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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

Hereditary Colorectal Cancer PowerPoint educational module

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Page 1: Hereditary Colorectal Cancer PowerPoint educational module

Hereditary Colorectal CancerPrepared by: June C Carroll MD, CCFP, FCFP

Sydney G. Frankfort Chair in Family MedicineMount Sinai Hospital, University of Toronto

Andrea Rideout MS, CGC, CCGCCertified Genetic CounsellorProject Manager – The Genetics Education Project

Sean Blaine BSc, MD, CCFPMount Sinai Hospital, University of TorontoStratford, Ontario

Funded by: Ontario Women’s Health Council

Version: January 2010

Page 2: Hereditary Colorectal Cancer PowerPoint educational module

Acknowledgments Reviewers: Members of The Genetics Education Project

(see slide 51) + Kara M. Semotiuk, MS, (C)CGC Genetic CounsellorHeidi Rothenmund, MS, (C)CGC Genetic CounsellorFamilial 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.

Page 3: Hereditary Colorectal Cancer PowerPoint educational module

Outline

Sporadic verses familial cancer Hereditary colorectal cancer syndromes Referral guidelines Benefits, risks and limitations of genetic

testing Management Case examples

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CancerAll 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

damagedCell accumulates too many mutations

reaches ‘threshold’ tumour development

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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

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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

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Proportion of Hereditary CRC

Sporadic 80%

Familial ~15%

Hereditary ~5%Lynch syndrome ~ 2-5%

FAP ~ <1%

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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

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Knudson ‘two-hit’ ModelHereditary Cancer

Birth: One mutation in one gene; Second gene non-mutated

ONE HIT

(hit=mutation)

SECOND HIT

Two mutations - one in each gene

CANCER

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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

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Inherited Colorectal CancerTwo 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 cancerPrevalence of 1 in 8,000 – 14,000*

Autosomal dominant inheritance

*Prevalence depends on population

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bb Bb

Bb bb Bb bb

CRC mutation

SusceptibleCRC gene

Autosomal Dominant Inheritance

Population Risk

Population Risk

SusceptibleCRC gene

Unaffected

Legend

B: CRC gene with mutation

b: normal CRC gene

Page 13: Hereditary Colorectal Cancer PowerPoint educational module

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

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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 cancerMore aggressive, proximal, right sided tumoursRisk for extra-colonic tumoursDistinct tumour pathology

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Cancer Risk in Individuals with Lynch syndrome (HNPCC) to Age 70 Compared to General Population

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

from: http://www.genetests.org

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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.

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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

Age Individuals with colon cancer

21 7%

45 87%

50 93%

From: http://www.genetests.org

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Consequences of FAP

~50-90% develop small bowel polypslifetime risk of small bowel malignancy is

4-12% ~50% develop gastric polyps

~10% gastric cancer ~10% develop desmoid tumours

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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

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Risk of Developing Colorectal Cancer

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%

From: http://www.cancer.gov

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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

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Case continued…

Father’s side of the family:uncle - CA ureter age 72uncle - CA colon age 56aunt - double primary: endometrial CA

age 45, colon CA age 681 cousin - endometrial CA age 402 cousins - both have colon CA

Page 23: Hereditary Colorectal Cancer PowerPoint educational module

Jane’s Family PedigreeLEGEND

Kidney

Colon

Endometrial

Breast

Jane, 26Linda Dx 38 CA - colon

Jeana Dx 40 Ca-Endometrial

Christa Dx 52CA – Colon

Mary

Dx 45 CA Endometrial

Dx 68 CA Colon

Bob Dx 56CA colon

Steve Dx 72CA Kidney

Paula Dx 66CA- Br

MI 72

Accident Nat Causes Stroke A&W

A&W A&WA&W

A&W A&W

Kevin, 67A&W

Page 24: Hereditary Colorectal Cancer PowerPoint educational module

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

Page 25: Hereditary Colorectal Cancer PowerPoint educational module

…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

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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

Page 27: Hereditary Colorectal Cancer PowerPoint educational module

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

Page 28: Hereditary Colorectal Cancer PowerPoint educational module

Risks/Benefits/Limitations of genetic testingPositive 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

Page 29: Hereditary Colorectal Cancer PowerPoint educational module

Risks/Benefits/Limitations of genetic testing? True Negative test resultPotential 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

Page 30: Hereditary Colorectal Cancer PowerPoint educational module

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

Page 31: Hereditary Colorectal Cancer PowerPoint educational module

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.

Page 32: Hereditary Colorectal Cancer PowerPoint educational module

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

Page 33: Hereditary Colorectal Cancer PowerPoint educational module

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

Page 34: Hereditary Colorectal Cancer PowerPoint educational module

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

Page 35: Hereditary Colorectal Cancer PowerPoint educational module

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.

Page 36: Hereditary Colorectal Cancer PowerPoint educational module

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

Page 37: Hereditary Colorectal Cancer PowerPoint educational module

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 detectedColectomyAnnual colonoscopy if colectomy is delayed

more than 1 year after polyps emerge

Page 38: Hereditary Colorectal Cancer PowerPoint educational module

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 managementAddressing family issues, self concept, body

imageDealing with future concerns

Referral to support groups

Page 39: Hereditary Colorectal Cancer PowerPoint educational module

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

Page 40: Hereditary Colorectal Cancer PowerPoint educational module

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, President16 Redford Road CanadaLondon, ON N5X 3V5Email: [email protected]

Page 41: Hereditary Colorectal Cancer PowerPoint educational module

Case Examples

Page 42: Hereditary Colorectal Cancer PowerPoint educational module

Assessing the Risk for Hereditary CRCUsing the Canadian Cancer Society triage card (below), what category of risk do the following family histories fit into?

Page 43: Hereditary Colorectal Cancer PowerPoint educational module

Case 1

Alz -75

↑Chol

A&W ↑Chol Colon CA

Dx 34

Aneurysm-65

A&W

AsthmaA&WYour Patient

Accident‘Old Age’-82

ID DM

Colon

Legend

A& W↑Chol

A&W

Page 44: Hereditary Colorectal Cancer PowerPoint educational module

Case 1

Colon

Legend

Page 45: Hereditary Colorectal Cancer PowerPoint educational module

Case 1Answer: Moderate risk for hereditary CRC 1st or 2nd 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

Page 46: Hereditary Colorectal Cancer PowerPoint educational module

Case 2

Alz -75

Endometrial Ca Dx 33

A&W Colon Ca Dx 50 IDDM

Aneurysm-65

A&W

AsthmaA&WYour Patient

Prostate Ca

Dx 72Kidney Ca

Dx 65

ID DMColon CaDx 49

↑Chol

A&W

Colon

Endometrial

Kidney

Prostate

Legend

Page 47: Hereditary Colorectal Cancer PowerPoint educational module

Case 2

Colon

Endometrial

Kidney

Prostate

Legend

Page 48: Hereditary Colorectal Cancer PowerPoint educational module

Case 2Answer: 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 1st 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

Page 49: Hereditary Colorectal Cancer PowerPoint educational module

Case 3

Alz -75

A&W

A&W ↑Chol IDDM

Aneurysm-65

A&W

AsthmaA&WYour Patient

Crohn’s disease

AccidentColon Ca

Dx 74

ID DMA& W↑Chol

Legend

Colon

Crohn’s

disease

A&W

Page 50: Hereditary Colorectal Cancer PowerPoint educational module

Case 3

Legend

Colon

Crohn’s

disease

Page 51: Hereditary Colorectal Cancer PowerPoint educational module

Case 3Answer: 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.

Page 52: Hereditary Colorectal Cancer PowerPoint educational module

Case 4

Alz -75

Colon CA

Dx 52

A&W ↑Chol IDDM

Aneurysm-65

A&W

AsthmaA&WYour Patient

AccidentColon Ca

Dx 74

ID DM

Colon

Legend

A& W↑Chol

A&W

Page 53: Hereditary Colorectal Cancer PowerPoint educational module

Case 4

Colon

Legend

Page 54: Hereditary Colorectal Cancer PowerPoint educational module

Case 4Answer: 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 5yearsB OR FOBT + flexible sigmoidoscopy q 5yearsI OR Double contrast barium enema q 5 years OR Colonoscopy q 10 yearsI

A = Good evidenceB = Fair evidenceI = Insufficient evidence

Page 55: Hereditary Colorectal Cancer PowerPoint educational module

Case 5

Alz -75

Chronic cough

A&WMesothelioma Dx 45 Smoker

A&W

Aneurysm-65

AsthmaA&WYour Patient

AccidentLung Ca Dx 74

NON-smoker

ID DMChronic coughLung Ca Dx 43Smoker

A&W

Colon

Lung

Legend

Colon – CA

Dx 61

Page 56: Hereditary Colorectal Cancer PowerPoint educational module

Case 5

Colon

Lung

Legend

Page 57: Hereditary Colorectal Cancer PowerPoint educational module

Case 5Answer: 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 FOBTA OR Flexible sigmoidoscopy q 5yearsB OR FOBT + flexible sigmoidoscopy q 5yearsI OR Double contrast barium enema q 5 years OR Colonoscopy q 10 yearsI

A = Good evidenceB = Fair evidenceI = Insufficient evidence

Page 58: Hereditary Colorectal Cancer PowerPoint educational module

Case 6

Alz -75

A&W Colon Ca Dx 42

~1000

polyps

Aneurysm-65

AsthmaA&WYour Patient

AccidentLung Ca Dx 74

Smoker

ID DMA&WA&W

Colon CA Dx 32

A&W

Legend

Colon CA

Lung CA

A&W

A&W

Page 59: Hereditary Colorectal Cancer PowerPoint educational module

Case 6

Legend

Colon CA

Lung CA

Page 60: Hereditary Colorectal Cancer PowerPoint educational module

Case 6Answer: High risk for hereditary CRC >10 colorectal adenomatous polyps

Personal history or1st or 2nd degree relative (suggestive of FAP)

Management:Suggestive of FAP:

Seek advice from a colorectal specialist

Offer referral to hereditary CRC/genetics clinic

Page 61: Hereditary Colorectal Cancer PowerPoint educational module

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

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References1. Offit K Clinical Cancer Genetics: Risk Counseling and Management.

Wiley-Liss, New York. 1998.

2. 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.

3. 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.

4. 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.

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References5. 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.

6. Lightning bolt photo credit: http://www.ghouli.com/articles/sp/mainstream_4b.htm

7. 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.

8. 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.

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References9. 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.

10. 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.

11. 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.

12. 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.

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References13. 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.

14. 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.

15. Kohlmann W, Gruber SB Hereditary nonpolyposis colorectal cancer. Gene Tests Reviews www.genetests.org last updated November 29, 2006. Accessed June 21, 2009.

16. Watson P, Lynch HT Cancer risk in mismatch repair gene mutation carriers. Familial Cancer 2001; 1: 57-60.

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References17. 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.

18. 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.

19. 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.

20. 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.

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References21. Burt RW, Jasperson KW Familial adenomatous polyposis.

www.genetests.org. Last updated July 24, 2008, accessed June 21, 2009.

22. 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.

23. 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.

24. Johns LE, Houlston RS A systematic review and meta-analysis of familial colorectal cancer risk. Am J Gastroenterol. 2001; 96:2992-3003.

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References25. 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.

26. 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.

27. 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.

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References

28. 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.

29. Yu H-JA, Lin KM, Ota DM, Lynch HT. Hereditary nonpolyposis colorectal cancer: preventive management. Cancer Treatment Rev 2003; 29:461-470.

30. 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.

31. 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.

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Extra Slides

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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 tissue2 repeats

Tumour tissue with MSI variable repeat size 5 & 3MSI is a pathology finding specific

to Lynch syndrome colon tumours

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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

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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: 1. Are deficient for immunohistochemical staining for

the proteins MSH2, MLH1, MSH6 and/or PMS2

2. Show evidence of genetic instability of small repetitive DNA sequences (microsatellites) when compared to normal tissue.