Lynch syndrome (LS) Hereditary Non-polyposis Colorectal Cancer (HNPCC) Developed by Dr. June Carroll , Dr. Judith Allanson, Ms. Shawna Morrison and Ms. Safa Yusuf Last updated June 2018

Disclaimer This presentation is for educational purposes only and should not be used as a substitute for clinical judgement. GEC-KO aims to aid the practicing clinician by providing informed opinions regarding genetic services that have been developed in a rigorous and evidence-based manner. Physicians must use their own clinical judgement in addition to published articles and the information presented herein. GEC-KO assumes no responsibility or liability resulting from the use of information contained herein.

Objectives Following this session the learner will be able to: Refer to their local genetics centre and/or order appropriate genetic testing for Lynch syndrome (LS) Discuss and address patient concerns regarding family history of LS Find high quality genomics educational resources appropriate for primary care We recommend that this module be used in conjunction with more detailed GEC-KO resources including the Lynch syndrome Messenger and on the run.

What is Lynch Syndrome? Lynch syndrome (LS), also known as Hereditary Non-Polyposis Colorectal Cancer, (HNPCC), is an inherited cancer predisposition syndrome Individuals with LS have a greatly increased risk for certain cancers 1 - 3% of CRC is attributable to LS LYNCH SYNDROME-RELATED CANCERS  ü Colorectal cancer ü Endometrial ü Kidney ü Gastric ü Ovarian ü Ureter ü Small bowel ü Hepatobiliary ü Pancreatic ü Brain ü Sebaceous (adenoma or carcinoma)  

Five facts about Lynch Syndrome 1. Genetics of Lynch Syndrome Autosomal Dominant Reduced penetrance and variable expressivity not all individuals who inherit a mutation in a LS gene will develop cancer (reduced penetrance) type and onset of cancer will vary between affected family members (variable expressivity) Caused by an inherited mutation in at least one of five mismatch repair genes (MLH1, MSH2, MSH6, PMS2, EPCAM)  Mismatch repair genes play an important role in a cell’s ability to repair DNA damage as a cell grows and divides by identifying and removing single nucleotide mismatches, insertions and deletion loops. Defects in the MMR pathway lead to an accumulation of mutations in a cell which may result in a malignancy   About 1 in 440 individuals are estimated to have a mutation in a Lynch syndrome gene

Five facts about Lynch Syndrome 1. Genetics of Lynch Syndrome 2. Who should be offered referral to genetics for possible genetic testing? Colorectal cancer (CRC) diagnosis at an early age (<50) – higher suspicion if <35years Endometrial cancer diagnosis at an early age (<50) Multiple primary LS-related cancer diagnoses, regardless of age A CRC diagnosis and one or more 1st degree relatives with a LS-related cancer, with one of the cancers diagnosed <50 yrs A CRC diagnosis and two or more 1st or 2nd degree relatives with LS- related cancers regardless of age

Reflex (automatic) testing of tumors for markers of Lynch Syndrome CRC tumor No tumor markers Analysis for tumor markers suggestive of LS Tumor markers No further testing The algorithm for LS testing ideally begins with immunohistochemical (IHC) analysis of a CRC tumour (it is possible to test other tumour types if a CRC tumour is not available) for the most common proteins associated with LS (MLH1, MSH2, MSH6 and PMS2). MSI: An important concept in LS pathology A microsatellite is an area of DNA with a repetitive sequence (i.e. CGCGCGCGC or GAAGAAGAA) These stretches of DNA are susceptible to acquiring errors when a mutation in a MMR gene is present Cancer arising as the result of a defective MMR gene exhibits an inconsistent number of microsatellite repeats when compared to normal tissue - this is called microsatellite instability (MSI) Approximately 90% of CRCs occurring in individuals with Lynch syndrome exhibit high MSI. Approximately 15% of sporadic cancers (not associated with LS) also exhibit high MSI. Genetic testing on blood sample on affected individual

Hereditary cancer panel results True Negative: familial pathogenic variant not found Reassurance Negative Uninformative: no known pathogenic variant found Family/personal history based screening Positive Pathogenic or likely pathogenic variant Guideline-based screening & management Family/personal history based screening Variant of Uncertain Significance (VUS) Uninformative: Neither confirms nor rules out hereditary cancer predisposition Periodic reclassification

Five facts about Lynch Syndrome 1. Genetics of Lynch Syndrome 2. Who should be offered referral to genetics for possible genetic testing? 3. How is genetic testing done? 4. What is the significance of a positive genetic test for LS? Increased risk of cancer

Cancer Risk to Age 70 in Individuals with Lynch Syndrome Compared to General Population Pop Risk MLH1 or MSH2 MSH6 Risk Mean age at onset Colon 4.5% 52-82% 44-61 10-22% 54 Endometrium 2.7% 25-60% 48-62 16-26% 55 Stomach <1% 6-13% 56 ≤3% 63

Five facts about Lynch Syndrome 1. Genetics of Lynch Syndrome 2. Who should be offered referral to genetics for possible genetic testing? 3. How is genetic testing done? 4. What is the significance of a positive genetic test for LS? 5. How might genetic testing benefit your patient?

Five facts about Lynch Syndrome 5. How might genetic testing benefit your patient? Positive result Clinical intervention may improve outcome Modify cancer surveillance options and age of initial screening Clarify and stratify family members’ cancer risk Identify at risk family members True negative result Avoid unnecessary clinical interventions Emotional relief, children can be reassured

Harms or limitations of genetic testing Positive result: Adverse psychological reaction Family issues/distress Uncertainty -incomplete penetrance Intervention may carry risk Discrimination Job, insurance Privacy, confidentiality True negative: Adverse psychological reaction (i.e. survivor guilt) Complacent attitude to health Uncertain result: Uncertainty Continued anxiety

Screening and surveillance For high risk individuals with MLH1 or MSH2 mutations and their first degree relatives who have not had genetic testing: Colon Cancer Colonoscopy every 1-2 years beginning between ages 20 and 25 or 2-5 years prior to the earliest diagnosis if that diagnosis was made before age 25 years, whichever is earlier Endometrial and Ovarian cancer There is no specific screening for endometrial or ovarian cancer Educate women about symptoms of endometrial cancer Prophylactic hysterectomy and bilateral salpingo-oophorectomy is a risk-reducing option that women who have completed childbearing can consider Other Extracolonic cancers Family history dependent

Screening and surveillance For intermediate risk individuals 1st degree relative with CRC age <60 or Two 1st degree relatives with CRC any age Colonoscopy beginning at age 40 or 10 years younger than earliest diagnosis of CRC 1st degree relative with CRC>60 or 2nd or 3rd degree relatives Colonoscopy beginning age 50 or 10 years younger than earliest dx of CRC

Screening and surveillance For patients who have a true negative result Provincial guidelines for population risk CRC screening should be followed i.e. Fecal Occult Blood Test every two years from age 50 For patients with an uninformative result or a VUS Recommendations will be based on a combination of factors, such as family history and, in cases where a VUS was identified, information about the VUS

Camille is a 37 year old woman Camille is a 37 year old woman. She is healthy, but reports that her mother was diagnosed in the past year with uterine cancer at age 58. When you take the family history, she tells you her brother had two colon cancers in his 30s and her paternal aunt had breast cancer at age 70. What are the red flags in Camille’s family history about which you should be concerned? Early onset cancer Multiple relatives with the same or associated cancers on the same side of the family Multiple cancer diagnoses in the same person All of the above None of the above

Camille is a 37 year old woman Camille is a 37 year old woman. She is healthy, but reports that her mother was diagnosed in the past year with uterine cancer at age 58. When you take the family history, she tells you her brother had two colon cancers in his 30s and her paternal aunt had breast cancer at age 70. What are the red flags in Camille’s family history about which you should be concerned? Early onset cancer Multiple relatives with the same or associated cancers on the same side of the family Multiple cancer diagnoses in the same person All of the above None of the above

Jane, 26 Dx 38 CRC Dx 40 Ca-Endometrial Dx 52 Dx 45 CA Endometrial Dx 68 CRC Dx 56 Dx 72 CA Kidney Dx 66 CA- Br MI 72 Accident Nat Causes Stroke A&W Jane is considering genetic testing for Lynch syndrome. Which of the following is true? One of Jane’s relatives with cancer has to have a positive genetic test result before Jane is eligible for provincially funded genetic testing for LS. Jane should have CRC screening with colonoscopy beginning at age 40 regardless of genetic testing. If Jane tests positive for one of the mutations associated with CRC, she will develop endometrial cancer at some point in her life. Jane couldn’t be carrying a mutation for LS because her father hasn’t had cancer. None of the above.

Jane, 26 Dx 38 CRC Dx 40 Ca-Endometrial Dx 52 Dx 56 Dx 72 CA Kidney Dx 66 CA- Br MI 72 Accident Nat Causes Stroke A&W Dx 45 CA Endometrial Dx 68 CRC Jane is considering genetic testing for Lynch syndrome. Which of the following is true? One of Jane’s relatives with cancer has to have a positive genetic test result before Jane is eligible for provincially funded genetic testing for LS. Jane should have CRC screening with colonoscopy beginning at age 40 regardless of genetic testing. If Jane tests positive for one of the mutations associated with CRC, she will develop endometrial cancer at some point in her life. Jane couldn’t be carrying a mutation for LS because her father hasn’t had cancer. None of the above.

Where do I find more information? www.geneticseducation.ca Check with your local genetics clinic about how testing may be organized