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.
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
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
Clinical testing available for 4 genes: MLH1 & MSH2 ( most common ), MSH6 & PMS2
Research testing may be available for other genes
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
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%
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
Confirmation of cancer history: pathology reports/death certificates
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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.
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.