Lynch Syndrome is the Most Common Cause of Hereditary Colorectal Cancer
Lynch syndrome (LS), an autosomal dominant familial cancer syndrome, is caused by inherited mutations in five genes (MLH1, MSH2, MSH6, PMS2, and EPCAM) that disrupt the mismatch repair (MMR) pathway. This disruption causes microsatellite instability (MSI) that may lead to oncogenesis.1,2
- Lynch syndrome is a genetic condition that accounts for about 3% of all colorectal cancer (CRC) cases and is associated with increased risk of gastric, brain, upper urinary tract, and endometrial cancer in women.1,2
- Not all microsatellite instability is associated with Lynch syndrome. 12%-15% is categorized as non-hereditary (sporadic) CRC.1
- Lynch syndrome, also known as hereditary non-polyposis colorectal cancer (HNPCC), is associated with a 52% - 82% lifetime risk of developing CRC and often presents at an early age of onset (mean age at diagnosis 44-61).2
- Females have a 25%-60% lifetime risk of endometrial cancer (EC) and it often presents at an early age of onset (mean age at diagnosis 48-62).2
Identification of Lynch Syndrome
An appropriate workup of Lynch syndrome is crucial not only for the patient, but also for the patient’s family: every individual diagnosed with Lynch syndrome, on average, will have three relatives with Lynch syndrome.4
The NCCN Guidelines® recommend that patients who meet the clinical testing criteria, which includes the modified Bethesda Guidelines or the Amsterdam Criteria, should be tested for Lynch syndrome.1,5 However, because the modified Bethesda Guidelines may miss up to 28% of all Lynch syndrome patients, many NCCN®member institutions and the Evaluation of Genomic Application in Practice and Prevention (EGAPP) working group endorse Lynch syndrome testing for all newly-diagnosed CRC patients as a cost-effective means of reducing mortality and morbidity.1
Targeted Approach to Lynch Syndrome Testing
Integrated Oncology’s diagnostic approach for Lynch syndrome is based on the NCCN Guidelines®.5
Testing Workup for Lynch Syndrome in Colorectal Cancer5
Test Service Offerings
Integrated Oncology provides a comprehensive menu of services backed by a team of more than 60 pathologists, including a team of genetic counselors that work directly with patients and family members to explain testing options for Lynch syndrome and the significance of a high risk or positive diagnosis.
|Lynch Syndrome Comprehensive Screening Evaluation||All samples will be tested forMLH1/MSH2/MSH6/PMS2 by IHC and for MSI by PCR. BRAF testing will be performed when abnormal MLH1 staining is observed to rule in sporadic MSI-related CRC, and MLH1 gene methylation status may additionally be performed if necessary. The comprehensive diagnostic workup requires both fixed tumor sample and normal tissue from the patient (or peripheral blood) as a control||Available as a single test option with a case summary report that includes an explanation of the test findings|
|Mismatch Repair Proteins by IHC||Determines MMR protein expression (MLH1,MSH2, MSH6 and PMS2) by IHC in tumor tissue.||Available individually or in panels|
|MSI by PCR||Microsatellite Instability (MSI) by PCR. This test requires both fixed tumor sample and normal tissue from the patient (or peripheral blood) as a control.||Available individually or in panels|
|BRAF Mutation Analysis||BRAF mutation analysis by PCR. This assay detects any amino acid change that has an A nucleotide at position 1799 in exon 15 of theBRAF gene. This test distinguishes between Lynch syndrome and sporadic non-colorectal tumors with methylation of MLH1.||Available as a single test or as a reflex option|
|MLH1 Gene Methylation||MLH1 gene methylation by PCR. This test distinguishes between Lynch syndrome and sporadic non-colorectal tumors with methylation of MLH1.||Available as a single test or as a reflex option|
Hereditary (Germline) Testing
MLH1 Comprehensive Analysis
MSH2 Comprehensive Analysis
MSH6 Comprehensive Analysis
PMS2 Comprehensive Analysis
|Full gene sequencing and multiplex ligation-dependent probe amplification (MLPA) for detecting large duplications and deletions.||Available as a single gene test or in multi-gene panels|
|EPCAM Deletion/Duplication Analysis||Multiplex ligation-dependent probe amplification (MLPA) for detecting large duplications and deletions.||Available as a single gene test|
MLH1 Deletion/Duplication Analysis
MSH2 Deletion/Duplication Analysis
MSH6 Deletion/Duplication Analysis
PMS2 Deletion/Duplication Analysis
|MLPA for detecting large duplications and deletions.||Each gene available as a single gene test|
MLH1 Targeted Analysis
MSH2 Targeted Analysis
MSH6 Targeted Analysis
PMS2 Targeted Analysis
|Targeted single-amplicon analysis for known mutation||Each gene available as a single gene test|
|Lynch Syndrome Comprehensive Screening Evaluation||Formalin-fixed paraffin-embedded block and either whole blood or paraffin-embedded normal tissue (for the MSI control)||If submitting whole blood: 3-7 mL in a lavender-top (EDTA) tube|
|MMR proteins by IHC||Formalin-fixed paraffin-embedded block or 2 unstained slides from paraffin block in 5 μm sections for each requested stain|
|MSI by PCR||Formalin-fixed paraffin-embedded block and either whole blood or paraffin-embedded normal tissue (for the control)||If submitting whole blood: 3-7 mL in a lavender-top (EDTA) tube|
|BRAF Mutation Analysis||Formalin-fixed paraffin-embedded block or 4 unstained slides from paraffin block in 5 μm sections and one H&E reference slide (or 5 slides w/o an H&E)||Formalin-fixed paraffin-embedded tissue block with tumor area ≥4 mm2 and ≥50% tumor preferred|
|MLH1 Gene Methylation||Formalin-fixed paraffin-embedded block or 4 unstained slides from paraffin block in 5 μm sections and one H&E reference slide (or 5 slides w/o an H&E)||Formalin-fixed paraffin-embedded tissue with tumor area ≥4 mm2 and ≥50% tumor preferred|
Hereditary (Germline) Testing
|MLH1/MSH2/MSH6/PMS2 and/or EPCAMtesting||Whole blood: 4-7 mL in a lavender-top (EDTA) tube|
- Giardiello, FM et al., Guidelines on genetic evaluation and management of Lynch syndrome: A consensus statement by the U.S. Multi-Society Task Force on Colorectal Cancer. Gastrointestinal Endoscopy 2014; 80:197-219.
- Kohlmann, W et al., Lynch syndrome. GeneReviews 2014: Available online. Accessed 1/14/2015.
- Kempers MJ et al., Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: a cohort study. Lancet Oncol 2011; 12:49-55.
- Hampel H et al., Feasibility of Screening for Lynch Syndrome Among Patients With Colorectal Cancer. J Clin Oncol 2008; 26:5783-8.
- The NCCN Clinical Practice Guidelines in Oncology – Genetic/Familial High-Risk Assessment: Colorectal (Version 2.2014). ©National Comprehensive Cancer Network, Inc. 2015.
NCCN® and NCCN Guidelines® are trademarks owned by the National Comprehensive Cancer Network, Inc.
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