Lynch syndrome (LS) is the most common dominantly inherited cancer syndrome. Its prevalence in a population may exceed 1:200 1.
LS predisposes the patient to several cancers. Carriers of the predisposing gene defect have an average risk of 70% of developing a cancer by the age of 70.
As the gene defect exists in every one of the carrier's cells, cancer may develop in practically any organ, but colorectal and uterine cancers are the most common.
Within the next few years, people with LS will form a significant risk group for cancer where follow-up measures should be directed individually depending on the predisposing gene defect, gender and age.
Background
Concentrated follow-up for early detection of cancer has significantly improved the prognosis of LS patients who develop cancer.
A person with the LS gene defect may be healthy as regards cancer or may have had cancer.
In Finland (population 5.5 million), the systematic collection and study of Finnish families with LS was started in 1982 and concentrated in the Finnish Lynch Syndrome Registry. About 400 families with LS have been identified, and there are close to 2 000 tested carriers of the gene defect who are alive and being followed up.
About 40% of the identified Finnish people with LS have exactly the same pathogenic MLH1 gene variant which has prevailed for dozens of generations and is widespread in the population.
Based on the prevalence of LS (1:200) 1, it can be estimated that there are 5 to 10 times more unidentified people in Finland who have inherited the mismatch repair (MMR) gene defect.
Diagnosis
LS should be suspected in patients diagnosed with colorectal cancer, cancer of the uterine corpus or several tumours typical for LS at an exceptionally young age. Many such patients have a family history suggesting LS. They should be referred to a specialized genetics department for assessment and guidance for any gene testing.
Gene testing can be used to find out whether the person carries a gene variant predisposing to cancer. Individuals who, based on the gene, have a high risk of cancer are offered follow-up facilitating early detection of cancer from the age of 25 years.
The offspring and siblings of those with the gene defect each carry a 50% risk of having inherited the gene defect predisposing to cancer. As the cancer risk of family members without the LS gene defect is equivalent to that of the normal population, their offspring need not be tested for the family LS gene defect or be followed up.
The diagnosis requires a pathogenic gene variant detected by sequencing in the MMR gene. The test is performed with a blood sample drawn from a live family member with a clinical picture consistent with the syndrome (history of LS cancer). This way, the predisposing variant running in the family can be detected and tested for in healthy family members at risk to identify those who have inherited LS.
LS screening may be carried out with immunohistochemical staining for the analysis of expression of MMR genes in all colorectal and uterine corpus cancer samples. Alternatively, the microsatellite instability (MSI) PCR test defining certain microsatellites can be done in patients with colorectal cancer. This will reveal potential cases of LS but the actual diagnosis must still be confirmed by sequencing the gene from a blood sample because changes seen in staining and MSI can also develop in a nonhereditary manner, as a result of somatic mutations occurring in a tumour.
LS testing will only be done for legal adults, with their consent, and after providing them with information on heredity. Children need not be tested because tumours only appear in adulthood. In LS, malignant turmours develop in childhood only if the child inherits a pathogenic LS-variant from both parents (homozygote). This CMMRD (constitutional mismatch repair deficiency) syndrome is rare 3.
National registries may reveal new LS families.
In Finland, many new LS families are found today as family members spontaneously contact the Finnish Lynch Syndrome Registry through the Registry website. There is a form there, where people can fill in their families' cancer data.
Cancer risk in people with the Lynch syndrome
A calculator based on observational studies can be used to assess the age-, gender-, gene- and organ-related lifetime cancer risk in any individual carrier of the LS gene defect 4. Link to a calculator: http://www.plsd.eu.
Even though carriers of the LS gene defect are offered regular colonoscopy monitoring with the aim of removing all polyps detected, nearly 50% of them develop cancer of the large intestine during their lifetime. Even though there is a high probability of cancer, the prognosis of the most common types of cancer (colorectal cancer and cancer of the uterine corpus) is good. The 10-year survival rates are 81-94% 5.
In patients with LS, some bowel cancers most probably develop directly on the mucosa without any benign, identifiable precursors 6.
Preventive surveillance for cancer
In 2020, European guidelines were published for surveillance based on the risk of developing a first or subsequent cancer associated with each MMR gene 7.
In people who have inherited the LS gene defect, colonoscopies should be started at the age of 25 years (in MSH6 and PMS2 gene defects at the age of 30-35 years) and continued every 3 years until the expected mortality associated with the person's age and general condition exceeds the risks associated with any bowel cancer 7.
Women who have inherited the LS gene defect should have a gynaecological checkup once after the diagnosis and be provided with information related to the risk of cancer of the uterus and ovarian cancer. With approaching menopause, prophylactic hysterectomy or ovariectomy may be considered.
No other regular screening is recommended for patients with LS so far, because there is no strong evidence for their benefits 7.
Today, with patients and doctors very well aware of hereditary susceptibility for cancer, cancers are detected early even based on symptoms.
Mortality results from tumours of the upper GI tract (pancreas, stomach, small intestine, bile ducts), certain urological tumours and rare brain tumours 9.
Other preventive measures
There is initial evidence that physical activity reduces and overweight increases the risk of cancer 10. A lifestyle that is generally considered healthy can be recommended for people with LS 7.
Low-dose (100-300 mg/day) aspirin is recommended for people with LS to lower the risk of colon cancer 7 but there is no consensus yet as to at what age medication should be started and how long it should be continued.
The use of aspirin for 2-4 years reduced the incidence of colorectal cancer by 50% for as long as 20 years 12.
For safety reasons, the treatment should, for the time being, be restricted to people below 65 years of age.
There is no difference in the risk of bleeding between daily doses of 100 and 300 mg of acetylsalicylic acid 13.
A vaccine has also been developed to boost cancer prevention in people with LS. The first results of clinical tests were published in 2020 14. It will be several years yet before the vaccine is possibly available for clinical use.
Treatment of cancer in people with the Lynch syndrome
If a person with LS is diagnosed with cancer, it is important to first make sure that there is no other cancer growing in any other organ, because the risk of concomitant tumours is increased.
In women, it is always important to check both the large intestine and the gynaecological status before performing any procedures.
Bowel cancers associated with LS are most often situated in the right large intestine.
In Finland, the established surgical procedure is subtotal colectomy with extended right colectomy and ileosigmoid anastomosis 15. The patient will retain the rectum and approx. 20 cm of the sigmoid colon, which will ensure normal bowel function and facilitate easy follow-up by colonoscopy.
For cancers based on MMR defects (or MSI-H cancers), there are immunomodulatory therapies available today, such as immune checkpoint inhibitors, of which pembrolizumab, for instance, is indicated in the treatment of metastasized MSI-H colon and rectal cancer in Europe.
References
Frankel W, Arends M, Frayling IM. Genetic tumour syndromes of the digestive system. In: Arends M, Carniero F, Lax S, editors. Dig Syst Tumours, WHO Classif Tumours, 5th Ed Vol 1. Lyon, France: International Agency for Research on Cancer; 2019. page 515-21.
Tabori U, Hansford JR, Achatz MI ym. Clinical Management and Tumor Surveillance Recommendations of Inherited Mismatch Repair Deficiency in Childhood. Clin Cancer Res 2017;23(11):e32-e37. [PubMed]
Dominguez-Valentin M, Sampson JR, Seppälä TT et al. Correction: Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database. Genet Med 2020;22(9):1569. [PubMed]
Dominguez-Valentin M, Seppälä TT, Sampson JR et al. Survival by colon cancer stage and screening interval in Lynch syndrome: a prospective Lynch syndrome database report. Hered Cancer Clin Pract 2019;17():28. [PubMed]
Ahadova A, Seppälä TT, Engel C et al. The "unnatural" history of colorectal cancer in Lynch syndrome: Lessons from colonoscopy surveillance. Int J Cancer 2021;148(4):800-811. [PubMed]
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]http://gut.bmj.com/content/67/7/1306
Sievänen T, Törmäkangas T, Laakkonen EK et al. Body Weight, Physical Activity, and Risk of Cancer in Lynch Syndrome. Cancers (Basel) 2021;13(8):. [PubMed]
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]
Jones WS, Mulder H, Wruck LM et al. Comparative Effectiveness of Aspirin Dosing in Cardiovascular Disease. N Engl J Med 2021;384(21):1981-1990. [PubMed]
Kloor M, Reuschenbach M, Pauligk C et al. A Frameshift Peptide Neoantigen-Based Vaccine for Mismatch Repair-Deficient Cancers: A Phase I/IIa Clinical Trial. Clin Cancer Res 2020;26(17):4503-4510. [PubMed]
Renkonen-Sinisalo L, Seppälä TT, Järvinen HJ et al. Subtotal Colectomy for Colon Cancer Reduces the Need for Subsequent Surgery in Lynch Syndrome. Dis Colon Rectum 2017;60(8):792-799. [PubMed].