adenomatous polyps in the colon and rectum. It affects 1/8,000 to 1/10,000 individuals and accounts for about 1% of all colorectal cancers.1 In individuals with classic FAP, colorectal polyps generally begin developing at an average age of 16 years.Colorectal cancer is inevitable without colectomy, and the average age of diagnosis in untreated individuals is age 35-40 years.3

Attenuated FAP (AFAP) is characterized by fewer colonic polyps (<100 polyps), diagnosis of colorectal cancer at a later age, and lower lifetime risk of colorectal cancer with appropriate surveillance.4 Other extracolonic manifestations associated with FAP include polyps of the gastric fundus and duodenum, dental anomalies, congenital hypertrophy of the retinal pigment epithelium (CHRPE), and other cancers. Variations in phenotype may relate to the location of the mutation within the APC gene.5

Germline bi-allelic mutations in MUTYH (one in each copy) cause MUTYH-Associated Polyposis (MAP) and account for >1% of all colorectal cancer (CRC) cases.6 While most hereditary cancer syndromes are inherited in an autosomal dominant pattern, MAP has autosomal recessive inheritance. Approximately 1% of the Caucasian population has one MUTYH mutation and is a carrier of this syndrome.7

Individuals with MAP have been estimated to have a up to an 80% chance of developing CRC in their lifetime.8 Individuals with MAP also have increased risks for colorectal polyposis, duodenal polyposis, and cancers of the duodenum, stomach, endometrium, and possibly breast.9-12 Additionally, while it remains an area of some debate, current research has suggested that carriers of one of the two common founder mutations in MUTYH (p.G396D and p.Y179C) are at a roughly 2-fold increased risk of developing CRC.13

Phenotypic expression is variable, but MAP often presents very similarly to Familial Adenomatous Polyposis (FAP) or Attenuated Familial Adenomatous Polyposis (AFAP). However, it is possible for MAP patients to develop CRC without polyposis, or to have serrated polyps or hyperplastic polyps in addition to adenomas.14 Since there is so much phenotypic overlap between APC and MUTYH, testing for them is often done simultaneously.

Testing Benefits & Indication 

Genetic analysis can confirm a diagnosis of FAP or MAP. Once a mutation is identified in someone, testing of at-risk family members can help identify carriers, including children, before clinical manifestations are present. Early identification of at-risk family members improves diagnostic certainty and reduces the need for costly and invasive screening procedures in those family members who have not inherited the disease-causing mutation.

Based on published guidelines15, APC and MUTYH genetic testing should be considered for any of the following:

  1. A personal history of >10 adenomas
  2. A personal history of adenomas and any of the following manifestations: duodenal/ampullary adenomas, desmoid tumors, papillary thyroid cancer, congenital hypertrophy of the retinal pigment epithelium (CHRPE), epidermal cysts, and/or osteomas
  3. Family history of FAP or MAP
  4. Known APC or MUTYH mutation(s) in the family
Test Description 

APC coding exons 1-15 and MUTYH coding exons 1-16, and well into the 5’ and 3’ ends of all the introns and untranslated regions, are analyzed by sequencing. Gross deletion/duplication analysis determines gene copy number for all coding exons. Additionally, all promoter 1B gross deletions as well as single nucleotide substitutions within the promoter 1B YY1 binding motif are analyzed and reported. Clinically significant intronic findings beyond 5 base pairs are always reported. Intronic variants of unknown or unlikely clinical significance are not reported beyond 5 base pairs from the splice junction. Genomic deoxyribonucleic acid (gDNA) is isolated from the patient’s specimen using standardized methodology and quantified. Sequence enrichment of the targeted coding exons and adjacent intronic nucleotides is carried out by a bait-capture methodology, using long biotinylated oligonucleotide probes followed by polymerase chain reaction (PCR) and next generation sequencing (NGS). Sanger sequencing is performed for any regions missing or with insufficient read depth coverage for reliable heterozygous variant detection. Reportable small insertions and deletions, potentially homozygous variants, variants in regions complicated by pseudogene interference, and single nucleotide variant calls not satisfying 100x depth of coverage and 40% het ratio thresholds are verified by Sanger sequencing.16  Gross deletion/duplication analysis of APC and MUTYH using read-depth from NGS data is also performed. Any copy number changes detected by NGS are confirmed by multiplex ligation-dependent probe amplification (MLPA) and/or targeted chromosomal microarray.

Mutation Detection Rate 

Prevalence of APC and MUTYH mutations among those with polyposis depends on the phenotype.14 Ambry's Adenomatous Polyposis testing can detect >99.9% of described mutations in APC and MUTYH, when present (analytic sensitivity).

Specimen Requirements 

Complete specimen requirements are available here or by downloading the PDF found above on this page.

Turnaround Time 
TEST CODE TECHNIQUE CALENDAR DAYS
8726 Adenomatous Polyposis APC and MUTYH  Gene Sequence and Deletion/
Duplication Analyses) 
14-21 
4662 MUTYH  Specific Site Analysis 7-14 
3042 APC Specific Site Analysis 7-14 

 

Specialty 
Genes 
APC
MUTYH
References 
  1. Lipton L, et al. The genetics of FAP and FAP-like syndromes. Fam Cancer. 2006. 5(3):221-226.
  2. Petersen GM, et al. Screening guidelines and premorbid diagnosis of familial adenomatous polyposis using linkage. Gastroenterology. 1991. 100(6):1658-1664.
  3. Bisgaard ML, et al. Familial adenomatous polyposis (FAP): frequency, penetrance, and mutation rate. Hum Mutat. 1994. 3(2):121-125. 
  4. Knudsen AL, et al. Attenuated familial adenomatous polyposis (AFAP). A review of the literature. Fam Cancer. 2003. 2(1):43-55. 
  5. Newton KF, et al. Genotype–phenotype correlation in colorectal polyposis. Clin Genet. 2011. 81(6):521-31.
  6. Samadder NJ, et al. Hereditary and Common Familial Colorectal Cancer: Evidence for Colorectal Screening. Digestive Diseases and Sciences. 2015. 60(3):734-47.
  7. Aretz S, et al. MUTYH-associated polyposis (MAP): evidence for the origin of the common European mutations p.Tyr179Cys and p.Gly396Asp by founder events. Eur J Hum Genet. 2014. 22(7):923-9.
  8. Jenkins MA, et al. Risk of Colorectal Cancer in Monoallelic and Biallelic Carriers of MYH Mutations: A Population-Based Case-Family Study. Cancer Epidemiol Biomarkers Prev. 2006. 15(2):312-314.
  9. Nielsen M, et al. Duodenal carcinoma in MUTYH‐associated polyposis. Journal of Clinical Pathology. 2006. 59(11):1212-5.
  10. Vogt S, et al. Expanded Extracolonic Tumor Spectrum in MUTYH-Associated Polyposis. Gastroenterology. 2009. 137(6):1976-85.e10.
  11. Rennert G, et al. MutYH Mutation Carriers Have Increased Breast Cancer Risk. Cancer. 2012. 118:1989-93.
  12. Win AK, et al. Risk of Colorectal Cancer for Carriers of Mutations in MUTYH, With and Without a Family History of Cancer. Gastroenterology. 2014. 146(5):1208-11.e5.
  13. Win AK, et al. Cancer risks for monoallelic MUTYH mutation carriers with a family history of colorectal cancer. Int J Cancer. 2011. 129(9): 2256–2262.
  14. Grover S, et al. Prevalence and phenotypes of APC and MUTYH mutations in patients with multiple colorectal adenomas. JAMA. 2012. 308(5):485-492.
  15. Syngal S, et al. ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. 2015. 110(2):223-62.
  16. Mu W, et al. Sanger confirmation is required to achieve optimal sensitivity and specificity in next-generation sequencing panel testing. J Mol Diagn. 2016. 18(6):923-932.