Universal molecular screening does not effectively detect Lynch syndrome in clinical practice

Area of Science:

• Oncology
• Genetics
• Cancer Screening

Background:

• Lynch syndrome (LS) accounts for 3% of colorectal cancer (CRC) cases.
• Immunohistochemistry (IHC) for mismatch repair (MMR) proteins is recommended for LS screening in CRC.
• This study evaluated population-based routine molecular screening for LS diagnosis.

Purpose of the Study:

• To assess the outcomes of universal IHC testing for MMR protein expression in incident CRC cases.
• To evaluate the effectiveness of current referral pathways to familial cancer clinics for LS diagnosis.
• To propose an improved strategy for LS detection in CRC patients.

Main Methods:

• A prospective case series of 1612 individuals with resected CRC undergoing universal IHC testing from 2004-2013.
• Abnormal IHC results led to assessment via modified Bethesda criteria or molecular criteria.
• Patients with abnormal results were referred to a familial cancer clinic for further evaluation and germ-line sequencing.

Main Results:

• 16.9% (274/1612) of cases showed loss of MMR gene expression.
• Only 29.9% (82/274) of patients with abnormal IHC attended a familial cancer clinic.
• Germ-line sequencing identified clinically significant abnormalities in 0.6% (10/82) of referred patients, with 8 additional cases from other referrals.

Conclusions:

• Universal IHC screening for LS in CRC has limited real-world yield due to reduced referrals and genetic testing.
• Factors such as younger age at diagnosis and specific MMR gene alterations (e.g., MSH6 loss) influenced referral.
• A 'one-stop' approach combining MMR testing and sequencing is proposed for more efficient universal incident case detection of LS.