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GENETIC MANAGEMENT OF A FAMILY HISTORY OF COLORECTAL CANCER EXCLUDING FAP Full Title of Guideline: Author (include email and role): GUIDELINES FOR THE GENETIC MANAGEMENT OF A FAMILY HISTORY OF COLORECTAL CANCER EXCLUDING FAP Dr Nora Shannon Consultant Clinical Geneticist Division & Speciality: Family Health Clinical Genetics Scope (Target audience, state if Trust Clinical Genetics department wide): Review date (when this version goes out November 2017 of date): Explicit definition of patient group to which it applies (e.g. inclusion and exclusion criteria, diagnosis): Changes from previous version (not Patients affected with or have a family history of bowel cancer. Please refer to guidelines for inclusion/ exclusion criteria. Previous version not on intranet applicable if this is a new guideline, enter below if extensive): Summary of evidence base this guideline has been created from: Evidence number 5 : expert committee reports or 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 15 GUIDELINES FOR THE GENETIC MANAGEMENT OF A FAMILY HISTORY OF COLORECTAL CANCER EXCLUDING FAP Aim That individuals at an increased genetic risk of colorectal and related cancers are offered appropriate evidence based care. Objectives 1. To achieve a consensus across our region 2. To ensure equity of service provision across the region. 3. To enable regional audit of the service. The population lifetime risk is around 1 in 16 in the UK. About 15-20% of new patients with colorectal cancer will have a family history of other affected relatives. About 1% of new cases of colorectal cancer will have FAP and 3-4% Lynch syndrome. Families who may be at increased risk of developing colorectal cancer and related cancers are identified on the basis of their family history of these cancers. These guidelines are for the management of patients with a family history of colorectal cancer who do not have FAP These guidelines include: A. Guidelines for referral of patients with a family history of colorectal cancer from primary care to a family history clinic. B. Guidelines for the management of individuals with a family history of colorectal and related cancers C. Guidelines for the use of tumour testing to assess risk D. Guidelines for assessing the significance of colorectal adenomas E. Heterozygote tumour risks in Lynch syndrome F. Guidelines for genetic testing of families with colorectal cancer G. Guidelines for genetic testing when there is a history of sebaceous neoplasm Page 2 of 15 A. GUIDELINES FOR REFERRAL OF PATIENTS WITH A FAMILY HISTORY OF COLORECTAL CANCER FROM PRIMARY CARE TO A FAMILY HISTORY CLINIC The family history of some patients may indicate that they are at increased risk of developing colorectal or related cancers. It may be helpful to refer these patients to a family history clinic to further assess their risk and for advice about appropriate management. Most hospitals now run a family history clinic under the auspices of the surgical unit or gastroenterology. Other cancers, which are important to include in the assessment of family history include endometrial, ovarian, renal pelvis, and ureteric or small bowel. Affected relatives should be in a first degree kinship ie they are first degree relatives of each other. At least one should be a first degree relative of the consultand if the consultand is unaffected. First-degree relatives (fdr) are parents, children, brothers or sisters. 1. Patients who DO NOT require referral and are at low risk 1 relative 1 fdr who developed colorectal cancer over the age of 50 2 relatives 2 first degree relatives (fdr) with an average age of colorectal cancer of greater than 70 (this includes where both parents are affected). Patients with the following family histories of cancer are at increased risk and require referral: 2. Refer to Local Screening Unit (Low-Moderate Risk): 1 relative 1 first degree relative (fdr) who developed colorectal cancer under the age of 50 2 relatives 2 relatives in a first degree kinship or both parents with an average age of colorectal cancer 60-70 3. Refer to Local Screening Unit (High-Moderate risk) 2 relatives 2 first degree relatives (fdr) on the same side of the family with colorectal cancer under the age of 60 3 relatives 3 or more close relatives on the same side of the family with colorectal, endometrial, ovarian, small bowel, ureteric or renal pelvis cancer. Page 3 of 15 B. GUIDELINES FOR THE MANAGEMENT OF INDIVIDUALS WITH A FAMILY HISTORY OF COLORECTAL AND RELATED CANCERS Screening recommendations for Low-moderate and High-moderate risk groups assume that MSI/IHC where performed is negative. Low Risk This group of patients do not require surveillance Low-Moderate risk Individuals at low-moderate risk have a modest increase in their colorectal cancer risk which equates to around a 1 in 12 life-time risk without screening. Current evidence suggests the following screening: 1 relative 1 fdr < 50: one colonoscopy at 55 or at first consultation, whichever is later. 2 relatives 2 relatives in a first degree kinship with an average age 60-70: one colonoscopy at 55 years or at first consultation, whichever is later. High-Moderate risk Individuals at high-moderate risk have an increase in their colorectal cancer risk which equates to around a 1 in 6 life-time risk without screening. Current evidence suggests the following screening: 2 relatives 2 relatives in a first degree kinship with an average age under 60 years: 5 yearly colonoscopy 50-75 yrs 3 relatives 3 relatives in a first degree kinship where no one affected is <50 years: 5 yearly colonoscopy 50-75 years High risk Individuals at high risk meet the Amsterdam or modified Amsterdam criteria and benefit from colonoscopy. Although colonoscopy has been shown to reduce colorectal cancer rate in patients with proven Lynch syndrome mutations and appears to be costeffective, surveillance of other organ systems has not yet been proven to be beneficial. Modified Amsterdam criteria 3 or more close relatives on the same side of the family with colorectal, endometrial, small bowel, renal pelvic or ureteric cancer. At least two successive generations are affected and one affected patient has had a cancer diagnosed at less than age 50. Page 4 of 15 The extracolonic cancers were chosen to provide a high mutation detection rate. The inclusion or exclusion of stomach cancer was debated and was not included in the final criteria. Hepatobilliary and brain (glioblastoma) were also excluded although these form part of the Bethesda criteria and therefore will often trigger MSI/IHC testing in the department. Screening for families with a mutation in a MMR gene or positive MSI/IHC (negative BRAF) suggestive of Lynch syndrome (affected and at 50% risk) Bowel: 18 monthly -2 yearly colonoscopy from 25 years for life. Screening age may be brought down if there has been a particularly young bowel cancer in a family Endometrium and ovary: Surveillance as recommended by local Gynaecologist from 35 years Some evidence that total abdominal hysterectomy with bilateral oopherectomy when childbearing is complete may improve outcome but balance of risks and benefits too close to justify a general recommendation and colonoscopy may subsequently become difficult Other: Gastric cancer – there is no established benefit to regular endoscopies and the risk is felt to be relatively low at 5%. The Mallorca group recommends screening for H.Pylori infection and eradication if found. Small bowel – currently the Mallorca group do not recommend surveillance. Urinary tract – the Mallorca group do not recommend surveillance. Studies have found the sensitivity of urine cytology to be low. Breast cancer – some studies have reported an increased risk of developing breast cancer which may or may not be confined to MLH1 carriers. At present women are recommended to take up the National Breast Screening Programme. Skin – there is no evidence base for screening for sebaceous adenomas or carcinomas. If there is a clinical evidence of these lesions, a family history or a mutation in MSH2 referral to a dermatologist for a one off assessment and advice can be considered. Page 5 of 15 Screening for families who fulfil the Modified Amsterdam criteria but are MSI/IHC/MMR gene negative Testing for other genes associated with bowel cancer should be considered depending on the histology and number of polyps in family members eg FAP, MYH. See guidelines for FAP for more details about these conditions. Screening should be reduced to 5 yearly if MSI/IHC is negative. Screening is usually offered from 35-75 unless there has been a younger cancer in the family when colonoscopies should start 5 years before the age of the youngest affected in the family. Screening for other cancers is not recommended if MSI/IHC is negative. Screening for families who are Amsterdam negative but MSI high (BRAF negative) and mutation has not been identified 3 yearly colonoscopy from 35 years for those affected and first degree relatives. If there is an endometrial cancer or loss of MSH6 on IHC discuss the pros and cons of referral to a gynaecologist if you have not been able to pursue genetic testing on lymphocyte DNA. Cases which are MSI high but where no mutation has been identified should be discussed with a consultant to consider alternative explanations. See section below about possibilities to consider where MSI is high but mutation testing is negative. Families where there are polyps In most cases the screening offered will be on the basis of the family history of cancer. 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 individuals have more than 10 adenomas identified, they will meet the diagnostic criteria for attenuated FAP and should be screened as such. They will qualify for additional genetic testing as per the flow chart. Page 6 of 15 C. GUIDELINES FOR THE USE OF TUMOUR TESTING TO ASSESS RISK The DNA mismatch repair complex functions as a spell-check system to repair errors occurring when DNA is replicated during cell division. In tumours that develop due to defective DNA mismatch repair, repetitive DNA sequences known as microsatellites have a tendency to undergo a high level of genetic alteration. High amounts of microsatellite instability (MSI) are found in nearly all the tumours that arise in individuals with Lynch syndrome and 15% of non-Lynch syndrome tumours. These latter tumours manifest either methylation of the MLH1 promoter or acquired mutation in the BRAF gene, which is absent in Lynch syndrome tumours. Immunohistochemisty (IHC) for MLH1, MSH2 and MSH6 allows targeted mutation analysis for the appropriate Lynch syndrome gene so these techniques are complimentary and help improve identification of families with an Lynch syndrome mutation. Strategies based on identification of patients suitable for tumour testing using the revised Bethesda guidelines have shown if MSI and loss of protein expression are identified, the postive predictive value of these results for an Lynch syndrome tumour is 29%, the negative predictive value if 99% and the overall accuracy is 98% compared to an overall accuracy of mutation prediction of 70% based on clinical criteria alone. Use of tumour testing is important as a recent study has clearly shown that in families who fulfil the Amsterdam criteria in whom MSI is not identified and IHC is normal, the mean age of diagnosis of colorectal cancer is older than in the patients with Lynch syndrome and the other tumours related to Lynch syndrome do not appear to occur and therefore surveillance for these tumours is not indicated. It has been suggested in this group of patients colonoscopy could start at a later age and would only be required 5 yearly. Tumour testing MSI should be offered to all families who fulfil the Revised Bethesda criteria or where there are two cases of CRC between 50-60 in a first degree kinship. Abnormal or inconclusive results are followed by IHC. Endometrial cancers are less likely to exhibit MSI and so if this is the only choice of tumour, IHC should also be requested. Dysplastic polyps are less likely to show MSI and tissue showing malignancy should be used when possible. Only polyps showing severe dysplasia should be analysed. If tumour tissue is not available, families who fulfil the modified Amsterdam criteria and in whom there is an affected relative from whom a DNA sample can be acquired, should be offered Lynch syndrome mutation analysis. MSI results can be used to determine screening intervals but normal MSI in tissues other than bowel tumours should be interpreted with caution and discussed with a consultant before decisions about screening intervals are made. Page 7 of 15 Abnormal tumour testing but normal mutation analysis Where MSI on tumour tissue is high and IHC shows abnormalities alternative explanations should be considered if mutation analysis is normal. Mutation analysis should be guided by IHC results. Cases should be discussed with a Consultant. EPCAM gene deletions account for 1-3% of all Lynch syndrome cases and lead to a high risk of bowel cancer (75% to the age of 70 years) and a low risk of endometrial cancer (12% to 70 years). Tumours are MSI high with loss of MSH2 and MSH6. The MLPA kit used in the lab for the last 3 years will detect these but review of testing should be considered in families who were tested before this. In tumours with high MSI and loss of MSH2 some individuals will have a 10Mb inversion on chromosome 2 (p21.1;22.2). This may be missed on routine cytogenetic analysis but should be detected if the laboratory are directed. Tumours which are MSI high and show loss of MLH1 and PMS2 have been seen with germline hypermethylation of the MLH1 promoter but this is an extremely rare mechanism. Testing can be requested via Northwick Park. Page 8 of 15 Revised Bethesda Criteria One affected individual: 1. Colorectal cancer diagnosed in a patient less than 50 years or 2. Two or more colorectal cancers in the same individual, or colorectal cancer and another tumour associated with Lynch syndrome* in the same individual, regardless of the age that each tumour was diagnosed. or 3. Colorectal cancer in a patient under 60 years of age, with histology suggestive of MSI-H (tumor-infiltrating lymphocytes, Crohn’s-like lymphocytic reaction, mucinous /signet-ring differentiation, or medullary growth pattern) Two affected individuals: 4. One individual with colorectal cancer, plus a first degree relative with colorectal cancer or Lynch syndrome-related tumour*, with one of the cancers diagnosed under age 50. Three affected individuals: 5. One individual with colorectal cancer, plus two first or second degree relatives with colorectal cancer or Lynch syndrome-related tumours* at any age. Additional referral criteria for Clinical Genetics/MSI: 6. Two relatives in a first degree kinship with bowel cancer at average age of 5060 years *Endometrial, ovarian, renal pelvis/ureter, gastric, small bowel, biliary tract, brain (usually glioblastoma as seen in Turcot syndrome), or sebaceous gland adenomas and keratoacanthomas in Muir–Torre syndrome. First-degree relatives (fdr) are parents, children brothers or sisters. Second degree relatives (sdr) include grandparents, grandchildren, aunts, uncles, nieces or nephews. Affected relatives should all be on the same side of the family, first degree relatives of each other and at least one should be a first degree relative of the individual being referred. Page 9 of 15 Algorithm for Laboratory Testing in Lynch syndrome (Lynch syndrome) Page 10 of 15 D. GUIDELINES FOR ASSESSING THE SIGNIFICANCE OF COLORECTAL ADENOMAS No No Does the patient meet the criteria for the in-house polyp panel? Yes CRC and ≥3 adenomatous polyps ≥5 adenomatous polyps <60 yrs ≥10 adenomatous polyps ≥60yrs In-house polyp panel including APC and MUTYH +ve -ve Manage as per guideline Does patient meet the criteria for Lynch syndrome testing? No Yes Bethesda criteria or 2 relatives in a first degree kinship with bowel cancer at average age 50-60 yrs Test as per protocol -ve +ve Manage as per guideline Page 11 of 15testing for mixed polyposis or hyperplastic polyposis if Consider diagnostic criteria fulfilled* * serrated polyposis syndrome - at least 5 serrated polyps proximal to the sigmoid colon, 2 of which are greater than 10 mm in diameter; (2) any number of serrated polyps occurring proximal to the sigmoid colon in an individual who has a firstdegree relative with serrated polyposis; and (3) more than 20 serrated polyps of any size distributed throughout the colon E. HETEROZYGOTE TUMOUR RISKS IN Lynch syndrome Tumours from the majority of Amsterdam criteria positive families are MSI postive. If mutation analysis is performed in MLH1, MSH2, PMS1 and PMS2 approximately 70% of patients will have a mutation. In CRC families who do not fulfil the Amsterdam criteria, 8-30% with have an MLH1 or MSH2 mutation. Cancer type Colon Endometrium Stomach Ovary Hepatobiliary tract Urinary tract Small bowel Brain/central nervous system Sebaceous neoplasms General Population risk 5.5% 2.7% <1% 1.6% <1% <1% <1% <1% Life time risk Mean age of onset 52-82% 25-60% 6-13% 4-12% 1.4-4% 1-4% 3-6% 1-3% 44-61 years 48-62 years 56 years 42.5 years Not reported 55 years 49 years 50 years <1% 1-9% Not reported Aamio et al (1999), Vasen et al (2001), American Cancer Society (2002), Hampel et al (2005), Ponti et al (2006), South et al (2008), Watson et al (2008), Barrow et al (2009), Stoffel et al (2009) MLH1 MSH2 MSH6 35-65% 35-75% Endometrial cancer 20-25% (women only) Ovarian cancer (women only) Bowel cancer 10-15% EPCAM Population Risk 20-70% (men) 15-20% 10-30% (women) 75% 6% 30-40% 25-70% 15% 15% 2% 10% Similar to population Similar to population 10% 1-2% From Royal Marsden guidelines Page 12 of 15 PMS2 Genotype/Phenotype Correlation Evidence is accumulating that the tumour risk for MLH1 and MSH2 may differ (Vasen et al (1996) Gastroenterology; 110: 1020-1027,Lin et al (1998) J Gastrointest Surg; 2: 6771, Vasen et al (2001) J Clin Oncol; 19: 4074-4080, Parc et al (2003) J Med Genet; 40:208-213). The lifetime risk of developing cancer at any site appears higher with MSH2 mutations. The risk of developing colorectal and endometrial cancer is increased in MSH2 heterozygotes compared to MLH1 heterozygotes. MSH2 heterozygotes have a significantly greater risk of developing urinary tract tumours (12%) compared to MLH1 heterozygotes (1.3%). In MSH6, the lifetime risk of CRC is 44% for men and 20% for women and 44% risk for endometrial cancer. It has been suggested that colonoscopy may be commenced from 30 in individuals from MSH6 families. In this region we have elected to keep bowel screening the same for all Lynch syndrome genes starting at 25 years. Metachronous Tumours Approximately 90% lifetime risk of a second colonic malignancy after one tumour resection (25% at 14 years, 50% at 20 years) Approximately 80% lifetime risk of developing a colonic cancer after an endometrial cancer (Parc et al (2003) J Med Genet; 40:208-213) F. GUIDELINES FOR GENETIC TESTING OF FAMILIES WITH COLORECTAL AND RELATED CANCERS. Patients with colorectal cancer who fall into the high-risk group who fulfil the Amsterdam criteria can be offered genetic testing in order to try and identify a mutation in one of the Lynch syndrome genes. Patients who undergo genetic testing must: 1) Be referred to the Clinical Genetics department 2) Receive genetic counselling about the implications of a positive result 3) Give informed, written consent for the test. 4) If terminally ill, blood can be taken by the referring physician for DNA storage and genetic counselling and discussion of testing can be performed at a later stage but the patient must identify a family member to whom the result can be given Criteria for a diagnostic genetic test 1) Individual has either colorectal or related cancer. 2) Individual comes from a high risk family that fulfils the modified Amsterdam Criteria. Every effort should be made to confirm the diagnoses using the available resources including hospital and GP notes and the cancer registry. 3) Tumour testing will be performed on patients fulfilling the Bethesda criteria or with 2 CRCs between 50-60 in a first degree kinship where samples are available. A subset of patients fulfilling the Bethesda criteria will go forward for Lynch syndrome molecular testing Once a mutation has been identified in an individual a predictive genetic test can be offered to unaffected at-risk individuals within the family. Page 13 of 15 Criteria for a predictive genetic test 1) Individual should be over 16 but in practice it is rare for testing to be requested below 18 years. 2) They should receive genetic counselling prior to the blood being taken which should include screening options discussion of prophylactic hysterectomy and oopherectomy in women who have completed their families insurance issues G. GUIDELINES FOR GENETIC TESTING WHEN THERE IS A HISTORY OF SEBACEOUS NEOPLASM For individuals referred with a sebaceous neoplasm the Mayo Muir-Torre syndrome risk score algorithm below should be used. Abnormal IHC on a sebaceous neoplasm is a poor predictor of Lynch syndrome. Those with a score of ≥ 2 should be offered molecular genetic testing. Variable Age at sebaceous neoplasm diagnosis 60 or older Younger than 60 Total number of sebaceous neoplasms 1 2 or more Personal history of any Lynch related cancer No Score 0 1 0 2 0 Yes 1 Family history of any Lynch related cancer No 0 Yes 1 Page 14 of 15 References 1. Guidance on Commissioning Cancer Services. 2. Cole TRP & Sleightholme HV (2000) BMJ; 301:366-368 3. Vasen HFA, et al (1998) Cancer; 82(9); 1632-1637 4. Jarvinen HK et al (1995). Gastroenterology; 108:1405-1411 5. Burke et al (1997) JAMA; 277 (11); 915-919 6. Cannon-Albright LA et al (1994) American Journal of Gastroenterology; 89(6): 827-831 7. Lindor et al (2006) JAMA; 296 :1507-1517 8. Pinol et al (2005) JAMA; 293:1986-1994 9. Hendriks et al (2004) Gastroenterology; 127:17-25 10. Lindor et al (2005) JAMA; 293:1979-1985 11. Watson et al (2008) Int J Cancer;123(2):444-449 12. GeneClinics : Lynch syndrome 2011 13. Cairns et al (2010)Gut ;59 :666-689 14. Kempers et al (2011) Lancet Oncol ;12 :49-55 Author: Dr N L Shannon, Clinical Genetics Service 6/11/15 Review Date: November 2017 Version 2 Page 15 of 15