Lynch Syndrome

GeneMate

In an earlier post we wrote about hereditary colorectal cancer syndromes, which can be divided into Lynch syndrome and polyposis syndromes. Lynch syndrome constitutes about 1-3% of all colorectal cancer and in this post, we will tell you more about the cause of Lynch syndrome, which cancer types are associated with Lynch syndrome, and which measures there are to prevent or reduce the risk of cancer. 

What causes Lynch syndrome?

Lynch syndrome is caused by hereditary pathogenic variants it the Mismatch Repair (MMR) genes, MSH2, MSH6, MLH1, and PMS2*.

The proteins encoded by these genes have an important role in DNA repair. The MSH2 protein forms a complex with the MSH6 protein, and this complex can recognize errors in DNA and repair these by removing the incorrect part and replacing it with a correct part of DNA. The MLH1 protein forms a complex with the PMS2 protein, and this complex coordinates other proteins important for DNA repair. Some pathogenic variants in the EPCAM-gene cause Lynch syndrome by inactivating the MSH2-gene. 

As many as one in 2791 individuals in the general population could be carriers of a pathogenic variant in any of the MMR-genes. In individuals with Lynch syndrome, pathogenic variants in MLH1 and MSH2 are most common and are found in 60-80%1. The remaining 20-40% is made up of pathogenic variants in MSH6, PMS2 and EPCAM.

However, pathogenic variants in MSH6 and PMS2 appear to be more common in the general population. This is likely because these genes are associated with a lower risk of cancer, or later age of onset, relative to MLH1 and MSH2. As a result, individuals with a pathogenic variant in these genes are not identified at the same rate and are not as readily diagnosed with Lynch syndrome.

Increased cancer risk due to Lynch syndrome

The lifetime risk of getting cancer for individuals with Lynch syndrome varies based on which gene carries the pathogenic variant, gender, and family history of cancer. The risks of colorectal and uterine cancer are estimated to be 30-70%2. There is also an increased risk of ovarian, urinary tract, gastric, and small intestine cancer as well as brain tumors.

When to suspect a hereditary colorectal cancer syndrome, including Lynch syndrome2

  • If anyone in the family has been diagnosed with colorectal or uterine cancer before 50 years of age.

  • If two or more in the same branch of the family have been diagnosed with colorectal or uterine cancer, one of which before 60 years of age.

  • If two or more in the same branch of the family have been diagnosed with colorectal or uterine cancer, one of which before 60 years of age.

  • If two or more in the same branch of the family have been diagnosed with colorectal, uterine, ovarian, small intestine, or urinary tract cancer, one of which before 60 years of age.

Risk-reducing measures for healthy carriers2

Healthy carries of a pathogenic variant in MSH2, MSH6, MLH1, or EPCAM are recommended colonoscopy every other year from 20–25 years of age. Healthy carries of a pathogenic variant in PMS2 are recommended colonoscopy every other year from 35–40 years of age.

Healthy female carriers of a pathogenic variant in any of the genes associated with Lynch syndrome are recommended removal of the ovaries, fallopian tubes, and uterus by prophylactic surgery at 35-40 years of age.

Other screening measures may also be warranted, depending on the family cancer history.

Risk-reducing measures in the absence of a genetic variant

As described in an earlier post, only a subset of the hereditary risk of colorectal cancer are due to an identifiable pathogenic variant. Even in the absence of a causative pathogenic variant, individuals may still have an increased risk as indicated by the family history. In these cases, a one-time colonoscopy is offered at 55 years of age to first-degree relatives of a family member diagnosed with colorectal cancer before 50 years of age or two# family members diagnosed at 50 years or older. In the case of three family members# with colorectal cancer, first-degree relatives should be offered colonoscopy every 5 years, starting 5 years before the earliest age of diagnosis in the family.

The GeneMate® test includes a genetic test and an assessment of your family’s cancer history, either of which can indicate an increased risk of colorectal cancer. Therefore, it is important that you fill in your family history when ordering the test. We will help you get in contact with the appropriate care provider if cancer screening is motivated.

* GeneMate® tests for pathogenic variants in the following genes: MLH1, MSH2, MSH6, PMS2, and EPCAM. The complete panel is available at genemate.se.

#The individuals diagnosed with colorectal cancer should all be first-degree relatives to each other

 

ORDER

 

Anna Hellquist, Genetic Counselor at iCellate Medical AB, PhD Cell and Microbiology

 

References

  1. Boland PM, Yurgelun MB, Boland CR. Recent progress in Lynch syndrome and other familial colorectal cancer syndromes. CA Cancer J Clin. 2018;68(3):217-231. doi:10.3322/caac.21448
  2. Nationellt vårdprogram tjock- och ändtarmscancer – RCC Kunskapsbanken. https://kunskapsbanken.cancercentrum.se/diagnoser/tjock-och-andtarmscancer/vardprogram/. Accessed January 15, 2021.