Study: Cancer may occur at earlier ages in later generations of families with Lynch syndrome

RELEVANCE

Most relevant for: Families with a known MLH1 mutation.

It may also be relevant for:

• previvors
• people with a genetic mutation linked to cancer risk

Relevance: High

Strength of Science: High

More rating details

What is anticipation?

Anticipation occurs when genetic diseases develop at younger ages or become more severe in later generations. Research shows that some hereditary cancers show anticipation.

Knowing if specific genes show anticipation is important because it can:

• help predict the age when family members might develop a disease and when they should start cancer screening.
• support choices about genetic counseling, testing and prevention.

What is this study about?

People with Lynch syndrome (LS) are at increased risk of developing cancer—especially colorectal and endometrial cancer—due to an inherited mutation in MLH1, MSH2/EPCAM, MSH6 or PMS2. Prior studies have reported cancer diagnoses of LS-related cancers 1 to 2 years earlier in successive generations of families with an MLH1, MSH2, EPCAM or MSH6 mutation, and as much as 7 years earlier for families with a PMS2 mutation. However, when researchers looked at the data excluding the probands, the evidence for anticipation often disappeared.

Why is this study important?

It is important to know whether your family’s LS mutation shows anticipation, so that cancer screening in the next generations can be done earlier, and cancers can be detected when they are most treatable.

To better understand if anticipation occurs in LS, researchers in this study looked at families with LS who had a known MLH1 mutation.

Study findings

The researchers chose to study families with MLH1 mutations because they are the most common mutations among people with LS (43%) and are strongly associated with colorectal and endometrial cancers.

This study included 31 families (703 individuals) with confirmed MLH1 mutations.

For each participating family, one person was designated as the “proband.” A proband is a person affected by a genetic condition and is typically the first person in a family who contacts healthcare professionals. Probands in this study had to have an MLH1 mutation and at least two first-degree relatives (father, mother, sibling or child) with cancer. Cancer diagnoses were collected from four generations of participants’ families: grandparents, parents, probands and their siblings, and the probands’ and siblings’ children.

Among the 703 participants:

• 130 had colorectal cancer.
  • Average age at diagnosis was almost 45.
• 13 had endometrial cancer.
  • Average age at diagnosis was 47.

.Researchers reported:

• A consistent decrease in age at cancer diagnosis from older to younger generations.
  • With probands included in the model:
    • Parents developed cancer about 12.5 years earlier than their grandparents.
    • Probands and their siblings developed cancer almost 7 years earlier than their parents.
    • Children developed cancer just over 10 years earlier than their proband's generation.
  • Without probands included in the model:
    • Parents of probands developed cancer almost 16 years earlier than their grandparents.
    • Siblings of probands developed cancer slightly more than 3 years earlier than their parents.
    • Children developed cancer almost 15 years earlier than probands.

What does this mean for me?

The results of this study suggest that screening for cancer in families with a known MLH1 mutation should begin at least 3 and possibly up to 16 years earlier than the person with the youngest age of a cancer diagnosis in the family. This supports NCCN guidelines that recommend cancer screening beginning 2 to 5 years before the youngest diagnosed family member with colorectal or endometrial cancer and 10 years before the youngest diagnosed family member with exocrine pancreatic cancer.

Although this study focused on MLH1, prior research suggests that anticipation may also apply to Lynch syndrome families with other mutations. If you are from a family with a known MLH1 or other Lynch syndrome mutation, talk to your healthcare providers to determine at what age you should begin cancer screening. Your healthcare providers should use your complete family cancer history to determine the optimal time to start screening.

Reference

Pandey AS, Drogan C, Huo D, et al. Anticipation in families with MLH1-associated Lynch syndrome. Cancer. 2025 Jan 1;131(1):e35589.

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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