Lynch Syndrome

Lynch Syndrome

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.

Tumor Testing

Test Description Testing Options
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

Test Description Testing Options

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

Specimen Requirements:

Tumor Testing

Test Specimen Requirements Comments
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

Test Specimen Requirements
MLH1/MSH2/MSH6/PMS2 and/or EPCAMtesting Whole blood: 4-7 mL in a lavender-top (EDTA) tube

References

  1. 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.
  2. Kohlmann, W et al., Lynch syndrome. GeneReviews 2014: Available online. Accessed 1/14/2015.
  3. 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.
  4. Hampel H et al., Feasibility of Screening for Lynch Syndrome Among Patients With Colorectal Cancer. J Clin Oncol 2008; 26:5783-8.
  5. 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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