Lynch syndrome: the hereditary bowel cancer you should know

Lynch syndrome: The hereditary form of bowel cancer you should know about

Lynch syndrome is the most common inherited cancer predisposition, and therefore also the most common inherited predisposition to colorectal cancer [5]. It is caused by a congenital fault in one of the body's DNA repair genes, and it increases the risk of cancer in the bowel, the womb and a number of other organs. Many people carry it without knowing. That matters, because once Lynch syndrome is known, the carrier can be offered a surveillance programme with regular colonoscopy, where precursors can be removed and cancer found earlier.

There is no reliable Danish figure for how many people have Lynch syndrome, or how many of them know their diagnosis. The European guidelines describe the condition as still underdiagnosed [5].

What do you notice?

The syndrome itself causes no symptoms. It is a predisposition, not a disease. What you may notice is one of the cancers it predisposes to. The most common are:

• Bowel cancer: the risk depends on which gene is affected, and the authors of the large series stress that counselling must also take account of sex and age. In the Prospective Lynch Syndrome Database, which followed 3,119 carriers prospectively, the cumulative incidence of colorectal cancer up to age 75 was 46 per cent for MLH1, 43 per cent for MSH2 and 15 per cent for MSH6, while PMS2 carriers had a lower risk [4]. These are observed incidences in an international cohort in which many attended colonoscopy surveillance. They are not individual lifetime risks. The cancer often arises before age 50 and frequently on the right side of the bowel
• Womb cancer (endometrial cancer): in the same cohort the cumulative incidence up to age 75 among female carriers was 43 per cent for MLH1, 57 per cent for MSH2 and 46 per cent for MSH6 [4]. Ovarian cancer is reported separately and was lower: 10 per cent for MLH1, 17 per cent for MSH2 and 13 per cent for MSH6 [4]. The two figures must not be added together or confused
• Cancer of the ovaries, stomach, small bowel, urinary tract, bile ducts, brain (Turcot variant) and skin (Muir-Torre variant)

Symptoms to be aware of if you or your family are affected: blood in the stool, persistent change in bowel habit, unexplained weight loss, iron deficiency anaemia, and in women abnormal bleeding, including bleeding between periods, heavier or longer bleeding than usual, and any bleeding after the menopause.

Why does it happen?

Lynch syndrome is caused by an inherited variant in one of four DNA repair genes: MLH1, MSH2, MSH6 or PMS2 (plus the related gene EPCAM). These genes normally correct small errors that arise when DNA is copied. When the repair system fails, cells accumulate mutations faster, and cancer can arise earlier and more often.

Lynch is inherited in an autosomal dominant manner. That means each first-degree relative (parents, siblings, children) of a carrier has a 50 per cent chance of having inherited it.

Today the main route to diagnosis runs through the tumour, not the family tree. The European guidelines recommend that tissue from colorectal and endometrial cancers is examined with immunohistochemistry for the four MMR proteins, optionally supplemented by MSI analysis [5]. How widely this is implemented varies between countries and departments, so it cannot be assumed that every tumour is actually tested. If one of the proteins is missing, it is a signal that Lynch syndrome may be present.

What happens next depends on the tumour type. Where MLH1 is lost in a colorectal tumour, testing for a BRAF mutation or for methylation of the MLH1 promoter is typical, because the finding often reflects an acquired change in the tumour rather than inheritance. In endometrial cancer BRAF is not used in the same way; there, methylation analysis is the relevant step [5].

The older Amsterdam and Bethesda criteria are still used as support, but they are no longer the primary entry point to assessment. Family history remains important, and you should mention it to your doctor if:

• There is bowel or womb cancer in the family before the age of 50
• Several people on the same side of the family have had Lynch-related cancers
• The same person has had more than one of the typical cancers

How is the diagnosis made?

Suspicion is raised by the family history or by MMR testing on a tumour. From there the pathway runs through a clinical genetics department:

• Genetic counselling before testing, covering the family tree, the possible results and their consequences.
• Germline analysis on a blood sample. This includes sequencing of the relevant genes and an analysis for larger deletions and duplications, which ordinary sequencing does not detect. If the variant is already known in the family, the test can be targeted at it.
• Interpretation of the result. A result may be a pathogenic variant, a normal analysis, or a variant of uncertain significance (VUS). A VUS is not a diagnosis, and it may be reclassified later. A finding in the tumour alone is also not a diagnosis in itself; it must be clarified whether the change is inherited.

If it is new in the family, all relevant genes are examined. It is never too late to have this clarified. Many people only recognise the family pattern after a bowel cancer diagnosis in a relative.

Treatment and surveillance

Lynch syndrome cannot be treated away, but the risk can be managed with a surveillance programme. The programme is set by the clinical genetics department together with the treating specialties, and the European guidelines are gene- and sex-specific [5]. What follows is therefore a description of the elements, not a finished plan for the individual.

Bowel:

• Regular colonoscopy is the cornerstone. The starting age depends primarily on which gene is affected, and the interval is set by the department that follows you [5]. Sex and family history feed into the risk assessment, but sex alone does not determine the interval. Polyps found are removed during the examination where possible, though in some cases this requires a repeat examination or a different procedure.
• Aspirin has been studied as prevention in the randomised CAPP2 trial, which showed fewer cases of bowel cancer among carriers on long-term treatment [2]. This is not treatment to start on your own. Dose, duration and bleeding risk must be weighed individually with the doctor who follows you.

Gynaecology for women:

• Screening with routine transvaginal ultrasound and endometrial biopsy has not been shown to reduce mortality from womb cancer. What matters most is that women with Lynch syndrome know the symptoms of abnormal bleeding, both a changed bleeding pattern during the fertile years and any bleeding after the menopause, and are assessed quickly when they occur [1].
• Risk-reducing surgery can be discussed once the family is complete. Removal of the womb addresses the risk of endometrial cancer, and removal of the ovaries and fallopian tubes the risk of ovarian cancer. These are two separate decisions, and both timing and extent depend on gene, age, other illness and the woman's own wishes [1, 5].

Other:

• The risk of cancer in the stomach, urinary tract and other organs is lower than for bowel and womb, and it is distributed differently between the genes [4]. Whether gastroscopy or urinary tract surveillance is offered is decided within the individual programme, not as a general annual routine.
• Where there are Muir-Torre features in the family, skin surveillance is considered together with the genetics department.

On a cancer diagnosis, MMR status matters for the choice of treatment. Tumours with defective mismatch repair may be sensitive to immunotherapy, but whether that is relevant depends on cancer type, stage and the overall oncological assessment. That decision is made in the oncology department.

When should you see a doctor?

Book an appointment with your GP and ask for a referral to a clinical genetics department if:

• You have a first-degree relative with bowel or womb cancer before the age of 50
• You have several relatives on the same side of the family with bowel, womb, stomach, ovarian, urinary tract or bile duct cancer
• You have had bowel cancer yourself before the age of 50
• Pathology on a tumour in the family has shown loss of MMR proteins

Blood in the stool, a persistent change in bowel habit, unexplained weight loss and abnormal vaginal bleeding all need investigation. How urgently depends on the extent and on what other symptoms are present. If bleeding is heavy, or you feel dizzy, look pale or faint, it is acute: call 112 for heavy, continuing bleeding, for fainting, or for severe sudden abdominal pain with a reduced general condition. If symptoms are less pronounced, contact your GP promptly and use the out-of-hours service outside opening times.

Frequently asked questions

Does everyone with Lynch syndrome get cancer? No. The risk is high, but not 100 per cent. Colonoscopy surveillance has been studied in observational cohorts, including the Prospective Lynch Syndrome Database, where carriers were followed prospectively while under surveillance [4]. There are no randomised trials that can quantify the effect precisely, and the size of the benefit cannot be given as a single number.

What about my children? Each child has a 50 per cent chance of having inherited the variant. Once the variant is known in the family, your children can be offered a targeted test. In Denmark predictive genetic testing is generally offered to adults, and the timing is agreed with the clinical genetics department based on when surveillance should begin.

Should I change my diet and lifestyle? A healthy lifestyle lowers general cancer risk, and stopping smoking is recommended for everyone. How much weight and physical activity matter specifically in Lynch syndrome is not settled. The best documented preventive measure is the surveillance programme, and aspirin has been studied in trials but must be agreed with your doctor.

Does Lynch syndrome have consequences for insurance and work? Danish law regulates when information about genetic predisposition may be obtained and used, including in insurance. The rules are complex, and they can be discussed with the clinical genetics department as part of counselling before you decide about testing.

My family has bowel cancer, but nobody under 50. Should I still be tested? Possibly. Lynch syndrome can still be the explanation in late-onset bowel cancer, particularly if MMR proteins are missing on the tumour. Let a specialist assess the family tree.

References

1. Crosbie EJ, Ryan NAJ, Arends MJ, et al. The Manchester International Consensus Group recommendations for the management of gynecological cancers in Lynch syndrome. Genet Med. 2019;21(10):2390-2400. PubMed
2. Burn J, Sheth H, Elliott F, et al. Cancer prevention with aspirin in hereditary colorectal cancer (Lynch syndrome), 10-year follow-up and registry-based 20-year data in the CAPP2 study: a double-blind, randomised, placebo-controlled trial. Lancet. 2020;395(10240):1855-1863. PubMed
3. Sundhed.dk. Lynch syndrome (Danish clinical handbook).
4. Møller P, Seppälä TT, Bernstein I, et al. Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome Database. Gut. 2018;67(7):1306-1316. PubMed
5. Seppälä TT, Latchford A, Negoi I, et al. European guidelines from the EHTG and ESCP for Lynch syndrome: an updated third edition of the Mallorca guidelines based on gene and gender. Br J Surg. 2021;108(5):484-498. PubMed

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This article provides general information and does not replace medical consultation. Contact your GP if you experience symptoms.