GENETIC MANAGEMENT OF A FAMILY HISTORY OF FAP or MUTYH ASSOCIATED POLYPOSIS. Family Health Clinical Genetics. Clinical Genetics department

Transcription

1 GENETIC MANAGEMENT OF A FAMILY HISTORY OF FAP or MUTYH ASSOCIATED POLYPOSIS Full Title of Guideline: Author (include and role): Division & Speciality: GUIDELINES FOR THE GENETIC MANAGEMENT OF A FAMILY HISTORY OF FAMILIAL ADENOMATOUS POLYPOSIS COLI (FAP) or MUTYH ASSOCIATED POLYPOSIS Dr Nora Shannon Consultant Clinical Geneticist Family Health Clinical Genetics Scope (Target audience, state if Trust wide): Review date (when this version goes out of date): Explicit definition of patient group to which it applies (e.g. inclusion and exclusion criteria, diagnosis): Changes from previous version (not applicable if this is a new guideline, enter below if extensive): Clinical Genetics department October 2019 Patients affected with or have a family history of FAP or MUTYH bowel cancer. Please refer to guidelines for inclusion/ exclusion criteria. No changes. Sections C to E may be superseded by the National Genomic Test Directory (to be published in 2019). Summary of evidence base this Evidence number 5 : expert committee reports or guideline has been created from: opinions and / or clinical experiences of respected authorities This guideline has been registered with the trust. However, clinical guidelines are guidelines only. The interpretation and application of clinical guidelines will remain the responsibility of the individual clinician. If in doubt contact a senior colleague or expert. Caution is advised when using guidelines after the review date or outside of the Trust. Page 1 of 8

2 GUIDELINES FOR THE GENETIC MANAGEMENT OF A FAMILY HISTORY OF FAMILIAL ADENOMATOUS POLYPOSIS COLI (FAP) or MUTYH ASSOCIATED POLYPOSIS Aim That individuals at an increased genetic risk of FAP are offered appropriate evidence based care. Objectives 1. To achieve a Trent wide consensus 2. To ensure equity of service provision across the region. 3. To enable regional audit of the service. About 1% of new cases of colorectal cancer will have FAP. FAP is an autosomal dominant condition with near 100% penetrance. In classical FAP, the mean age for symptoms is 29 and the mean age for colorectal cancer is 36. The condition is diagnosed by the presence of 100 or more adenomatous polyps in the colon and rectum. Polyps and tumours tend to occur in the left side of the colon, have chromosome instability and there is an early age at diagnosis in classical FAP. 100% of patients will develop CRC without surveillance and surgery. Other clinical findings include gastric and duodenal polyps, epidermoid cysts, osteomas of the mandible, dental abnormalities, bony exostoses, CHRPE s (congenital hypertrophy of retinal pigment epithelium), desmoid tumours, papillary thyroid cancer in females only, brain tumours and hepatoblastomas. The risk of developing cancer in gastroduodenal polyposis is 7%. 25% of cases are secondary to a new mutation. Mutations at the 5 end of the gene give rise to attenuated FAP (AFAP) with fewer adenomas, adenomas located proximal to the splenic flexure, adenomas which tend to be flat rather than polypoid, gastric fundal polyps and duodenal adenomas and the average age of colorectal cancer is 55. There is overlap with AFAP and HNPCC. MUTYH Associated Polyposis or mutations in POLE or POLD1 are an alternative explanation for an attenuated FAP presentation. 0.7% of CRC is due to MUTYH. Affected individuals typically have polyps with an average age of CRC of 50 years. The risk of CRC over a lifetime is % % develop duodenal adenomas with a 4% lifetime risk of cancer. Risks of other growths are debated but may include skin, ovary and bladder. Page 2 of 8

3 These guidelines include: A. Guidelines for identification of patients with FAP and MUYTH B. Guidelines for the management of individuals with FAP and MUYTH and their relatives C. Guidelines for molecular genetic testing D. Guidelines for assessing the risk of colorectal adenomas E. Guidelines for screening someone with a family history of polyps and no identified mutation A. GUIDELINES FOR IDENTIFICATION AND REFERRAL OF PATIENTS WITH FAP, MUTYH OR A SUSPECTED DIAGNOSIS The following patients are at increased risk and should be referred to the Clinical Genetics Service: Patients affected by FAP (more than 100 adenomatous polyps in the colon or rectum) First degree relatives (fdr) of a patient with FAP Patients with adenomatous bowel polyps and gastric or duodenal polyps, epidermoid cysts, osteomas of the mandible, dental abnormalities, bony exostoses, CHRPE s (congenital hypertrophy of retinal pigment epithelium), desmoid tumours, papillary thyroid cancer in females only, brain tumours and hepatoblastomas. Patients with CRC and 3 adenomatous polyps 5 adenomatous polyps <60 years 10 adenomatous polyps 60 years Page 3 of 8

4 B. GUIDELINES FOR THE MANAGEMENT OF PATIENTS WITH FAP AND MUTYH AND THEIR RELATIVES Classical FAP Affected / Mutation positive Annual flexible sigmoidoscopy from Once polyps identified, colonoscopy and discuss prophylactic colectomy Risk of cancer in retained rectum is in the range of 12-29% and therefore annual rectal stump surveillance (sigmoidoscopy) is required post surgery 2. Upper GI From 25 years, 3 yearly endoscopy Patients with large numbers of polyps may require to undergo endoscopy annually 3. Genetic testing Mutation analysis of APC gene if not previously undertaken in another affected family member. Mutations are identified in 80% of families If the phenotype could be attenuated FAP, see section on other genes to consider Relatives at 50% risk Annual flexible sigmoidoscopy from between 11 and 15 If no polyps found continue annual sigmoidoscopy If polyps found: biopsy and manage as affected 2. Eyes consider opthalmological examination to look for CHRPE s [diagnostic test] 3. Upper GI From 25 years, 3 yearly endoscopy 4. Genetic testing Predictive genetic testing if APC mutation previously identified in an affected family member from age 10 Stop screening if predictive test negative Page 4 of 8

5 Attenuated FAP Affected / mutation positive Annual / 2 yearly colonoscopy and polypectomy from 25-65; if polyp number too great, proceed to prophylactic subtotal colectomy Annual rectal stump surveillance (sigmoidoscopy) is required post surgery 2. Upper GI From 25 years, 3 yearly endoscopy Patients with large numbers of polyps may require to undergo endoscopy annually 3. Desmoid disease Manage according to individual patient 4. Genetic testing Genetic testing of APC if not previously undertaken in another affected family member If mutation analysis is negative consider MYH if inheritance is compatible with autosomal recessive, or POLE and POLD1 testing Relatives at 50% risk annual / 2 yearly colonoscopy from Upper GI From 25 years, 3 yearly endoscopy 3. Desmoid disease manage according to individual patient presence may suggest specific FAP mutations 4. Genetic testing predictive testing if APC mutation previously identified in an affected family member stop screening if predictive test negative Page 5 of 8

6 MUTYH Associated Polyposis Affected / mutation positive Annual / 2 yearly colonoscopy and polypectomy from 25-65; if polyp number too great, proceed to prophylactic subtotal colectomy Annual rectal stump surveillance (sigmoidoscopy) is required post surgery 2. Upper GI From 25 years, 3 yearly endoscopy Patients with large numbers of polyps may require to undergo endoscopy annually 3. Genetic testing Mutation analysis of MUTYH forms the basis of this diagnosis supported by a pedigree compatible with recessive inheritance As the diagnosis is made on the basis of genetic testing relatives screening will be informed by their genetic test results MUTYH Associated Polyposis carriers (heterozygote) 1-2% of Northern Europeans are carriers for this condition. Current evidence suggests they have a moderately increased risk of bowel cancer and as such the departmental policy is to recommend a one off colonoscopy at 55 yrs of age or at diagnosis, whichever is later. C. GUIDELINES FOR MOLECULAR GENETIC TESTING IN FAP Every attempt should be made to obtain a DNA sample from an affected family member for mutation analysis If a mutation is not identified but linkage is possible in an FAP family, linkage can be used for predictive testing in large families if they are informative Whenever possible, predictive testing should be offered to at risk family members before surveillance commences and this is usually around the age of after appropriate counselling or before 25 yrs in attenuated families or MUTYH The in-house polyp panel should be offered to those who are affected and meet the testing criteria on the following page In families with an attenuated phenotype alternative explanations such as mixed polyposis or hyperplastic polyposis should be considered against their diagnostic criteria. Page 6 of 8

7 D.GUIDELINES FOR ASSESSING THE SIGNIFICANCE OF COLORECTAL ADENOMAS No Does the patient meet the criteria for the in-house polyp panel? No Yes CRC and 3 adenomatous polyps 5 adenomatous polyps <60 yrs 10 adenomatous polyps 60yrs In-house polyp panel including APC and MYH -ve +ve Manage as per guideline Does patient meet the criteria for Lynch syndrome testing? No Yes Bethesda criteria 2 relatives in a first degree kinship with bowel cancer at average age yrs Test as per protocol -ve +ve Manage as per guideline Consider testing for mixed polyposis or hyperplastic polyposis if diagnostic criteria fulfilled Page 7 of 8

8 E. GUIDELINES FOR SCREENING SOMEONE WITH A FAMILY HISTORY OF POLYPS AND NO IDENTIFIED MUTATION In most cases the screening offered will be on the basis of the family history of cancer as polyp numbers will be low. Individuals who have polyps identified will have a repeat colonoscopy based on the number of polyps and their histology as per the guidelines published in Gut in 2010 by Cairns et al. Where an individual in a family has more than 10 adenomas identified, they will meet the diagnostic criteria for attenuated FAP and they and their first degree relatives should be screened as such. Individuals with more than 100 adenomas meet the diagnostic criteria for FAP and first degree relatives and affecteds should be screened accordingly regardless of a negative genetic test. References 1. Guidance on Commissioning Cancer Services. Improving Outcomes in Colorectal Cancer 2. The UK Northern Region genetic register for familial polyposis coli: use of age of onset, congenital hypertrophy of the retinal pigment epithelium and DNA markers in risk calculation (1991). Burn et al, J Med Genet; 28: Guidance on gastrointestinal surveillance for hereditary non-polyposis colorectal cancer, familial adenomatous polyposis, juvenile polyposis and Peutz-Jeghers syndrome (2002) Dunlop. Gut; 51 (Supplement V):v21- v27 4. Classification of familial adenomatous polyposis: a diagnostic nightmare (1998). Lynch HT, Smyrk TC. Am J Hum Genet; 62: Increased colorectal incidence in obligate carriers of heterozygous mutations in MUTYH. Gastroenterology. 2009;137: Risk of colorectal cancer in carriers of mutations in MUTYH, with and without a family history of cancer Gastroenterology.2014 May:146(5); Author: Review Date: Dr N L Shannon, Consultant Clinical Geneticist, Nottingham City Hospital 2/12/18 October Sections C to E may be superseded by the National Genomic Test Directory (to be published in 2019). Version 1.1 Page 8 of 8