Lynch Syndrome: Tumour Screening vs Germline Confirmation

Two Different Questions

Tumour screening asks whether a cancer shows signs of mismatch-repair deficiency. Germline testing asks whether the person carries an inherited pathogenic variant that would explain such a deficiency and confer lifelong risk.

The first is done on the tumour and is now near-universal in colorectal and endometrial cancer; the second is done on normal DNA, usually blood or saliva, after appropriate counselling and consent.

How Tumour Screening Works

Two methods are used, often together. Immunohistochemistry checks whether the four mismatch-repair proteins (MLH1, MSH2, MSH6, PMS2) are present in tumour cells. Molecular microsatellite instability testing looks for the length changes at repetitive DNA that accumulate when repair fails.

A tumour that shows protein loss or high microsatellite instability is described as mismatch-repair deficient. This is the screening-positive result that triggers further steps.

Why Deficiency Is Not the Same as Lynch Syndrome

Most mismatch-repair-deficient colorectal cancers are sporadic, caused by acquired silencing of the MLH1 gene through promoter methylation, frequently alongside a BRAF V600E mutation. These are not inherited.

Reflex testing for MLH1 methylation and BRAF is therefore used to sort likely-sporadic cases from those that warrant germline testing. Tumours with unexplained protein loss, or loss of MSH2, MSH6 or PMS2, are more likely to reflect Lynch syndrome.

Confirming the Diagnosis

Germline testing of the mismatch-repair genes, and of EPCAM for a specific deletion that silences MSH2, is used to confirm Lynch syndrome. Panel testing can also reveal that the underlying cause is a different predisposition gene entirely.

Some patients have biallelic somatic (tumour-only) mismatch-repair gene mutations, which explain the deficiency without inherited risk. Distinguishing this from Lynch syndrome may require paired tumour and germline analysis.

Interpretation Notes

A mismatch-repair-deficient or microsatellite-instability-high tumour result has treatment relevance in its own right, since it can indicate benefit from immune-checkpoint inhibitors, but that is separate from the inherited-risk question.

Only a confirmed germline pathogenic variant establishes Lynch syndrome and drives surveillance and family testing recommendations.

Key Takeaways

• ·Tumour screening (immunohistochemistry, microsatellite instability) flags possible Lynch syndrome.
• ·Most deficient colorectal cancers are sporadic, from MLH1 methylation with BRAF V600E.
• ·Germline testing on normal DNA is required to confirm Lynch syndrome.
• ·Tumour deficiency has its own treatment relevance separate from inherited risk.