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 1.0.0
• GENE/GENE PANEL: APC
• Condition: Familial Adenomatous Polyposis
• Mode(s) of Inheritance: Autosomal Dominant

Actionability Rationale

This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.

Final Consensus Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Colectomy / Colorectal Cancer	2	3A 1	2B	1	8AB

1. Scores where the tier of evidence recommendation of the Working Group differs from the evidence level tier Summary Report.

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

Prevalence of the Genetic Condition

Approximately 4.8% of men and women will be diagnosed with colorectal cancer (CRC) in their lifetime. There are an estimated 1.1 million people currently living with CRC in the U.S.
Familial adenomatous polyposis (FAP) accounts for ≤1% of CRC cases. [1, 2, 3, 4]

Clinical Features

FAP is characterized by the development of hundreds to thousands of adenomas in the colorectum; classical FAP is based on the presence of ≥100 polyps.
Extracolonic manifestations are variably present and include desmoid tumors and other malignancies. [5, 2, 6, 7, 3, 8, 9, 4]

Natural History

Colorectal adenomatous polyps begin to appear, on average, by age 16. By age 35, 95% of FAP patients have polyps.
In virtually all cases, the adenomas will develop into CRC if left untreated.
The mean age of CRC diagnosis in untreated individuals is 39 years; 93% of untreated patients develop CRC by age 50. [2, 3, 8, 9, 4]

2. How effective are interventions for preventing harm?

Patient Management

It is recommended that carriers of the APC mutation be referred for genetic counseling, and be followed by a GI specialist. (Tier 2) [10, 5, 11, 12, 13]

Prophylactic (procto)colectomy is recommended when the number and size of the polyps impede surveillance of the colon. The chance of rectal carcinoma after ileorectal anastomosis (IRA) is estimated to be 12-43%, depending on endoscopic surveillance. The chance of adenomas in the pouch following ileal pouch-anal anastomosis (IPAA) ranges from 8-62%, depending on surveillance. (Tier 2) [10, 2, 11, 12, 4]

Non-aspirin NSAIDs may be effective for reducing the number and size of colorectal polyps and adenomas in individuals with FAP. NSAIDs use has resulted in a 7-30% decrease in rectal polyps following IRA. (Tier 1) [2, 14, 15]

Registry-based screening of individuals with FAP has been shown to lead to a reduction in CRC incidence and CRC-related mortality. Odds ratios for CRC incidence following registration range from 0.09-0.44. Odds ratios for CRC-related mortality range from 0.11-0.22. (Tier 1) [3]

Surveillance

Endoscopic surveillance for colorectal polyps, adenomas, and/or CRC is recommended annually or semi-annually, until colectomy. CRC incidence was found to be 3-10% among cases identified through surveillance, compared to 50-70% in symptomatic FAP cases. (Tier 2) [10, 16, 17, 18, 2, 11, 19, 13, 4, 20]

Regular endoscopic surveillance of the duodenum is advised. However, the efficacy of this surveillance in reducing CRC incidence is not known. (Tier 1) [2]

Additional surveillance may include: annual thyroid exam, annual physical exam with a focus on central nervous system disorders, annual abdominal palpation. However, these screening methods have not been shown to be effective in reducing CRC incidence. (Tier 2) [10]

Circumstances to Avoid

No circumstances-to-avoid recommendations have been provided for the Adult context.

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

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

APC mutations occur in 1 in 10,000 births. (Tier 3) [4]

APC mutations can be identified in 80-93% of FAP cases. (Tier 3) [2, 21]

Penetrance

Virtually 100% of untreated individuals with FAP will develop CRC. (Tier 3) [2, 3, 22, 8, 4, 20]

Relative Risk

No relative risk estimates were identified.

Expressivity

Development of colorectal adenomas is variable, including variability in the number of adenomas within families with the same APC mutation; 50% of patients have polyps by age 15-16, and 95% by 35 years of age. The presence of duodenal adenomas ranges from 33-92%; 26-51% of FAP patients develop stomach polyps. (Tier 3) [2, 8]

Desmoid tumors occur in 10-25% of FAP cases. (Tier 3) [9]

Both inter- and intrafamilial phenotypic variability are common. (Tier 3) [8]

4. What is the Nature of the Intervention?

Nature of Intervention

Endoscopic surveillance is burdensome for individuals. [2, 21]

NSAIDs may be associated with an increased risk of serious cardiovascular events, particularly in patients with pre-existing cardiovascular risk factors. NSAIDs can also cause upper gastrointestinal toxicity. [15]

There is a small but appreciable risk of complications from colonoscopy including perforation, bleeding, and death. [11]

(Procto)Colectomy is associated with possible intra- and post-operative complications.

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

Chance to Escape Clinical Detection

General population CRC screening is recommended at age 50. Given the early age of development of adenomas and CRC in FAP patients, general population screening would not allow for prophylactic measures to be taken. (Tier 1) [16]

Date of Search: 05.13.2014

Reference List

1. Colon and Rectum Cancer.. National Cancer Institute, SEER Stat Fact Sheets, US Department of Health and Human Services, National Institutes of Health. 2-24-2014.. (2014) Website: https://seer.cancer.gov/statfacts/html/colorect.html

2. Association of Comprehensive Cancer Centres. Hereditary colorectal cancer. Amsterdam, The Netherlands Association of Comprehensive Cancer Centres. Other. (2009) Website: https://www.guidelinecentral.com/summaries/hereditary-colorectal-cancer/

3. 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.

4. 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.

5. Colorectal Screening for Cancer Prevention in Asymptomatic Patients. Other. (2013) Website: http://www2.gov.bc.ca/assets/gov/health/practitioner-pro/bc-guidelines/colorectal_screening.pdf

6. Familial adenomatous polyposis. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=733

7. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. FAMILIAL ADENOMATOUS POLYPOSIS 1; FAP1. MIM: 175100: 2016 Aug 31. World Wide Web URL: http://omim.org.

8. KW Jasperson, RW Burt. APC-Associated Polyposis Conditions. 1998 Dec 18 [Updated 2014 Mar 27]. 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/NBK1345

9. Sinha A, Tekkis PP, Gibbons DC, Phillips RK, Clark SK. Risk factors predicting desmoid occurrence in patients with familial adenomatous polyposis: a meta-analysis. Colorectal Dis. (2011) 13(11):1222-9.

10. Colorectal Cancer Screening. Other. (2013) Website: https://www.google.com/url?q=http://www.nccn.org/professionals/physician_gls/PDF/colorectal_screening.pdf&sa=U&ved=0ahUKEwiXjIKKne7KAhVW8WMKHUGaDQ0QFggEMAA&client=internal-uds-cse&usg=AFQjCNEBO4lGlL14PJhntw-PBiiCaGupJg

11. 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.

12. Church J, Simmang C. Practice parameters for the treatment of patients with dominantly inherited colorectal cancer (familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer). Dis Colon Rectum. (2003) 46(8):1001-12.

13. Rex DK, Johnson DA, Anderson JC, Schoenfeld PS, Burke CA, Inadomi JM. American College of Gastroenterology guidelines for colorectal cancer screening 2009 [corrected]. Am J Gastroenterol. (2009) 104(3):739-50.

14. Asano TK, McLeod RS. Non steroidal anti-inflammatory drugs (NSAID) and Aspirin for preventing colorectal adenomas and carcinomas. Cochrane Database Syst Rev. (2004(2):CD004079)

15. Cooper K, Squires H, Carroll C, Papaioannou D, Booth A, Logan RF, Maguire C, Hind D, Tappenden P. Chemoprevention of colorectal cancer: systematic review and economic evaluation. Health Technol Assess. (2010) 14(32):1-206.

16. Colorectal Cancer Screening. Other. (2012) Website: https://www.icsi.org/guidelines__more/catalog_guidelines_and_more/catalog_guidelines/catalog_prevention__screening_guidelines/colorectal/

17. Guidelines for preventive activities in general practice Colorectal cancer (CRC). Other. (2012) Website: http://www.racgp.org.au/your-practice/guidelines/redbook/early-detection-of-cancers/colorectal-cancer-%28crc%29/

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

19. Ko C, Hyman NH. Practice parameter for the detection of colorectal neoplasms: an interim report (revised). Dis Colon Rectum. (2006) 49(3):299-301.

20. Winawer S, Fletcher R, Rex D, Bond J, Burt R, Ferrucci J, Ganiats T, Levin T, Woolf S, Johnson D, Kirk L, Litin S, Simmang C. Colorectal cancer screening and surveillance: clinical guidelines and rationale-Update based on new evidence. Gastroenterology. (2003) 124(2):544-60.

21. Aretz S, Vasen HF, Olschwang S. Clinical utility gene card for: familial adenomatous polyposis (FAP) and attenuated FAP (AFAP). Eur J Hum Genet. (2011) 19(7).

22. Dunlop MG. Guidance on gastrointestinal surveillance for hereditary non-polyposis colorectal cancer, familial adenomatous polypolis, juvenile polyposis, and Peutz-Jeghers syndrome. Gut. (2002) 51 Suppl 5:V21-7.