• Background
• Lynch syndrome:
• Referral criteria
• Features
• Genetic testing
• Colorectal cancer diagnosed < age 50
• Recommendations for cancer screening and risk reduction
• Case examples
• Lynch syndrome awareness day - June 12, 2010

Background

• Family histories of colorectal cancer can be classified as:
• sporadic (70-75%), or
• multifactorial/familial (20-25%), or
• hereditary (5-10%)
• Only those with a personal or family history that suggests an inherited predisposition should be referred to the Hereditary Cancer Program.  See Assessing Family History for examples.  

Lynch Syndrome                                                                                                        
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• Lynch syndrome and Hereditary Nonpolyposis Colorectal Cancer (HNPCC) have been used interchangeably to describe hereditary patterns of colorectal/other cancers. Lynch syndrome is the term used currently by the Hereditary Cancer Program.
• Lynch syndrome accounts for about 2-5% of all colorectal cancer cases.
• At least four genes are currently known to be associated with Lynch syndrome: MLH1, MSH2, MSH6 and PMS2. All are involved in DNA repair.
• Lynch syndrome is inherited in an autosomal dominant manner.

• available in BC through the Hereditary Cancer Program for individuals/families who meet eligibility criteria
• carrier testing is offered if a Lynch syndrome gene mutation has already been identified in the family
• "index" testing for a family usually begins colorectal tumour tissue, ideally from:
• the individual with the youngest diagnosis of colorectal cancer, or
• an individual with multiple primary cancers

Colorectal tumour tissue is analyzed for:                                                                     
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• microsatellite instability (MSI)
• presence of the MLH1, MSH2, MSH6 & PMS2 proteins (via immunohistochemistry) 

If the tumour tissue results are normal (microsatellite stable and proteins intact), the likelihood of Lynch syndrome is low. Screening recommendations are then made based on family history of cancer.
Approximately 90% of Lynch syndrome colorectal tumours will show some degree of microsatellite instability when there is a mutation in the MLH1, MSH2, MSH6 or PMS2 genes. 

If the tumour tissue results are suggestive of Lynch syndrome:

• further genetic testing may be done on a blood sample to detect a germline mutation
• possible index results:
• positive - a mutation is identified in a Lynch syndrome gene. Relatives are eligible for "carrier" testing for the specific familial mutation.
• uninformative - a mutation is not identified in the Lynch syndrome gene. Carrier testing is not available to relatives. Does not rule out the presence of Lynch syndrome in the family. Further assessment is required and may include testing of additional affected family members.
• unclassified variant – a change in the gene that is not yet understood and may or may not be related to an increased risk of cancer. Carrier testing is not available to relatives. Does not rule out the presence of Lynch syndrome in the family. Further assessment is required.

Genetic testing for colorectal cancer diagnosed < age 50                                                 
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The BC Cancer Agency’s Genetics Laboratory now offers Microsatellite Instability (MSI) genetic testing for all new cases of colorectal cancer diagnosed in individuals < 50 years of age. MSI testing looks for genomic instability involving repetitive DNA sequences. 15% of sporadic colorectal cancer is MSI-high, compared to 90% of Lynch syndrome-related colorectal cancer. 

MSI testing does not require referral to the Hereditary Cancer Program, and can be ordered directly by surgeons, oncologists, pathologists and family physicians.  Requisitions and related patient information are available at Pathology Request Forms.  


Cancer screening and risk reduction recommendations for individuals with confirmed Lynch syndrome mutation. These guidelines also apply to those at 50% risk of having inherited a mutation. top

• colonoscopy: 
• begin at age 25 (or 5-10 years before the youngest diagnosis in the family, whichever is earlier)
• repeat every 1-2 years until age 40, and annually thereafter
• this interval has been reported in the literature to significantly reduce the incidence of colorectal cancer in Lynch syndrome.
• annual gynecologic examination and prompt investigation into any unusual bleeding between menstrual periods or after menopause
• prophylactic hysterectomy and bilateral salpingo-oophorectomy to be considered after age 35-40 or when childbearing is complete.
• annual endometrial biopsy with transvaginal ultrasound can be considered:
• begin at age 25-35 if the family history includes endometrial cancer
• begin at age 35 if the family history does not include endometrial cancer
• the effectiveness of this approach to screening has not been proven
• no standard screening recommendations have been developed for other cancers associated with Lynch syndrome as optimal screening remains undefined and controversial.

Lynch Syndrome Case Examples                                                                                                   
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pedigrees will be added to illustrate these cases

1. 36 year old male is diagnosed with an invasive adenocarcinoma of the rectum. His father, now 70, was diagnosed with colorectal cancer at age 52. A paternal aunt was diagnosed with colorectal cancer at age 58 and died of her disease at age 62. The young man is referred to the Hereditary Cancer Program. After genetic counselling, he consents to genetic testing for Lynch syndrome. A tumour tissue block from his cancer diagnosis is tested for microsatellite instability and loss of mismatch repair proteins through immunohistochemistry. The tumour is found to be microsatellite stable and all proteins are intact. This result reduces the likelihood that Lynch syndrome provides an explanation for the family history of colorectal cancer. As an inherited predisposition has not been ruled out, screening continues to be based on the pattern of cancer in the family.

2. 42 year old female is diagnosed with an endometrial adenocarcinoma. Her father was diagnosed with a transitional cell carcinoma of the ureter at age 52, followed by a carcinoma of the transverse colon at age 55. He died at age 58. Her brother, now age 44, was diagnosed with an adenocarcinoma of the cecum at age 32. This man consents to genetic testing for Lynch syndrome through the Hereditary Cancer Program. His tumour demonstrates microsatellite instability and loss of the MSH2 protein. Further molecular genetic testing on a blood sample identifies a pathogenic mutation in the MSH2 gene. Carrier testing for this specific mutation is now offered to all interested family members.