Adult Summary Report

Secondary Findings in Adult Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Adult): Passed (Consensus scoring is Complete)
• Curation Status (Adult): Released - Under Revision 2.2.2
• Status (Pediatric): Incomplete (Consensus scoring is Incomplete)
• GENE/GENE PANEL: MUTYH
• Condition: MUTYH-Associated Polyposis
• Mode(s) of Inheritance: Autosomal Recessive

Actionability Assertion

• MUTYH ⇔ 0012041 (familial adenomatous polyposis 2; fap2): Strong Actionability

Actionability Rationale

All experts agreed with the assertion computed according to the rubric. This assertion applies specifically to the autosomal recessive form of the condition.

Final Consensus Scores

Gene Condition Pairs: MUTYH ⇔ 0012041 (OMIM:608456)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Colorectal cancer / Colonoscopy with polypectomy	2	3C	3C 1	2	10CC
Upper GI (stomach or duodenum) cancer / Upper Endoscopy with polypectomy	2	2C	2D 2	2	8CD

1. Evidence for effectiveness extrapolated from Lynch syndrome

2. Evidence for effectiveness extrapolated from familial adenomatous polyposis

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

Approximately 4.3% of men and women will be diagnosed with colorectal cancer (CRC) in their lifetime. MUTYH-associated polyposis is caused by biallelic pathogenic variants. MAP is estimated to account for <1% of population-based CRC cases, and up to 2% of familial or early-onset CRC cohorts. Assuming a CRC frequency of 5% in the general European population, the overall prevalence is assumed to be around 1 in 5000. In one study, MAP was found in 2 out of 444 (0.5%) of unselected CRCs; another population study found a prevalence of 0.4% in 1042 population-based CRC cases. In a large (2,239 cases and 1,845 controls) population-based case–control study from Scotland, 0.8% of CRC cases <55 years old and 0.54% of all cases had MAP. [1, 2, 3, 4]

Clinical Features

MAP predisposes individuals to an attenuated polyposis phenotype and an increased risk of CRC. Most individuals with MAP have 10 to a few hundred polyps in the colon, although some might have over 1,000. The predominant polyp type is adenomatous, though hyperplastic, sessile serrated, traditional serrated or mixed types can occur. Duodenal polyps are found in 17-25% and duodenal cancer is estimated at 4-5%. Other extraintestinal manifestations have been reported including ovarian cancer, bladder cancer, breast cancer, endometrial cancer, skin tumors, and thyroid cancer, although it is still not clear if the lifetime risk of these malignancies is increased. Although rare, other findings seen in patients with MAP have included sebaceous gland adenomas, carcinomas and epitheliomas, lipomas, congenital hypertrophy of the retinal pigment epithelium, osteomas, desmoid tumors, epidermoid cysts, and pilomatrixomas. [2, 3, 5, 6, 7]

Natural History

Colorectal adenomatous polyps present, on average, at age 50. In the absence of timely surveillance, the lifetime risk for CRC ranges from 40% to almost 100%. The risk of CRC by age 50 years is 19% and by age 60 years is 43%, with an average age of CRC onset of 48 years (median age of presentation 45 – 59 years). CRC has presented in some individuals with MAP in the absence of polyposis. Duodenal polyps are found in 4-25% of individuals with MAP; the lifetime risk for duodenal cancer in individuals with MAP is 4-5% with the average age of diagnosis of 61 years. Stomach cancer occurs in 1% of individuals with MAP at an average age of diagnosis of 38 years. Most major ethnic groups seem to have mutations in the MUTYH gene. There appear to be a number of founder mutations common to specific ethnic groups. [2, 3, 5, 6, 8, 9, 10]

2. How effective are interventions for preventing harm?

Patient Management

To establish the extent of disease and needs of an individual diagnosed with MAP, the following evaluations are recommended:
• Review of personal medical history with emphasis on those features related to MAP (or colorectal cancer): colon polyps with the majority being adenomas, colon cancer, rectal bleeding, abdominal pain and discomfort, bloating, diarrhea
• Colonoscopy and review of pathology
• Upper endoscopy and review of pathology
• Baseline thyroid ultrasound examination
• Consultation with a clinical geneticist and/or genetic counselor (Tier 4) [2]

It is recommended that patients be managed by physicians or centers with expertise in MAP and that management be individualized to account for genotype, phenotype, and personal considerations. (Tier 2) [6]

Surgical evaluation and counseling is recommended, if appropriate, for individuals with a low polyp burden. (Procto)Colectomy with IRA or IPAA is recommended for patients with significant polyposis not manageable by polypectomy. (Tier 2) [3, 6, 7, 8, 10, 11]

A retrospective observational study of 14 patients with MAP reported that of the 11 cases that underwent total colectomy with IRA and yearly proctoscopic surveillance, none developed rectal cancer during surveillance (median duration was 5 years). (Tier 2) [3]

After colectomy with IRA in a large series of patients with attenuated familial adenomatous polyposis (AFAP), an average of 3.4 recurrent polyps (range, 0–29) and only one cancer was found in the postcolectomy rectal remnant over a mean follow-up of 7.8 years (range, 1–34 years). (Tier 2) [3]

Surveillance

Colonoscopy and polypectomy are recommended starting in early adulthood (age and frequency varies by guideline and polyp burden). Although indirect evidence suggests colonoscopic surveillance and polypectomy may be effective in CRC control, this has yet to be definitively determined for MAP. There is no literature to date of any control subjects with bi-allelic MUTYH mutations who have reached the age of 55 years without developing CRC or polyposis. (Tier 2) [3, 5, 6, 7, 8, 10, 11]

Though evidence was not identified for the effectiveness of screening programs in patients with MAP, evidence indicates that screening in Lynch Syndrome patients at 1-3 year intervals decreases the risk of CRC. Five out of six studies found a significantly reduced incidence rate of CRC with surveillance (OR estimates ranged from 0.11 to 0.35), while the sixth study reporting an OR of 0.93 was not significant. Two out of four studies have shown a significant reduction in CRC-related mortality with surveillance (OR estimates range from 0.04 to 0.17), while three of the four studies reported no mortality in the study arm with surveillance. (Tier 5) [12]

Upper endoscopy, including duodenoscopy, is recommended for screening for gastric and proximal small bowel tumors, though frequency and age to begin surveillance varies by guideline. Upper endoscopy should be supplemented with a side-viewing duodenoscopy, and examination of the stomach should include random sampling of fundic gland polyps. Upper gastrointestinal screening has not been demonstrated to improve prognosis but is nonetheless recommended in view of the cancer risk and expectation that mortality can be improved. (Tier 2) [3, 5, 6, 7, 8, 10, 11]

Duodenal surveillance appears to be of benefit in familial adenomatous polyposis (FAP), with the median survival after a screen detected cancer was 8 years (95% CI, 5.9 - not estimated), versus 0.8 years (95% CI, 0.03-1.7) after symptomatic cancer (p < 0.0001) (Tier 5) [13]

Annual thyroid screening by ultrasound should be recommended to individuals affected with familial colon polyposis syndromes including MAP. This recommendation is made on the basis of data for FAP. An increased risk for thyroid cancer to individuals with MAP has not been demonstrated. (Tier 2) [3, 8, 11]

An annual physical exam is recommended. (Tier 2) [6]

Circumstances to Avoid

No recommendations were identified.

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Recessive

Prevalence of Genetic Variants

It is estimated that 1-2% of the general northern European population is heterozygous for a MUTYH mutation. The prevalence of biallelic carriers of MUTYH mutations can be derived as 1:40,000-1:10,000. (Tier 3) [1, 2, 3, 5]

Penetrance

The penetrance of colorectal polyposis is unknown, with up to 1/3 of MAP patients developing CRC in the absence of polyposis, suggesting incomplete penetrance. (Tier 3) [2]

Penetrance of CRC in MAP has been estimated from 43 to 100%. (Tier 3) [1, 2, 3, 5]

For the lifetime risk of extracolonic tumors in MAP, in a study of 276 MAP patients, 17% had extracolonic lesions, with an estimated 38% lifetime risk of extracolonic malignancy that is approximately double the risk in the general population. The lifetime risk of duodenal cancer in MAP has been estimated to be 4-5%. Gastroduodenal polyposis is reported in over 20% of cases. Although gastric lesions have been found in up to 11% of patients with MAP and an estimated 1% develop stomach cancer, data are currently lacking to support an increased risk of gastric cancer. (Tier 3) [3, 5, 7]

Relative Risk

In a study of 20,565 CRC cases and 15,524 controls, patients with MAP demonstrated a 28-fold increase in risk for CRC (OR=28.3, 95% confidence interval (CI): 6.95–115). A pooled meta-analysis of all published and unpublished datasets showed an increased risk for MAP (OR: 10.8, 95% CI: 5.02–23.2). (Tier 1) [14]

Expressivity

Development of colorectal adenomas is variable. (Tier 3) [3, 6, 7]

4. What is the Nature of the Intervention?

Nature of Intervention

There is a small but appreciable risk of complications from colonoscopy including perforation, bleeding, and death. [5]

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

Surveillance recommendations for MAP begin at an earlier age than the general population screening recommendations. (Tier 2) [3, 5, 6, 7, 10]

Date of Search: 05.16.2014 (updated 01.31.2018)

Reference List

1. Aretz S, Genuardi M, Hes FJ. Clinical utility gene card for: MUTYH-associated polyposis (MAP), autosomal recessive colorectal adenomatous polyposis, multiple colorectal adenomas, multiple adenomatous polyps (MAP) - update 2012. Eur J Hum Genet. (2013) 21(1).

2. M Nielsen, H Lynch, E Infante, R Brand. MUTYH-Associated Polyposis. 2012 Oct 04 [Updated 2015 Sep 24]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: http://www.ncbi.nlm.nih.gov/books/NBK107219

3. Syngal S, Brand RE, Church JM, Giardiello FM, Hampel HL, Burt RW. ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. (2015) 110(2):223-62; quiz 263.

4. National Cancer Institute,. SEER Stat Fact Sheets: Colon and Rectum Cancer. (2018) Website: http://seer.cancer.gov/statfacts/html/colorect.html

5. Cairns SR, Scholefield JH, Steele RJ, Dunlop MG, Thomas HJ, Evans GD, Eaden JA, Rutter MD, Atkin WP, Saunders BP, Lucassen A, Jenkins P, Fairclough PD, Woodhouse CR. Guidelines for colorectal cancer screening and surveillance in moderate and high risk groups (update from 2002). Gut. (2010) 59(5):666-89.

6. National Comprehensive Cancer Network,. Genetic/Familial High-Risk Assessment: Colorectal (version 3.2017). Other. (2017) Website: http://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf

7. Vasen HF, Moslein G, Alonso A, Aretz S, Bernstein I, Bertario L, Blanco I, Bulow S, Burn J, Capella G, Colas C, Engel C, Frayling I, Friedl W, Hes FJ, Hodgson S, Jarvinen H, Mecklin JP, Moller P, Myrhoi T, Nagengast FM, Parc Y, Phillips R, Clark SK, de Leon MP, Renkonen-Sinisalo L, Sampson JR, Stormorken A, Tejpar S, Thomas HJ, Wijnen J. Guidelines for the clinical management of familial adenomatous polyposis (FAP). Gut. (2008) 57(5):704-13.

8. Balmana J, Balaguer F, Cervantes A, Arnold D. Familial risk-colorectal cancer: ESMO Clinical Practice Guidelines. Ann Oncol. (2013) 24 Suppl 6:vi73-80.

9. Hegde M, Ferber M, Mao R, Samowitz W, Ganguly A. ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis). Genet Med. (2014) 16(1):101-16.

10. Diagnosis and Management of Colorectal Cancer. SIGN. (2015) Website: http://www.sign.ac.uk/pdf/sign126.pdf

11. Stoffel EM, Mangu PB, Limburg PJ. Hereditary colorectal cancer syndromes: American Society of Clinical Oncology clinical practice guideline endorsement of the familial risk-colorectal cancer: European Society for Medical Oncology clinical practice guidelines. J Oncol Pract. (2015) 11(3):e437-41.

12. Barrow P, Khan M, Lalloo F, Evans DG, Hill J. Systematic review of the impact of registration and screening on colorectal cancer incidence and mortality in familial adenomatous polyposis and Lynch syndrome. Br J Surg. (2013) 100(13):1719-31.

13. Bulow S, Christensen IJ, Hojen H, Bjork J, Elmberg M, Jarvinen H, Lepisto A, Nieuwenhuis M, Vasen H. Duodenal surveillance improves the prognosis after duodenal cancer in familial adenomatous polyposis. Colorectal Dis. (2012) 14(8):947-52.

14. Theodoratou E, Campbell H, Tenesa A, Houlston R, Webb E, Lubbe S, Broderick P, Gallinger S, Croitoru EM, Jenkins MA, Win AK, Cleary SP, Koessler T, Pharoah PD, Kury S, Bezieau S, Buecher B, Ellis NA, Peterlongo P, Offit K, Aaltonen LA, Enholm S, Lindblom A, Zhou XL, Tomlinson IP, Moreno V, Blanco I, Capella G, Barnetson R, Porteous ME, Dunlop MG, Farrington SM. A large-scale meta-analysis to refine colorectal cancer risk estimates associated with MUTYH variants. Br J Cancer. (2010) 103(12):1875-84.