Cancer susceptibility genes for colorectal cancers

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What are the susceptibility genes for colorectal cancers?

We all have two copies of every gene in our body, inherited from each of our parents. Genes have different functions and instruct our cells to do different things.

High penetrance cancer susceptibility genes are a group of genes that protect the body from developing a cancer, usually through correcting DNA mistakes and repairing DNA copies.

If there’s a pathogenic change in one of these genes, it means they won’t be able to function properly. With a gene not working properly, some of that protection against cancer is lost.

Over time, DNA mistakes can accumulate which puts someone with a change in one of these genes at risk of developing colorectal, endometrial and other related cancers over their lifetime.

Read the genomics toolkit which covers colorectal cancers.

Below is more information about individual genes and their associated risks if there is a pathogenic change in them.

MLH1

Estimated lifetime cancer risk for carriers of germline pathogenic variants in MLH1

Cancer risks for MLH1 and MSH2 mutation carriers - PMC (nih.gov)

Cancer Risk Associated with Inherited MLH1 Mutations (facingyourrisk.org)

Structural destabilization and chaperone-assisted proteasomal degradation of MLH1 as a mechanism for Lynch syndrome

 

Structural destabilization and chaperone-assisted proteasomal degradation of MLH1 as a mechanism for Lynch syndrome | BioRxiv

MSH2

Estimated lifetime cancer risk for carriers of germline pathogenic variants in MSH2

Cancer risk and MSH2 gene mutations (facingyourrisk.org)

 


 

Identification of novel pathogenic MSH2 mutation and new DNA repair genes variants: investigation of a Tunisian Lynch syndrome family with discordant twins (biomedcentral.com)

MSH2: Associated risks

For detail, please see UKCGG: Management Guidelines for MSH2 Mutation Carriers

Dominguez-Valentin M et al. Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database. Genet Med. 2019

 

 

MSH6

Estimated lifetime cancer risk for carriers of germline pathogenic variants in MSH6

 

MSH6 is a human gene that provides instructions for making the DNA mismatch repair protein MSH6. This protein is involved in the recognition and repair of errors that occur during DNA replication, including mismatches and small insertion-deletion loops. MSH6 forms a complex with another protein, MSH2, to detect and bind to DNA mismatches. This complex then recruits other proteins to repair the mismatch, ultimately preventing mutations that can lead to cancer and other genetic diseases.

Mutations in the MSH6 gene have been linked to Lynch syndrome, a hereditary form of colon cancer, as well as other cancers such as endometrial and ovarian cancers. Individuals with MSH6 mutations may have an increased risk of developing Lynch syndrome-associated cancers at an earlier age compared to individuals with mutations in other DNA mismatch repair genes. In addition, some studies suggest that MSH6 mutations may be associated with an increased risk of other types of cancer, such as pancreatic and prostate cancer.

 

Location of MSH6

 

MSH6: Associated risks

For detail, please see UKCGG: BRCA1 Germline Pathogenic Variant Carriers Management Guidelines for Healthcare Professionals

PMS2

Estimated lifetime cancer risk for carriers of germline pathogenic variants in PMS2

The PMS2 (PMS1 homolog 2, mismatch repair system component) gene is located on chromosome 7. The PMS2 gene protein plays an important role in repairing DNA damage. Inherited alterations in PMS2 are associated with Lynch Syndrome. Therefore people with an inherited PV in PMS2 are potentially at risk of many cancers, but particularly, colorectal and endometrial cancers.

 

PMS2 location

 

PMS2: Associated risks

For detail, please see UKCGG: Management Guidelines for PMS2 Mutation Carriers

 

Management recommendations

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