Hereditary colorectal cancer: Lynch syndrome
Most colorectal cancers arise sporadically, with no inherited cause. But roughly 1 in 25 patients with colorectal cancer has Lynch syndrome — the most common hereditary form, responsible for 3-5% of all cases.
The difference between knowing and not knowing is large, and not only for the patient: a diagnosis of Lynch changes surveillance for children, siblings and parents, some of whom may still be healthy and can stay that way.
What it is, briefly
Lynch syndrome is caused by an inherited mutation in one of the genes that repair DNA copying errors — MLH1, MSH2, MSH6, PMS2 or EPCAM. When one of them fails, errors accumulate and cancer risk rises substantially.
It is inherited in an autosomal dominant manner: each child of a carrier has a 50% chance of inheriting the mutation.
Prevalence in the general population is estimated at roughly 1 in 279 people — far more common than most people imagine.
The risk figures
| Lifetime risk | |
|---|---|
| Colorectal cancer, Lynch syndrome | 50-70% |
| Colorectal cancer, general population | about 4% |
| Endometrial cancer, Lynch syndrome | 40-60% |
The risk varies considerably with the gene involved — the literature reports ranges from 9% to 61% for colorectal cancer depending on the mutation. That variation matters practically: MLH1 and MSH2 carriers have higher risks than MSH6 and PMS2 carriers, and surveillance is adjusted accordingly.
Lynch syndrome also raises the risk of other cancers: ovary, stomach, small bowel, urinary tract, biliary tract, skin.
What it means in rectal cancer
Lynch syndrome is classically associated with right-sided colon tumours, but rectal cancer occurs too, and several aspects are specific.
Young age is the signal. A rectal cancer in someone under 50 deserves genetic investigation. Incidence in young adults is rising, and not all cases are hereditary — most are not — but at that age testing must at least be discussed.
The extent of surgery can change. A young patient with Lynch and rectal cancer carries a significant risk of developing a second, metachronous cancer in the remaining colon. That changes the surgical discussion: a more extensive resection may be considered instead of a segmental one. It is a decision with important functional trade-offs, taken together with the patient — but it cannot be taken at all if the Lynch diagnosis arrives after the operation.
Subsequent surveillance is different and more frequent than usual.
This is the practical reason why testing should be done at diagnosis, not after treatment.
How it is detected
The order is two steps, and the first is not a genetic test.
Step 1 — testing the tumour. On the biopsy fragment or the surgical specimen, immunohistochemistry is performed for the four MMR proteins, or MSI testing. It does not cost much, requires no additional procedure, and guidelines recommend it for all newly diagnosed colorectal cancers. In population-based cohorts this universal approach had 100% sensitivity and 93% specificity.
A dMMR result does not automatically mean Lynch — the most common cause is in fact an acquired rather than inherited change. Hence step two.
Step 2 — genetic testing, from blood, which confirms or excludes the inherited mutation. It is done with genetic counselling.
The same dMMR result has a second immediate consequence: it opens the discussion about immunotherapy.
When to think about Lynch
Universal testing should make this list unnecessary, but in practice it does not happen everywhere. Think about Lynch if:
- You had colorectal cancer under the age of 50
- You have first-degree relatives with colorectal or endometrial cancer, particularly at young ages
- The family contains several cancers from the Lynch spectrum, in the same person or in close relatives
- You have already had two different cancers from that spectrum
- Your pathology report mentions dMMR or MSI-high
If any of these applies and testing has not been offered, ask for it.
What it means for the family
This is the part with the greatest impact, and the one most often missed.
When a mutation is confirmed, first-degree relatives — parents, siblings, children — have a 50% chance of carrying it. They can be tested directly for the already identified mutation, which is simple and cheap compared with the initial testing. This is called cascade testing.
Relatives who have not inherited the mutation return to general-population risk and are spared unnecessary intensive surveillance. Relatives who have inherited it enter a programme that genuinely works.
A Lynch diagnosis is not only bad news about a disease. It is also the information that can prevent the next cancer in the family.
Surveillance
For mutation carriers, colonoscopy is done at short intervals — usually every 1-2 years — and starts far earlier than ordinary screening, the starting age being set according to the gene involved and the family history.
The short interval is not bureaucratic excess: in Lynch, the adenoma-to-carcinoma sequence is faster than the usual 7-15 years, and a ten-year interval would miss precisely the tumours surveillance is meant to prevent.
For women, gynaecological surveillance is added, and in some situations prophylactic surgery is discussed once childbearing plans are complete.
What to ask
- Was MMR or MSI testing done on my tumour? What was the result?
- If it is dMMR, does genetic testing and counselling follow?
- If Lynch is confirmed, what does it mean for the extent of my operation?
- Who in my family should be tested, and how?
- At what interval should I have colonoscopy from now on?
The information in this article is educational. Genetic testing is done with specialist counselling, and interpretation of results belongs to the geneticist and treating doctor.