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Study: Colorectal cancer in people with Lynch syndrome can include types of cancer found more typically in people without Lynch syndrome

When people with Lynch syndrome (LS) develop cancer, their tumors typically have a related set of features or biomarkers known as deficient mismatch repair (dMMR) and high microsatellite instability (MSI-High). However, occasionally people with Lynch syndrome have cancers that are proficient in mismatch repair (pMMR or MMR-P) and have microsatellite stability (MSS or MSI-Low) –more like the colorectal cancers found in people without Lynch syndrome. This study shows that 10 percent of people with Lynch syndrome may have these types of cancers. This can change treatment recommendations. (Posted 9/5/24)

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RELEVANCE

Most relevant for: People with Lynch syndrome and people with colorectal cancer who may have Lynch syndrome.

It may also be relevant for:

people with colorectal cancer
people with a family history of cancer
people with a genetic mutation linked to cancer risk
previvors

Relevance: Medium-High

Strength of Science: Medium-High

Relevance rating details

What is this study about?

This study looked at characteristics of colorectal cancers among people with . People with Lynch syndrome are most likely to have tumors with two related biomarkers: deficient mismatch repair or (also called ) and high (). These biomarkers are important because they can predict whether a tumor is likely to respond to treatment with . Researchers asked what percentage of colorectal cancer patients with Lynch syndrome do not have these biomarkers. That is, how often do people with Lynch syndrome have cancers that are mismatch repair proficient (pMMR) or are microsatellite stable (also called MSS). These cancers may need to be treated differently.

Why is this study important?

This study shows that people with Lynch syndrome may occasionally have colorectal cancers that are pMMR. Knowing whether a cancer is dMMR or pMMR may help to select which treatments might be most beneficial. This information could also influence family screening recommendations. If a person with Lynch syndrome has a pMMR colorectal cancer, their family members who are negative for Lynch syndrome would still be considered to have a family history of colorectal cancer.

Study findings

Lynch syndrome and any cancer

From a large study of 17,617 people with many types of cancer, 242 had an in one of the Lynch syndrome genes, meaning they had Lynch syndrome.

Lynch syndrome gene	LS and any cancer (242 people)
MSH2/EPCAM	86 of 242 (36%)
	57 of 242 (24%)
	50 of 242 (21%)
	49 of 242 (20%)

Lynch syndrome-associated colorectal cancer

Among 242 people with cancer and Lynch syndrome, 86 had at least one colorectal cancer. A total of 99 colorectal cancers were evaluated in this study.

Lynch syndrome gene	LS and colorectal cancer
MSH2/EPCAM	35 of 99 (35%)
MSH6	30 of 99 (30%)
MLH1	19 or 99 (19%)
PMS2	15 of 99 (15%)

Most but not all tumors in people with Lynch syndrome are dMMR

Researchers used two tests to test colorectal tumors for dMMR or pMMR. One test looked at tumor for microsatellite instability, while the other test looked for proteins in the tumor.

Among the 99 tumor:

90% were dMMR
10% were pMMR

Lynch syndrome gene	Percentage of people with a tumor that was pMMR
MSH2/EPCAM	3 % (1 of 29)
MLH1	0 % (0 of 26)
MSH6	11 % (2 of 18)
PMS2	46 % (6 of 13)

Comparing dMMR and pMMR colorectal tumors

Colorectal cancers that are pMMR (and not associated with Lynch syndrome) are typically diagnosed at advanced stages: 60% of pMMR colorectal cancers were diagnosed at a late (), while only 13% of dMMR colorectal cancers were metastatic at diagnosis.

At diagnosis, people with pMMR tumors were older (average 58 years) than those with dMMR tumors (average 43 years). The difference in tumor location within the colon (left side vs right side) was not meaningful.

Current guidelines recommend all people with dMMR colorectal cancer have a further evaluation for Lynch syndrome. Of the people in the study with pMMR tumors, 6 (of 9) met the current criteria for genetic testing for Lynch syndrome based on their personal and/or family history of cancer. Three people with Lynch syndrome with a pMMR tumor did not meet the current guidelines for genetic testing, despite having colon cancer.

What does this mean for me?

The study found that 90 percent of colorectal cancers associated with Lynch syndrome are dMMR, which is consistent with previous research. However, 10 percent of colorectal tumors among people with Lynch syndrome are pMMR and would be treated differently than a dMMR tumor.

People with Lynch syndrome due to inherited mutations in PMS2 and MSH6 are more likely to develop pMMR colon cancers than people with mutations in MLH1 or MSH2/EPCAM. People with Lynch syndrome who had pMMR tumors were more often diagnosed at late stages.

The study emphasizes the importance of testing all colorectal tumors for MMR status, even in the setting of someone with known Lynch syndrome. The presence of dMMR can help determine treatment. For example, whether immunotherapy is likely to be effective or not. This study shows that individuals with Lynch syndrome can develop non-Lynch syndrome associated colorectal cancers, and therefore it is important to confirm whether a colorectal tumor is dMMR, as this may have an impact on treatment and management of at-risk family members.

Reference

Ranganathan M, Sacca, RE, et al., Prevalence and clinical implications of mismatch repair-proficient colorectal cancer in patients with Lynch syndrome. Journal of Clinical Oncology; 2023; 7:e2200675.

Disclosure: FORCE receives funding from industry sponsors, including companies that manufacture cancer drugs, tests and devices. All XRAYS articles are written independently of any sponsor and are reviewed by members of our Scientific Advisory Board prior to publication to assure scientific integrity.

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