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

Epidemiology and Clinical Features

  • 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
  • Every individual diagnosed with Lynch syndrome, on average, will have three relatives with Lynch syndrome.4
     

Diagnostic Approach Based on NCCN Guidelines®

Tumor Testing Summary Table

Click on test name for specimen requirements and additional information

Test Description
Lynch Syndrome Comprehensive Screening Evaluation

All samples will be tested for MLH1/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.

Mismatch Repair Proteins by IHC

Determines MMR protein expression (MLH1, MSH2, MSH6 and PMS2) by IHC in tumor tissue

Microsatellite Instability (MSI) by PCR

Identify tumors with microsatellite instability. High-frequency microsatellite instability (MSI-H) is associated with Lynch syndrome.

BRAF Mutation Analysis

This test distinguishes between Lynch syndrome and sporadic non-colorectal tumors with methylation of MLH1

MLH1 Promoter Methylation Analysis by PCR

This test distinguishes between Lynch syndrome and sporadic non-colorectal tumors with methylation of MLH1

MLH1/MSH2/MSH6/PMS2/EPCAM
Somatic Tumor Mismatch
Repair Sequencing and Deletion/Duplication Test

This test assesses the tumor for a pathogenic genetic variant (MLH1/MSH2/MSH6/PMS2/EPCAM), if found, the variant will be evaluated in blood to determine germline/hereditary status

Hereditary (Germline) Testing Summary Table

Click on test name for specimen requirements and additional information

Test Description
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

EPCAM Deletion/Duplication Analysis

Multiplex ligation-dependent probe amplification (MLPA) for detecting large duplications and deletions

MLH1 Deletion/Duplication Analysis
MSH2 Deletion/Duplication Analysis
MSH6 Deletion/Duplication Analysis
PMS2 Deletion/Duplication Analysis

MLPA for detecting large duplications and deletions

MLH1 Gene Sequencing (Known Mutation)
MSH2 Gene Sequencing (Known Mutation)
MSH6 Gene Sequencing (Known Mutation)
PMS2 Gene Sequencing (Known Mutation)

Targeted single-amplicon analysis for known mutation

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. National Comprehensive Cancer Network. Genetic/Familial High Risk Assessment: Colorectal Version 1.2018.
http://www.nccn.org. Published July 12, 2018. Accessed August 30, 2018.