MSI

Lynch syndrome

Lynch syndrome (LS) is an inherited cancer syndrome with autosomal dominant type of inheritance. It is caused by changes in MLH1, MSH2, MSH6, PMS2, EPCAM genes and is associated with an increased risk of developing such malignant neoplasms as colorectal cancer (CRC), endometrial cancer, gastric cancer, ovarian cancer, etc. (see Table 1). The frequency of Lynch syndrome in the population is 1:300.

A diagnosis of Lynch syndrome is made if a patient is tested positive with a germline mutation in one of the genes associated with the syndrome (MLH1, MSH2, MSH6, PMS2, EPCAM).

Diagnostics

Diagnostic criteria for testing for Lynch syndrome include ^{[3, 5]}:

Revised Bethesda criteria

• CRC, endometrial cancer, and other “syndromic” tumors in patients <50 years of age
• Synchronous and metachronic CRC or synchronous and metachronic “syndromic” tumors
• CRC with MSI-H status in patients <60 years
• ≥1 first-degree relatives with any of the “syndromic” tumors aged <50 years
• ≥2 first-degree relatives with any of the “syndromic” tumors diagnosed at any age
• Patients with CRC or any of the “syndromic” tumors and a first-degree relative with “syndromic” ZNO diagnosed <50 years
• Patients with CRC or any of the “syndromic” tumors and ≥2 first- and second-degree relatives with “syndromic” ZNOs diagnosed at any age

The updated Amsterdam II criteria:

• ≥3 relatives with cancers associated with Lynch syndrome
• ≥2 consecutive generations in the family have oncological diseases associated with the syndrome
• ≥1 relative diagnosed with “syndromic” ZNO <50 years
• 1 relative must be first-degree related to two others
• Familial adenomatous polyposis should be ruled out
• The tumor has been histologically verified

In addition to the above criteria, in clinical practice, geneticists and oncologists also use risk calculation programs, such as PREMM, MMRPro, MMRPredict. I would like to note that 25% of families with Lynch syndrome do not meet the criteria for these models.

The syndrome manifestation

Depending on what gene is affected, the LS symptoms will vary ^{[3, 6]}:

• > 10% for carriers of changes in the MLH1 and MSH2 genes, the risk of ovarian cancer.
• ≤ 13% for carriers of the pathological variant in MSH6, the risk of ovarian cancer is characteristic of tumors with an MSI‑low/stable (MSI‑low/stable) status.
• < 3% PMS2 carriers are at risk of ovarian cancer, characterized by low penetrance of the syndrome (relatively low risks of developing cancer).
• < 10% of EPCAM carriers are at risk of ovarian cancer, and there is a relatively low risk of developing endometrial cancer.
• 15% of colorectal cancers are associated with high-grade MSI (MSI‑H/high) [2] — they have defects in MMR system.
• 90% of LS associated colorectal cancers also have a high MSI (MSI‑H/high).

According to the clinical guidelines of the Ministry of Health of the Russian Federation and the NCCN (US National Cancer Network), dMMR/MSI status assessment is recommended for patients with CRC and endometrial cancer in order to increase the detection of patients with Lynch syndrome ^{[4, 9]}.

Reference

1. Gian Luigi De’ Angelis, Lorena Bottarelli, Cinzia Azzoni, Nicola De’ Angelis, Gioacchino Leandro, Francesco Di Mario, Federica Gaiani, Francesca Negri. Microsatellite instability in colorectal cancer. Acta Biomed. 2018 Dec 17;89(9-S):97-101.
2. Aaltonen LA, Salovaara R, Kristo P, Canzian F, Hemminki A, Peltomäki P, Chadwick RB, Kääriäinen H, Eskelinen M, Järvinen H, et al. Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the disease. N Engl J Med. 1998;338: 1481–1487
3. Diagnosis and management of hereditary cancer: tabular based clinical and genetic aspects, Henson J.W., Resta R.G., Elsevier, 2021, ISBN 978-0-323-90746-0,
4. https://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf
5. Handbook of clinical cancer genetics, Matloff E.T., published by LWW, 2013, ISBN 13: 978-1-4511-9098-4
6. https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf
7. Lynch HT, Snyder CL, Shaw TG, Heinen CD, Hitchins MP. Milestones of Lynch syndrome: 1895–2015. Nat Rev Cancer. 2015;15(3):181—94.
8. Matthew B. Yurgelun, MD, and Heather Hampel, MS. Recent Advances in Lynch Syndrome: Diagnosis, Treatment, and Cancer Prevention. American Society of Clinical Oncology Educational Book 38 (May 23, 2018) 101-109.
9. http://www.oncology.ru/association/clinical-guidelines/2018/rak_obodochnoy_kishki_pr2018.pdf
10. https://www.nccn.org/professionals/physician_gls/pdf/colon_blocks.pdf