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  • Slide 1 : Title
  • Slide 2 : Acknowledgements Health care providers must use their own clinical judgment in addition to the information presented herein. The authors assume no responsibility or liability resulting from the use of information in this presentation.
  • Slide 3 : Outline
  • Slide 4 : Cancer 1 All cancer is genetic because it is caused by an accumulation of mutations (gene changes) in local cells that leads to tumour development. Threshold effect: During the cell cycle, as the cell goes through DNA replication and mitosis, mistakes or mutations occur in the cell’s genetic code. These mistakes are normally corrected by a class of genes known as DNA mismatch repair genes. Our cells have a series of checks and balances to maintain the rate of new cell growth and cell death. This balance is maintained by several classes of genes: tumour suppressors, oncogenes and DNA mismatch repair genes. A cell accumulates mutations either by chance or environmental exposures or due to an inherited defect in the normal DNA repair system. When there are too many changes in the cell’s genetic code, the cell is unable to repair the mutations and/or regulate cell growth. At this point, irreversible changes in the cell’s DNA lead to an atypical cell - with uncontrolled proliferation, this can lead to the development of a tumor.
  • Slide 5 : Sporadic Cancer In cases of sporadic cancer, mutations in the genes that regulate and maintain the cell cycle and DNA integrity occur after birth Colorectal cancer (CRC) is multifactorial – it is caused by the interaction of many factors such as age, lifestyle, environmental exposures, genetic or chance/unknown factors. Sporadic cancer generally has a later onset (after 50 years of age) than inherited cancer.
  • Slide 6 : Clustering of Cancer in Families Approximately 20% of people with CRC have a family history. ~ 15 % of CRC is familial – these people have a first- or second-degree relative who has also been diagnosed with CRC. These cases could be due to: Common (unidentified) susceptibility genes Common environment exposures Common lifestyle Chance: Approximately 1 in 14 or 7% of Canadian men and 1 in 6 or 6 % of Canadian women will develop CRC in their lifetime. 2 ~ 5 % of CRC is hereditary – in these cases a person is born with an inherited predisposition to cancer. Majority is hereditary nonpolyposis colorectal cancer (Lynch syndrome) and <1% is due to familial adenomatous polyposis (FAP). 3,4,5 Others include rare genetic syndromes associated with an increased risk of cancer.
  • Slide 7 : Proportion of colorectal cancer due to sporadic or inherited factors Graph: Sporadic: 80% Familial: 15% Hereditary 5%: Lynch syndrome 2-5% and FAP <1%
  • Slide 8 : Knudson’s ‘Two-Hit’ Hypothesis – Sporadic Cancer 1, 6 Knudson proposed the existence of cancer susceptibility genes that are inherited in an autosomal dominant manner. For sporadic cancer; susceptibility genes are normal or non-mutated at birth. Throughout a person’s lifetime they may acquire a ‘hit’ or a mutation in a cancer susceptibility gene. Later in life if a person is exposed to a second ‘hit’ or mutation in a cancer susceptibility gene, this can lead to cancer. These acquired mutations are somatic; they are not present in every cell and are not inherited.
  • Slide 9 : Knudson’s ‘Two-Hit’ Model – Inherited Cancer Predisposition 1, 4 If a person is born with a germline mutation in a cancer susceptibility gene; they are born with one ‘hit.’ Germline mutations are present at conception and are in every cell of the body and can be inherited. So in the case of inherited colorectal cancer syndrome, the first hit is inherited in an autosomal dominant manner and is present in every cell in the body. The second ‘hit’ is a somatic mutation – a mutation present only in the cell that acquired this mutation. So in the case of inherited colorectal cancer syndrome the second hit is not inherited and occurs by chance in a single cell – possibly due to exposure to an environmental toxin etc. If a person has inherited a mutation in a cancer predisposition gene like the genes involved in Lynch syndrome or FAP, generally the age of onset of cancer is earlier, as it would take less time to acquire a second ‘hit’ than someone who has cancer due to two random (somatic) hits.
  • Slide 10 : Compared to sporadic cancer hereditary cancer has… Sporadic and hereditary cancers have different genetic pathways leading to the development of cancer. This leads to general differences in their clinical presentation.
  • Slide 11 : Inherited Colorectal Cancer Lynch syndrome Estimated prevalence (number of cases of a disease existing in a given population at a specific period in time): 1 in 3,000 7 (this may be an under estimate) Founder effect in Newfoundland, Italian-Quebec families, Danish and Finnish. 3 Familial Adenomatous polyposis (FAP) Estimated prevalence 1 in 8,000 – 14,000 8
  • Slide 12 : Autosomal Dominant Inheritance All of the susceptibility genes for Lynch syndrome are inherited in an autosomal dominant pattern, meaning that only 1 abnormal copy of the Lynch syndrome genes is needed to increase an individual’s predisposition to colon, endometrial and other Lynch syndrome spectrum cancers. The APC gene that causes FAP is also inherited in an autosomal dominant manner; this gene is ~100% penetrant meaning that virtually everyone who inherits the gene will develop colon cancer. The capital “B” in this diagram is the cancer predisposition mutation. The normal copy of the gene is represented by the lower case “b”. There is a 50:50 risk for an affected parent to pass on this mutation to their children of either sex.
  • Slide 13 : Colorectal cancer genes… when mutated Lynch syndrome: Mutations in DNA repair genes lead to an accumulation of somatic mutations that may result in malignancy. The nature of mutated DNA repair genes leads to microsatellite instability in the tumour, which can be diagnosed on pathological examination. This is a hallmark of Lynch syndrome. Microsatellites are repetitive segments of DNA. Microsatellite instability is the presence of a discrepancy between the size of microsatellites in DNA from tumour tissue compared to non-tumour tissue from the same person. For more information on microsatellites see ‘Extra Slides’ at the end of this slide show. 90% of CRC tumours from Lynch syndrome patients show microsatellite instability compared with only 10-15% of sporadic cancers. 9 Some groups have proposed that all tumours showing microsatellite instability should be screened for the common Lynch syndrome mutations. 10
  • Slide 14 : Hereditary Nonpolyposis Cancer (Lynch syndrome) Lynch syndrome genetically heterogeneous - 4 genes: MLH1 & MSH2 (most common), MSH6 & PMS2 Research testing may be available for other genes Autosomal dominant High penetrance 70-80% Prentrance is the proportion of individuals with a mutation causing a disorder who exhibit symptoms of the disorder Characterized by: 11 Early onset of diagnosis (average age 45 rather than 69) 12 More aggressive adenomas More proximal or ‘right sided’ CRC tumours (70% before splenic flexure) Tumours show microsatellite instability on pathology exam Risk for extra-colonic tumours
  • Slide 15 : Cancer Risk in Individuals with Lynch syndrome to Age 70 Compared to the General Population 12-19 Mutations in MSH2 are more often associated with extra-colonic cancer than mutations in MLH1 . Families who have mutations in MSH6 may have an excess of endometrial cancer compared to colon cancer. Note transitional cell (urothelial) cancer is the specific subtype of renal cancer that is associated with Lynch syndrome. The figures in this chart are based on studies of high-risk families. A recent study of low risk families proposes that the risk for colorectal cancer and endometrial cancer is much lower than previously reported. In this study, the risk for colorectal cancer in men by age 70 was 27%, for women 22% and the risk for endometrial cancer was 32%. 20 In addition to family history, other factors that affect a mutation carrier’s risk of developing cancer include: Variable penetrance – Some Lynch syndrome mutation carriers may never get cancer. FAP is virtually ~100% penetrant. Environmental & genetic modifiers Nature of the mutation Variable age of onset – Some may develop cancer very early i.e. 30’s, others may have a late onset i.e. after age 50
  • Slide 16 : Familial Adenomatous Polyposis 8 High penetrance ~100% for classic FAP
  • Slide 17: Consequences of FAP (1) 8
  • Slide 18 : Consequences of FAP (2) 21 Other: osteomas, dental abnormalities, congenital hypertrophy of the retinal pigment epithelium (CHRPE)
  • Slide 19 : Red Flags for hereditary colorectal cancer – consider referral to Genetics 22 A good reference for referral criteria to hereditary cancer clinics and criteria for genetic testing: Predictive Cancer Genetics Steering Committee. Ontario physicians’ guide to referral of patients with family history of cancer to a familial cancer genetics clinic or genetics clinic. Ontario Medical Review 2001; 68(10):24-29. Please note these guidelines are currently under revision
  • Slide 20 : Risk of developing colon cancer 23,24 Taking an accurate family history is important to determine your patient’s risk of many common conditions like CRC. Data in this chart was derived from meta-analyses of case control and cohort studies, u sing data from cancer family clinic patient populations. 26
  • Slide 21 : Case: Jane Demographics
  • Slide 22 : Case continued
  • Slide 23 : Case: Jane’s family history Family history –3-generations, note both affected and unaffected family members, age at diagnosis, current age and whether affected members alive or deceased. Note that circles denote females, squares denote males, and joining lines indicate a relationship such as spouse or sibs and a diagonal line means deceased. Jane, a 26 year-old woman indicated by the arrow, is your patient; her mother was diagnosed with breast cancer at 66, no other known cases of cancer on her mother’s side of the family. Jane’s father’s family: 1 uncle diagnosed with transitional cell/kidney cancer at 72 and a second uncle diagnosed with CRC at 56. An aunt with 2 primary cancers: one endometrial cancer at 45 and colon cancer at 68. Two of Jane’s first cousins were diagnosed with CRC and a third with endometrial cancer. Drawing a pedigree assists in determining relationships i.e. are all affected on same side of family? This family has four members affected with colon cancer in two generations, two of which were diagnosed <50 years of age plus two additional members with Lynch syndrome – associated cancers.
  • Slide 24 : Jane was referred to genetics…. A genetics consultation involves 1 History: The patient’s family medical and exposure history may be taken by phone prior to the genetic counselling session; some genetics clinics might send the patient a detailed questionnaire by mail. This allows for patients to contact family members and clarify cancer diagnosis, age of onset and helps to obtain accurate family history information. It is important to confirm family members’ diagnoses of cancer with pathology reports as the patient’s reported cancer site may turn out to be in a different organ/location. Risk assessment: Based on the information collected, the patient will receive estimation of his/her risk of carrying a mutation in one of the Lynch syndrome genes. Population risks and Lynch syndrome carrier risks for cancer will also be discussed. Genetic testing has implications not only for the patient’s health but also for their psychological well-being, insurability and for their family members. Therefore a psychological assessment is an important part of offering genetic testing. Assessing the patient’s interest, motivation and readiness for genetic testing Does the patient have the coping skills to deal with the results; do they have a support system? A history of psychological issues? Has the patient considered the impact on family members? Is the patient psychologically prepared to undergo testing?
  • Slide 25 : A genetics consultation involves 2 Eligibility: The family history is analysed to determine which family member should be offered testing first. The family member with the highest likelihood of carrying a mutation in one of the Lynch syndrome genes is the family member who should be offered genetic testing first. This would usually be the youngest family member diagnosed with cancer. In Jane’s case this would be her paternal aunt with both colon and endometrial cancer. The genetic testing procedure is described as well as the risks, benefits and limitations of testing. Screening recommendations given for patient and relatives regardless of genetic testing eligibility and regardless of whether they proceed with testing Management recommendations are made following disclosure of results.
  • Slide 26 : Recommendations for Jane’s family The history of cancer in Jane’s father’s family is suggestive of Lynch syndrome. Note the multiple cases of early onset colon cancer and her paternal aunt with two primary cancers - endometrial and colon. The most appropriate person in Jane’s family to offer genetic testing would be Jane’s aunt who has been diagnosed with two primary cancers. If her aunt does not agree to genetic testing then the youngest affected member would be the next person to approach. If a mutation is identified in one of Jane’s family members then sequential testing of the family can proceed. Jane’s father can be tested and then Jane if he tests positive. If Jane’s father tests negative then there is no reason to offer Jane testing as she would not be at risk to carry a mutation. If no mutation is identified then the family is still at increased risk for colon and possibly other Lynch syndrome spectrum cancers. Cancer screening recommendations: Colonoscopy q1-2 years Consider referral to a gynecologist to discuss endometrial screening
  • Slide 27 : Results from Genetic Testing POSITIVE: a deleterious mutation has been identified. Your patient should be following high risk screening recommendations for colon cancer and for endometrial and ovarian cancer. Consider referral for psychological support to help adjust to the diagnosis If they have colon cancer then they are at risk for a second primary -either a second colon cancer or, in the case of Lynch syndrome, other related cancers. Patients with FAP should consider risk-reducing surgery. NEGATIVE: interpretation depends on whether or not a deleterious mutation has been previously identified in the family. If a deleterious mutation has been previously identified in the family, then this is the best result - a true negative - and your patient should follow population screening recommendations for colon cancer as they are still at risk for sporadic cancer. If no deleterious mutation has been previously identified and your patient has cancer then the results are uninformative. There may be a mutation in APC gene or the Lynch syndrome genes that is not detectable by the current technology. The family history of cancer may be caused by a yet to be discovered gene. The family history of cancer may be due to chance or common environmental factors. The family may have a rare genetic syndrome that has an associated increased risk for cancer. VARIANT OF UNKNOWN SIGNIFICANCE: It is not known if the changes identified in your patient’s DNA are harmful or benign. A patient may carry a variation in their APC gene or Lynch syndrome genes. The variation may be a harmless polymorphism – a change in genetic code that will not alter the function of the APC or Lynch syndrome proteins and therefore will not cause an increased risk for cancer but; The patient still has an increased risk for cancer based on family history. The family history of cancer may be caused by a yet to be discovered gene. The family history of cancer may be due to chance or common environmental factors The variant may really be a harmful mutation causing a predisposition to cancer. Studying other family members with cancer to see whether or not the mutation is tracking with cancer in the family may provide clarification for this family. For example if the variant is NOT found in a family with cancer then the variant may not be harmful. The clinical significance of these variants may be clarified with further research. Patient should still follow high risk screening recommendations. The false positive rate of genetic testing for Lynch syndrome is equal to the rate of sample mix up ~<1 in 10,000 and the false negative rate is very low .
  • Slide 28 : Potential Risks/Benefits/Limitations of Genetic Testing 1 Positive Result: Benefits Explains the pattern of cancer in the family and provides clinical information. Clinical intervention may improve outcome (specific guidelines will be listed later) Family members at risk can be identified and offered testing May benefit from more intensive screening or clinical intervention if positive Positive health behaviour can be reinforced Reduces uncertainty – can move forward acceptance of the disease and consider options for management Positive Result: Risks Adverse psychological reactions Anxiety, depression, grief, isolation, loss of control Guilt or shame for passing it on to their children Fear of disfigurement, of becoming a burden, of dying Fatalistic attitude toward health Family issues – some members may not want this information Uncertainty - incomplete penetrance- some mutation carriers will never develop cancer Unnecessary anxiety, interventions etc. Possible discrimination: insurance, employment Confidentiality issues Surgical intervention (if taken) carries risk
  • Slide 29 : Potential Risks/Benefits/Limitations of Genetic Testing 2 Negative Result: Benefits Avoidance of unnecessary clinical interventions i.e. no need to consider risk reducing surgery (colectomy). Emotional - relief Children can be reassured Negative Result: Risks If a mutation was previously identified in the family and the patient’s result is negative, this is the best possible outcome. However the patient may still have adverse psychological reactions (uncommon): Survivor guilt, isolation Family dynamics – the patient may not feel they ‘belong’ to or feel accepted by the disease group (other family members who are at high risk for cancer and are acting as support for the other high-risk family members). Patients may feel that their risk of developing cancer is zero and may be reluctant to participate in screening. – may become complacent
  • Slide 30 : Potential Risks/Benefits/Limitations of Genetic Testing 3 Uninformative result: Benefits Some patients may experience relief that they do not carry a definite mutation. For others, the uncertainty may cause stress. Uninformative result: Risks Some patients may wish to continue high-risk screening or opt for surgical interventions. Patient might stop taking an active role in their health care Adverse psychological reactions – fear of uncertainty, frustration, family dynamics
  • Slide 31 : What is the benefit to the patient of having genetic testing? 1 Can anything be done to change risk/outcome? Canadian Association of Gastroenterology and the Canadian Digestive Health Foundation: Guidelines on colon cancer screening: 25 Lynch syndrome: Colonoscopy every 1-2 years beginning at age 20 or 10 years younger than the earliest case in the family, whichever comes first. Patients with Lynch syndrome : European guidelines from an evidence based review followed by a workshop in 2006 recommend: 26 Screening for CRC should begin between 20 and 25 years. The upper age limit of colonoscopy screening should depend on the patient’s general health and should be made on an individual basis. The optimal interval between colonoscopy is every 1 to 2 years.
  • Slide 32 : What is the benefit to the patient of having genetic testing? 2 Can anything be done to change risk/outcome? US Cancer Genetic Studies Consortium Recommendations: 11 Full colonoscopy to the cecum is recommended every 1 – 3 years beginning age 25 years. Studies show a 65% reduction in mortality from CRC with regular colonoscopies in mutation positive individuals. 27 British study of patients at moderate and high risk for colon cancer based on family history: 28 Lynch syndrome patients with colonoscopies every 1 to 3 years had an estimated 72% reduction in mortality. Individuals at moderate risk for colon cancer with colonoscopies at 5 year intervals had an 81% reduction in mortality. Other cancers: There is no evidence to support screening for other cancers. Annual screening for endometrial cancer beginning at age 25 to 35 years has been suggested. The optimal method of screening has not been determined – choices include endometrial aspirate or transvaginal ultrasound. – no evidence for benefit at this time 11 Other surveillance: ovarian cancer screening (serum CA-125 and transvaginal ultrasound) – no evidence of benefit at this time 11 Other groups have recommended screening for Lynch syndrome associated tumours based on family history of those specific cancers. For a history of gastric cancer - screening can be done with esophagogastroduodenoscopy, for those with a history of cancer of renal pelvis or ureter - screening includes urinalysis, urine cytology, cytoscopy and ultrasound to evaluate the upper uroepithelial tract. 29
  • Slide 33 : What is the benefit to the patient of having genetic testing? 1 Can anything be done to change risk/outcome? European guidelines from and evidenced based review followed by a workshop in 2006 recommend at age 30 to 35 years: 26 Gynecological examination Trans-vaginal ultrasound and aspiration biopsy Category of evidence III, grade C The value of surveillance for endometrial cancer is unknown Consider prophylactic hysterectomy and bilateral salpingo-oophorectomy to reduce site specific cancers grade C
  • Slide 34: What is the benefit of genetic testing? 30 Can anything be done to change risk /outcome ? Screening for endometrial cancers
  • Slide 35: What is the benefit of genetic testing? Can anything be done to change risk outcome? Evidence for risk reducing surgery: 31 While no peritoneal cancers were detected in the study period; the risk for peritoneal cancer is approximately 1% in BRCA1/2 mutation carriers after BSO – it is unknown if the risk for peritoneal cancer is comparable for women with Lynch syndrome following BSO.
  • Slide 36: What is the benefit of genetic testing? Can anything be done to change risk /outcome? Lynch syndrome other cancers: 32 Less commonly other cancers are associated with Lynch syndrome. Screening is only recommended for these cancers if there is a family history of these cancers with the Lynch syndrome mutation: Skin cancer screening via dermatology exam Small bowel cancer screening via capsule endoscopy Pancreaticobiliary tumour screening via endoscopic ultrasound
  • Slide 37 : What is the benefit to the patient of having genetic testing? 3 8,21 Can anything be done to change risk/outcome? Canadian Association of Gastroenterology and the Canadian Digestive Health Foundation: Guidelines on colon cancer screening: 25 FAP: Sigmoidoscopy annually beginning at age 10-12 years. Attenuated FAP: Colonoscopy annually beginning at age 16-18 years. Patients with FAP: Non-steroidal anti-inflammatory drugs (NSAIDs).  Some NSAIDs have been shown to cause regression of adenomas in FAP and to decrease the number of polyps requiring ablation in the remaining rectum of persons who have had a subtotal colectomy. NSAID use before colectomy remains experimental.
  • Slide 38 : Management of Mutation Carriers – Psychological 1 Offer referral to a psychologist, nurse-counsellor Help patient adjust to new information Counselling can assist the patient make the best management decision for their situation and can help them adjust to their decision. i.e. adjustment to surgical menopause after oophorectomy. Address emotional issues: self concept, guilt at having passed on mutation to children, dealing with risk of cancer. Stress management Offer referral to support group Nutritional assessment - some women feel the need to take control of their lives – some feel a sense of control by modifying their life style to include healthy eating and exercise.
  • Slide 39 : Management of Mutation Carriers – Psychological 2 Women who test positive or negative for a Lynch syndrome mutation may benefit from additional support in these situations: History of depression or anxiety Poor coping skills Multiple losses – particularly from cancer Loss of a parent at a young age Recent loss Multiple surgical procedures
  • Slide 40 : Resources
  • Slide 41 : Case Examples
  • Slide 42 : Assessing the Risk of Hereditary Colorectal Cancer These case examples are designed to accompany the Canadian Cancer Society Hereditary Colorectal Cancer triage/management cards. To order triage cards (at no cost), contact your local chapter of the Canadian Cancer Society. For the pedigrees: the arrow denotes “Your Patient”, shaded circles or squares denote family members affected with cancer – for the specific type of cancer see the legend.
  • Slide 43 : Case 1 Pedigree: Your patient’s mother diagnosed with colon cancer at 34 years of age.
  • Slide 44 : Case 1 Answer: Moderate risk for hereditary CRC
  • Slide 45: Case 1 Management
  • Slide 46 : Case 2 Pedigree: One 1st degree relative with colon cancer diagnosed at 50. One second-degree relative diagnosed with colon cancer 50 years. One third-degree relative with Lynch syndrome-related cancer (endometrial) diagnosed <50 years.
  • Slide 47 : Case 2 Answer: High risk for hereditary CRC
  • Slide 48 : Case 2 Management
  • Slide 49 : Case 3 Pedigree Your patient has Crohn’s disease One 2nd degree relative with colon cancer >50 years
  • Slide 50 : Case 3 Answer: Low risk for hereditary CRC but still at increased risk of CRC
  • Slide 51: Case 3 Management
  • Slide 52 : Case 4 Pedigree One 2nd degree relative with colon cancer >50 years One 3rd degree relative with colon cancer >50 years
  • Slide 53 : Case 4 Answer: Population risk for CRC
  • Slide 54 : Case 4 Management
  • Slide 55 : Case 5 Pedigree One maternal 2nd degree relative with colon cancer >50 years. Two paternal 2nd degree relatives with lung cancer (smoker) and mesothelioma (smoker) 50 year.
  • Slide 56 : Case 5 Answer Population risk for CRC
  • Slide 57: Case 5 Management
  • Slide 58 : Case 6 Pedigree: One 1st degree relative with >1000 polyps <50 years One 2nd degree relative with lung cancer (smoker)
  • Slide 59 : Case 6 Answer: High risk for hereditary CRC
  • Slide 60: Case 6 Management
  • Slide 61 : The Genetics Education Project Committee
  • Slide 62 : References 1
  • Slide 63 : References 2
  • Slide 64 : References 3
  • Slide 65 : References 4
  • Slide 66 : References 5
  • Slide 67 : References 6
  • Slide 68 : References 7
  • Slide 69 : References 8
  • Slide 70 : The Genetics Education Project Logo

Hereditary Colorectal Cancer PowerPoint educational module Hereditary Colorectal Cancer PowerPoint educational module Presentation Transcript

  • Hereditary Colorectal Cancer
    • Prepared by: June C Carroll MD, CCFP, FCFP
    • Sydney G. Frankfort Chair in Family Medicine
    • Mount Sinai Hospital , University of Toronto
    • Andrea Rideout MS, CGC, CCGC
      • Certified Genetic Counsellor
      • Project Manager – The Genetics Education Project
      • Sean Blaine BSc, MD, CCFP
      • Mount Sinai Hospital, University of Toronto
      • Stratford, Ontario
    • Funded by: Ontario Women’s Health Council
    • Version: January 2010
  • Acknowledgments
    • Reviewers : Members of The Genetics Education Project (see slide 51)
      • + Kara M. Semotiuk, MS, (C)CGC Genetic Counsellor
      • Heidi Rothenmund, MS, (C)CGC Genetic Counsellor
      • Familial GI Cancer Registry, Mount Sinai Hospital
    • Funded by: Ontario Women’s Health Council as part of its funding to The Genetics Education Project
    • * Health care providers must use their own clinical judgment in addition to the information presented herein. The authors assume no responsibility or liability resulting from the use of information in this presentation.
  • Outline
    • Sporadic verses familial cancer
    • Hereditary colorectal cancer syndromes
    • Referral guidelines
    • Benefits, risks and limitations of genetic testing
    • Management
    • Case examples
  • Cancer
    • All cancer involves changes in genes….
    • Threshold effect :
    • During mitosis & DNA replication
      • mutations occur in the cell’s genetic code
    • Mutations are normally corrected by DNA repair mechanisms
    • If repair mechanism or cell cycle regulation is damaged
      • Cell accumulates too many mutations
        • reaches ‘threshold’
        • tumour development
  • Sporadic Cancer
    • All cancer arises from changes in genes….
      • But NOT all cancer is inherited
      • Most CRC is sporadic ~75 – 80%
        • Due to acquired mutations throughout a person’s lifetime:
          • Causes unknown – multifactorial
          • Interaction of many factors: age, environment, lifestyle, chance, unknown factors
      • Sporadic cancer generally has a later onset
  • Clustering of Cancer in Families
    • ~6% lifetime risk of CRC in general population
    • ~20% of people with CRC have a family history:
    • ~15% of CRC is familial :
      • Environmental factors
      • Chance
      • Undiscovered gene mutation
      • Generally not eligible for genetic testing
    • ~5% of CRC cancer is hereditary
      • Caused by an inherited gene mutation that puts them at increased risk for cancer
        • Majority is Lynch syndrome/HNPCC (Hereditary Non-Polyposis Colorectal Cancer)
        • Small fraction is Familial Adenomatous Polyposis (FAP) or other rare cancer syndromes
      • May be eligible for genetic testing
  • Proportion of Hereditary CRC Sporadic 80% Familial ~15% Hereditary ~5% Lynch syndrome ~ 2-5% FAP ~ <1% 
  • Knudson ‘two-hit’ Model Sporadic Cancer Birth : Two non-mutated copies of the gene One mutation in one gene ; Second gene non-mutated  ONE HIT ( hit=mutation) SECOND HIT Two mutations - one in each gene CANCER
  • Knudson ‘two-hit’ Model Hereditary Cancer Birth : One mutation in one gene ; Second gene non-mutated ONE HIT ( hit=mutation) SECOND HIT Two mutations - one in each gene CANCER
  • Compared to sporadic cancer people with hereditary cancer have…
    • A higher risk of developing cancer
    • A younger age of onset of cancer
      • Generally < 50 years of age
    • Multiple primary cancers
    • Generally have a family history of cancer
    • Hereditary cancer is less common in the general population than sporadic cancer
  • Inherited Colorectal Cancer
    • Two common syndromes:
    • Lynch syndrome
      • Also known as Hereditary Non Polyposis Colorectal Cancer or HNPCC
      • ~2 - 5% of colorectal cancer
      • Prevalence of 1 in 200 - 2,000*
    • Familial Adenomatous Polyposis (FAP)
      • <1% of colorectal cancer
      • Prevalence of 1 in 8,000 – 14,000*
    • Autosomal dominant inheritance
    • *Prevalence depends on population
  • bb B b B b bb B b bb CRC mutation Susceptible CRC gene Autosomal Dominant Inheritance Population Risk Population Risk Susceptible CRC gene Unaffected Legend B: CRC gene with mutation b: normal CRC gene
  • Colorectal cancer genes…
    • Lynch syndrome (HNPCC) :
      • Mutations in DNA repair genes lead to an accumulation of mutations which may result in malignancy.
    • FAP:
      • Mutations in a tumour suppressor gene cause an increase in cell proliferation and a decrease in cell death.
    when mutated
  • Lynch syndrome (HNPCC)
    • Lynch syndrome is genetically heterogeneous
      • Clinical testing available for 4 genes: MLH1 & MSH2 ( most common ), MSH6 & PMS2
      • Research testing may be available for other genes
    • High penetrance
    • Characterized by:
      • Earlier onset than sporadic cancer
      • More aggressive, proximal, right sided tumours
      • Risk for extra-colonic tumours
      • Distinct tumour pathology
  • Cancer Risk in Individuals with Lynch syndrome (HNPCC) to Age 70 Compared to General Population from: http:// www.genetests.org Cancer General Population Risk Lynch syn. Risk Mean Age of Onset in Lynch Colon 7 % 80% 45 years Endometrium 2.7% 20-60% 46 years Stomach <1% 11-19% 56 years Ovary 1.5% 9-12% 42.5 years Hepatobiliary tract <1% 2-7% 54 years Urinary tract <1% 4-5% ~55 years Small Bowel <1% 1-4% 49 years Brain / CNS <1% 1-3% 50 years
  • Familial Adenomatous Polyposis
    • Chromosome 5, APC gene
    • High penetrance
    • Characterized by:
      • Early onset
      • >100 adenomatous polyps
      • Variant form:
        • Attenuated FAP may occur with >10 but <100 polyps.
  • Consequences of FAP
    • Colorectal adenomatous polyps begin to appear at an average age of 16 years (range 7-36 years)
    • Average age at diagnosis: 34-43 years, when >95% have polyps
    From: http:// www.genetests.org Age Individuals with colon cancer 21 7% 45 87% 50 93%
  • Consequences of FAP
    • ~50-90% develop small bowel polyps
      • lifetime risk of small bowel malignancy is 4-12%
    • ~50% develop gastric polyps
      • ~10% gastric cancer
    • ~10% develop desmoid tumours
  • Red Flags for hereditary colorectal cancer – consider referral to genetics
    • Multiple cases in family with Lynch syndrome/HNPCC spectrum of cancers with at least 1 relative with CRC or endometrial CA
    • CRC at <45 years
    • Multiple Lynch syndrome cancers in 1 family member
    • Family member with FAP or >10 adenomatous polyps
    • Family member with known mutation
    • Family member with colonic adenoma or cancer with high microsatellite instability (MSI)
      • See extra slides following references for more information about MSI
    • Not all who are referred will have genetic testing
  • Risk of Developing Colorectal Cancer From: http:// www.cancer.gov  Family History Relative Risk for CRC Absolute Risk of CRC by age 79 No family history 1 4% 1 FDR with CRC 2 9% >1 FDR with CRC 4 16% 1 FDR Dx <45 yrs 4 15% 1 FDR Dx CRC adenoma 2 8%
  • Case
    • Jane - healthy 26 y.o.
    • Office visit for a routine pap smear and renewal of birth control pills
    • History:
      • Any cancer in the family?
        • Mother with breast cancer at 66
  • Case continued…
    • Father’s side of the family:
        • uncle - CA ureter age 72
        • uncle - CA colon age 56
        • aunt - double primary: endometrial CA age 45, colon CA age 68
        • 1 cousin - endometrial CA age 40
        • 2 cousins - both have colon CA
  • Jane’s Family Pedigree Jane, 26 Linda Dx 38 CA - colon Jeana Dx 40 Ca-Endometrial Christa Dx 52 CA – Colon Mary Dx 45 CA Endometrial Dx 68 CA Colon Bob Dx 56 CA colon Steve Dx 72 CA Kidney Paula Dx 66 CA- Br MI 72 Accident Nat Causes Stroke A&W A&W A&W A&W A&W A&W Kevin, 67 A&W LEGEND Kidney Colon Endometrial Breast
  • Jane was referred to genetics… A genetics consultation involves:
    • Detailed family history information
    • Pedigree documentation
      • Confirmation of cancer history: pathology reports/death certificates
    • Medical & exposure history
    • Empiric risk assessment
    • Hereditary cancer / genetic risk assessment
    • Psychological assessment
  • … A genetics consultation involves:
    • Assessment of eligibility for genetic testing
      • Availability of living affected relative to be tested first
    • Discussion of risks, benefits & limitations of test
    • Testing and disclosure of genetic test results
      • May be months before results are available
    • Determining patient’s thoughts about colorectal cancer - motivations for testing
    • Screening/management recommendations
  • Recommendations for Jane’s family
    • Jane’s paternal family history is suggestive of Lynch syndrome/HNPCC.
    • Jane was asked to discuss genetic testing with her family members diagnosed with cancer.
    • Appropriate to test an affected member first.
    • If a mutation found in one of the Lynch syndrome genes then sequential testing of the family can be performed.
    • If Jane’s family declines genetic testing then family members should follow high risk screening recommendations for CRC.
    • Colonoscopy q1-2 years; consider referral to a GYN to discuss endometrial cancer screening
  • Results from Genetic Testing
    • Positive
      • Deleterious mutation identified
    • Negative
      • Interpretation differs if a mutation has previously been identified in the family
        • Mutation known – true negative
        • Mutation unknown – uninformative
    • Variant of unknown significance
      • Significance will depend on how variant tracks through family, i.e. is variant present in people with disease?
      • Can use software to predict functional significance
      • Check with lab: ? reported previously
  • Risks/Benefits/Limitations of genetic testing Positive test result
    • Potential Benefits :
    • Clinical intervention may improve outcome
    • Family members at risk can be identified
    • Positive health behaviour can be reinforced
    • Reduction of uncertainty
    • Potential Risks :
    • Adverse psychological reaction
    • Family issues/distress
    • Uncertainty -incomplete penetrance
    • Insurance/job discrimination
    • Confidentiality issues
    • Intervention may carry risk
  • Risks/Benefits/Limitations of genetic testing? True Negative test result
    • Potential Benefits:
    • Avoidance of unnecessary clinical interventions
    • Emotional - relief
    • Children can be reassured
    • Potential Risks:
    • Adverse psychological reaction (i.e. survivor guilt)
    • Dysfunctional family dynamics
    • Complacent attitude to health
  • Risks/Benefits/Limitations of genetic testing? Uninformative test result
    • Potential Benefits:
    • Future research may clarify test results
    • Importance of positive health behaviour can be reinforced
    • Some relief
    • Potential Risks:
    • Continue clinical inventions which may carry risks
    • Complacent attitude to health
    • Uncertainty
    • Continued anxiety
  • What is the benefit of genetic testing? Can anything be done to change risk /outcome?
    • Patients with Lynch syndrome/HNPCC:
      • Colonoscopy beginning age 20-25 or 10 years younger than youngest CRC or adenomatous polyp diagnosis, whichever comes first
      • Subsequent colonoscopy every 1-2 years
        • Category of evidence III, grade C
      • Vasen et al. J Med Genet. 2007; 44:353-362.
  • What is the benefit of genetic testing? Can anything be done to change risk /outcome?
    • Evidence for screening in Lynch syndrome/HNPCC:
        • Cohort study of CRC screening – 15 yr F/U
        • Subgroup of Lynch syndrome carriers
        • CRC in 8/44 with colonoscopy q3 years vs. 19/46 controls ( p=0.02)
        • RR of CRC = 0.44 (95% CI 0.2-0.9)
        • RR of death = 0.35 (95% CI 0.1-0.99)
        • 15 yr survival 92% vs. 74%
    Jarvinin et al Gastroenterology 2000
  • What is the benefit of genetic testing? Can anything be done to change risk /outcome?
    • Lynch syndrome/HNPCC gynecological cancers:
      • Little evidence re GYN cancer screening
      • Educate re symptoms of endometrial & ovarian cancer
      • Beginning age 30-35 consider 1-2 years:
        • Gynecological examination
        • Trans-vaginal ultrasound +/- aspiration biopsy
          • Category of evidence III, grade C
        • CA125
      • Consider prophylactic hysterectomy and bilateral salpingo-oophorectomy (BSO)
        • Grade C
      • Vasen et al. J Med Genet. 2007; 44:353-362
  • Lynch syndrome - Evidence for screening for endometrial cancer (EC):
    • Finnish HNPCC registry – chart review for 10 years
    • N=175 EC screening; N=83 no EC screening
    • Screening consisted of: GYN exam (100%), trans-vaginal U/S (94%), endometrial biopsy (74%)
    • Median screening interval 3 years/ Median age 52 years
    • Screening group: 14 cases of EC detected
      • 11 cases by screening alone
      • 2 cases by manifesting symptoms (interval cancers)
      • 1 case occult cancer found at the time of hysterectomy
      • 0 EC deaths
    • No screening group:
      • Number of EC cases not reported
      • 6 EC deaths
    • Survival curves: 100% screening group; 92% no screening
    • Differences b/w survival curves not significant (P=0.4)
    • Renkonen-Sinisalo Int J Cancer 2006:120:821-824
  • What is the benefit of genetic testing? Can anything be done to change risk /outcome?
    • Lynch syndrome – evidence for risk reducing surgery
      • Chart Review of HNPCC mutation positive women
      • Hysterectomy N = 61
        • No cases of endometrial cancer
      • No hysterectomy N = 254
        • 69 cases of endometrial cancer – 33%
        • P<0.001
      • Bilateral salpingo-oophorectomy (BSO) N=47
        • No cases of ovarian cancer
      • No BSO N=223
        • 12 cases of ovarian cancer – 5.5%
        • P=0.09
      • No peritoneal cancers in the study period
    • Schmeler et al. NEJM 2006;354261-269.
  • What is the benefit of genetic testing? Can anything be done to change risk /outcome?
    • Lynch syndrome/HNPCC screening for other cancers:
    • ONLY if there is a family history of the type of cancer listed below - controversial
      • Gastric cancer
        • Gastroduodenoscopy q1-2 years beginning age 30 – 35 years
      • Urinary tract cancer
        • Renal U/S + urine cytology q1-2 years beginning age 30 to 35 years
      • Other cancers
        • Screen as per family history of skin, small bowel, pancreaticobiliary cancers
  • What is the benefit of genetic testing? Can anything be done to change risk/outcome?
    • Patients with FAP:
      • Sigmoidoscopy every 1-2 years beginning at age 10 to 12
        • subsequent colonoscopy every 1-2 years
      • Colonoscopy once polyps are detected
      • Colectomy
      • Annual colonoscopy if colectomy is delayed more than 1 year after polyps emerge
  • Management of Mutation Carriers Consider…
    • Psychosocial support to assist with:
      • Adjusting to new information
        • most adjust within 3-6 months
        • subset remain psychologically distressed
      • Making decisions regarding management
      • Addressing family issues, self concept, body image
      • Dealing with future concerns
    • Referral to support groups
  • Management of Mutation Carriers Consider…
    • Additional psychosocial support may be needed for high risk individuals such as those with:
      • History of depression/anxiety
      • Poor coping skills
      • Inadequate social support / conflict in the family
      • Multiple losses in the family
      • Loss of parent at a young age
      • Recent loss
      • Multiple surgical procedures
  • Resources
    • The National Cancer Institute:
      • http:// www.cancer.gov /
    • Gene Tests: http:// www.genetests.org
    • Colon Cancer Alliance:
      • http:// www.ccalliance.org /
    • Canadian Cancer Society: www.cancer.ca
    • Cancer Genetics Support Group of Canada (CHGSGC):
      • Contact Name: Nancy Schofield, President
      • 16 Redford Road Canada
      • London, ON N5X 3V5
      • Email: [email_address]
  • Case Examples
  • Assessing the Risk for Hereditary CRC Using the Canadian Cancer Society triage card (below), what category of risk do the following family histories fit into?
  • Case 1 Alz -75 ↑ Chol A&W ↑ Chol Colon CA Dx 34 Aneurysm-65 A&W Asthma A&W Your Patient Accident ‘ Old Age’-82 ID DM A& W ↑ Chol A&W Colon Legend
  • Case 1 Colon Legend
  • Case 1
    • Answer:
    • Moderate risk for hereditary CRC
    • 1 st or 2 nd degree relative with CRC ≤35
    • Management:
      • Offer referral to hereditary CRC/Genetics Clinic
      • Colonoscopy q 3-5 years starting 10 years younger than youngest CRC diagnosis
      • Educate patient about symptoms of endometrial cancer
  • Case 2 Alz -75  Endometrial Ca Dx 33 A&W Colon Ca Dx 50 IDDM Aneurysm-65 A&W Asthma A&W Your Patient Prostate Ca Dx 72 Kidney Ca Dx 65 ID DM Colon Ca Dx 49 ↑ Chol A&W Colon Endometrial Kidney Prostate Legend
  • Case 2 Colon Endometrial Kidney Prostate Legend
  • Case 2
    • Answer:
    • High risk for hereditary CRC
    • ≥ 3 relatives on the same side of the family, at least 1 CRC and ≥2 with any combination of Lynch syndrome-associated cancer AND
      • 1 is a 1 st degree relative of the other 2 and
      • 1 relative diagnosed <50 and
      • At least 2 successive generations (suggestive of Lynch syndrome)
    • Management:
      • Offer referral to hereditary CRC/genetics clinic
      • Colonoscopy q 1-2 years beginning age 20 or 10 years younger than youngest CRC diagnosis
      • Educate patient about symptoms of endometrial cancer
  • Case 3 Alz -75 A&W A&W ↑ Chol IDDM Aneurysm-65 A&W Asthma A&W Your Patient Crohn’s disease Accident Colon Ca Dx 74 ID DM A& W ↑ Chol A&W Legend Colon Crohn’s disease
  • Case 3 Legend Colon Crohn’s disease
  • Case 3
    • Answer:
    • Low risk for Hereditary CRC but still at increased risk of CRC
    • Personal history of inflammatory bowel disease
    • Management:
      • Seek advice from gastroenterologist or surgeon for individuals with inflammatory bowel disease.
  • Case 4 Alz -75 Colon CA Dx 52 A&W ↑ Chol IDDM Aneurysm-65 A&W Asthma A&W Your Patient Accident Colon Ca Dx 74 ID DM A& W ↑ Chol A&W Colon Legend
  • Case 4 Colon Legend
  • Case 4
    • Answer:
    • Population risk
    • Meets none of the other risk criteria
    • Still has a 1 in 16 lifetime risk of sporadic CRC
    • Management:
      • Beginning at age 50:
        • Annual or biennial fecal occult blood testing (FOBT) A OR
        • Flexible sigmoidoscopy q 5years B OR
        • FOBT + flexible sigmoidoscopy q 5years I OR
        • Double contrast barium enema q 5 years OR
        • Colonoscopy q 10 years I
    A = Good evidence B = Fair evidence I = Insufficient evidence
  • Case 5 Alz -75 Chronic cough A&W Mesothelioma Dx 45 Smoker A&W Aneurysm-65 Asthma A&W Your Patient Accident Lung Ca Dx 74 NON-smoker ID DM Chronic cough Lung Ca Dx 43 Smoker A&W Colon – CA Dx 61 Colon Lung Legend
  • Case 5 Colon Lung Legend
  • Case 5
    • Answer:
    • Population risk for CRC
    • Patient’s family worked in a shipyard insulating pipes
      • Asbestos exposure increases risk of lung and mesothelioma cancers
      • High incidence of lung cancer due to common environment exposures
    • Management:
      • Beginning at Age 50:
        • Annual or biennial FOBT A OR
        • Flexible sigmoidoscopy q 5years B OR
        • FOBT + flexible sigmoidoscopy q 5years I OR
        • Double contrast barium enema q 5 years OR
        • Colonoscopy q 10 years I
    A = Good evidence B = Fair evidence I = Insufficient evidence
  • Case 6 Alz -75 A&W Colon Ca Dx 42 ~1000 polyps Aneurysm-65 Asthma A&W Your Patient Accident Lung Ca Dx 74 Smoker ID DM A&W A&W Colon CA Dx 32 A&W A&W A&W Legend Colon CA Lung CA
  • Case 6 Legend Colon CA Lung CA
  • Case 6
    • Answer:
    • High risk for hereditary CRC
    • >10 colorectal adenomatous polyps
      • Personal history or
      • 1 st or 2 nd degree relative (suggestive of FAP)
    • Management:
      • Suggestive of FAP:
        • Seek advice from a colorectal specialist
      • Offer referral to hereditary CRC/genetics clinic
  • The Genetics Education Project Committee
    • June C Carroll MD CCFP
    • Judith Allanson MD FRCP FRCP(C) FCCMG FABMG
    • Sean Blaine MD CCFP
    • Mary Jane Esplen PhD RN
    • Sandra Farrell MD FRCPC FCCMG
    • Judy Fiddes
    • Gail Graham MD FRCPC FCCMG
    • Jennifer MacKenzie MD FRCPC FAAP FCCMG
    • Wendy Meschino MD FRCPC FCCMG
    • Joanne Miyazaki
    • Andrea L. Rideout MS CGC CCGC
    • Cheryl Shuman MS CGC
    • Anne Summers MD FCCMG FRCPC
    • Sherry Taylor PhD FCCMG
    • Brenda Wilson BSc MB ChB MSc MRCP(UK) FFPH
  • References
    • Offit K Clinical Cancer Genetics: Risk Counseling and Management . Wiley-Liss, New York. 1998.
    • Statistics from the Canadian Cancer Society: http://www.ontario.cancer.ca/ccs/internet/standard/0,3182,3543_14447_371429_langId-en,00.html accessed on June 22, 2005.
    • Hampel H, Frankel WL, Martin E, Arnold M, Khanduja K, Kuebler P, Nakagawa H, Sotamaa K, Prior TW, Westman J, Panescu J, Fix D, Lockman J, Comeras I, de la Chapelle A. Screening for Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med 2005; 352: 1851-1860.
    • Mitchell RJ, Farrington SM, Dunlop MG, Campbell H. Mismatch repair genes hMLH1 and hMSH2 and colorectal cancer: a huge review. Am J Epidemiol 2002; 156:885-902.
  • References
    • Ponz de Leon M, Sassatelli R, Benatti P, Roncucci L. Identification of hereditary nonpolyposis colorectal cancer in the general population. The 6-year experience of a population-based registry. Cancer 1993; 71:3493-3501.
    • Lightning bolt photo credit: http://www.ghouli.com/articles/sp/mainstream_4b.htm
    • Dunlop MG, Farrington SM, Nicholl I, Aaltonen L, Petersen G, Porteous M, Carothers. Population carrier frequency of hMSH2 and hMLH1 mutations. Br J Cancer 2000; 83: 1643-1645.
    • American Gastroenterological Association (The Clinical Practice and Practice Review Committee). AGA technical review on hereditary colorectal cancer and genetic testing. Gastroenterology 2001;121:198-213.
  • References
    • Salovaara R, Loukola A, Kristo P, Kaariainen H, Ahtola H, Eskelinen M, Harkonen N, Julkunen R, Kangas E, Ojala S, Tulikoura J, Valkamo E, Jarvinen H, Jukka-Pekka M, Aaltonen L, de la Chapelle A. Population-based molecular detection of hereditary nonpolyposis colorectal cancer. J Clin Oncol 2000;18: 2193-2200.
    • Wijnen JT Vassen HFA, Khan PM, Zwinderman AH, van der Klift H, Mulder A, Tops C, Moller P, Fodde R. Clinical findings with implications for genetic testing in families with clustering of colorectal cancer. N Engl J Med. 1998; 339:511-518.
    • Burke W, Petersen G, Lynch P, Botkin J, Daly M, Garber J, Khan MJE, McTiernan A, Offit K, Thompson E, Varricchio C for the Cancer Genetics Studies Consortium. Recommendations for follow-up care of individuals with an inherited predisposition to cancer. I. Hereditary nonpolyposis colon cancer. JAMA 1997; 277:915-918.
    • Lin K, Shashidaran M, Ternent C, Thorson AG, Blatchford GJ, Christensen MA, Lanspa SJ, Lemon SJ, Watson P, Lynch H. Colorectal and extracolonic cancer variations in MLH1/MSH2 hereditary nonpolyposis colorectal cancer kindreds and the general population. Dis Colon Rectum . 1998; 41: 428-433.
  • References
    • Vasen HFA, Wijnen JT, Menko FH Kleibeuker JH, Taal BG, Griffioen G, Nagengast FM, Meijer-Heijboer EH, Bertario L, Varesco L, Bisgaard M_L, Mohr J, Fodde R, Khan PM. Cancer risk in families with hereditary colorectal cancer diagnosed by mutational analysis. Gastroenterology 1996; 110:1020-1027.
    • The Canadian Cancer Society, National Cancer Institute of Canada, Statistics Canada, Provincial/Territorial Cancer Registries, Public Health Agency of Canada. Canadian Cancer Statistics 2005 http://www.cancer.ca/vgn/images/portal/cit_86751114/48/28/401594768cw_2005stats_en.pdf Accessed June 21, 2005.
    • Kohlmann W, Gruber SB Hereditary nonpolyposis colorectal cancer. Gene Tests Reviews www.genetests.org last updated November 29, 2006. Accessed June 21, 2009.
    • Watson P, Lynch HT Cancer risk in mismatch repair gene mutation carriers. Familial Cancer 2001; 1: 57-60.
  • References
    • Rodriquez-Bigas MA, Vassen HF, Lynch HT, Waston P, Myrhoj T, Jarvinen HJ, Meckllin JP, Macrae F, St. John DJB, Bertario L, Fidalgo P, Madlensky L, Rozen P, and the International Collaborative Group on HNPCC. Characteristics if small bowel carcinoma in hereditary nonpolyposis colorectal carcinoma. Cancer 1998; 83:240-244.
    • Aarnio M, Sankila R, Pukkala E, Salovaara R, Aaltonen LA, de la Chapelle A, Peltomaki P, Mecklin J-P, Jarvinen HJ. Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer 1999; 81:214-218.
    • Aarnio M, Mecklin J-P, Aaltonen LA, Nystrom-Lahti M, Jarvinen HJ.Life-time risk of different cancer in the hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Int J Cancer 1995; 64:430-433.
    • Quehenberger F, Vasen HFA, van Houwelingen HC. Risk of colorectal and endometrial cancer for carriers of hMLH1 and hMSH2 gene: correction for ascertainment. J Med Genet 2005; 42:491-496.
  • References
    • Burt RW, Jasperson KW Familial adenomatous polyposis. www.genetests.org . Last updated July 24, 2008, accessed June 21, 2009.
    • Predictive Cancer Genetics Steering Committee. Ontario physicians’ guide to referral of patients with family history of cancer to a familial cancer genetics clinic or genetics clinic. Ontario Medical Review 2001; 68(10):24-29.
    • National Cancer Institute. Genetics of Colorectal Cancer (PDQ). http://www.nci.nih.gov/cancertopics/pdq/genetics/colorectal/HealthProfessional/page2 Assessed on June 21, 2009. Johns LE, Houlston RS A systematic review and meta-analysis of familial colorectal cancer risk. Am J Gastroenterol . 2001; 96:2992-3003.
    • Johns LE, Houlston RS A systematic review and meta-analysis of familial colorectal cancer risk. Am J Gastroenterol . 2001; 96:2992-3003.
  • References
    • Leddin D, Hunt R, Champion M, Cockeram A, Flook N, Gould M, Kim Y-I, Love J, Morgan D, Natsheh S, Sadowski D, for the Canadian Association of Gastroenterology and the Canadian Digestive Health Foundation committee on colorectal cancer screening. Can J Gastroenterologgy 2004;18:93-99.
    • Vasen HFA, Moslein G, Alonso A, Bernstein I, Bertario L, Burn J, Capella G, Engel C, Frayling I, Friedl W, Hes FJ, Hodgson S, Mecklin J-P, Moller P, Nagengast F, Parc Y, Renkonen-Sinisalo L, Sampson JR, Stormorken A, Wijnen J. Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer). J Med Genet 2007;44:353-362.
    • Jarvinen HJ, Aarnio M, Mustonen H, Aktan-Collan K, Aaltonen LA, Peltomaki P, de la Chapelle A. Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 2000; 118:829-834.
  • References
    • Dove-Edwin I, Sasieni P, Adams J, Thomas HJW Prevention of colorectal cancer by colonoscopic surveillance in individuals with a family history of colorectal cancer: a 16 year, prospective, follow-up study. BMJ. 2005; 331:1047-1049.
    • Yu H-JA, Lin KM, Ota DM, Lynch HT. Hereditary nonpolyposis colorectal cancer: preventive management. Cancer Treatment Rev 2003; 29:461-470.
    • Renkonen-Sinisalo L, Butzow R,Leminen A, Lehtovirta P, Mecklin J-P, Jarvinen HJ. Surveillance for endometrial cancer in hereditary nonpolyposis colorectal cancer syndrome. Int. J. Cancer. 2006; 821-824.
    • Schmeler KM, Lynch HT, Chen L-M, Munsell MF, Soliman PT, Clark MB, Daniels MS, White KG, Boyd-Rodgers SG, Conrad PG, Yang KY, Rubin MM, Sun CC, Slomovitz BM, Gershenson DM, Lu KH. Prophylactic surgery to reduce the risk of gynaecologic cancers in Lynch syndrome. NEJM 2006;345:261-269.
    • Koornstra JJ, Mourits MJE, Sijmons RH, Leliveld AM, Hollema H, Kleibeuker JH. Management of extracolonic tumours in patients with Lynch syndrome. Lancet Oncology 2009;120:400-408.
  •  
  • Extra Slides
  • What is Microsatellite Instability (MSI)?
    • Microsatellites are repetitive segments of DNA
    • The same number of repeats are present
    • in every cell
    • Microsatellite Instability :
    • The number of microsatellite repeats differs between normal cells/tissue and tumour cells/tissue
    Normal microsatellite with 2 repeats Normal tissue 2 repeats Tumour tissue with MSI variable repeat size 5 & 3 MSI is a pathology finding specific to Lynch syndrome colon tumours
  • Pathology & Genetic Evidence for Increased Risk of Hereditary CRC
    • Principle: Mutations of the genes MSH2, MLH1, MSH6 and PMS2 increase the rate of genetic mutation in human cells.
    • Small repetitive sequences (microsatellites) are very susceptible to increases in the mutation rate.
    • These repetitive sequences can be surveyed to see if there are differences in their sequence between the normal and tumor tissues from an individual.
    • If changes are seen the tumor can be referred to as showing “microsatellite instability”.
    • Typically there is good concordance between seeing that a tumor is by immunohistochemistry immunodeficient for one of these gene products and the finding of microsatellite instability.
    • Observing either one or both in a tumor increases the likelihood a familial mutation is present
  • Pathology and Genetic Evidence for Increased Risk of Hereditary Colorectal Cancer
    • Colonic ademoma or other Lynch syndrome associated cancers can be found in the laboratory to have one or both of the following properties which increase the likelihood a familial mutation is responsible.
    • The tumors:
      • Are deficient for immunohistochemical staining for the proteins
        • MSH2, MLH1, MSH6 and/or PMS2
      • Show evidence of genetic instability of small repetitive DNA sequences (microsatellites) when compared to normal tissue.