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

In families with Lynch syndrome mutations, cancer may occur at an earlier age with each generation. This study looked at the effect called anticipation in families with MLH1-associated Lynch syndrome. (Posted 10/3/25)

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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

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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 (LS) are at increased risk of developing cancer—especially colorectal and endometrial cancer—due to an in , MSH2/EPCAM, or . Prior studies have reported cancer diagnoses of LS-related cancers 1 to 2 years earlier in successive generations of families with an , , or mutation, and as much as 7 years earlier for families with a 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 mutation.

Study findings

The researchers chose to study families with 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 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 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 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 , prior research suggests that anticipation may also apply to families with other mutations. If you are from a family with a known or other 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 . 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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Questions To Ask Your Doctor

  • I have an mutation. When should I begin cancer screening?
  • My family has a known mutation. When should cancer screening start for future generations?
  • I have a mutation in an LS gene other than . Given my family history, when should I begin cancer screening?
  • What cancer screening tests do you recommend?

Open Clinical Trials

The following screening and prevention studies are open to people with

Colorectal cancer

Gynecologic cancers

 cancer

Pancreatic cancer

  • NCT03568630: Blood Markers of Early Pancreas Cancer. This pancreatic cancer study involves blood samples taken over time to identify biomarkers of pancreatic cancer in high-risk people. Enrollment is open to people with certain mutations linked to increased cancer risk.
  • NCT03250078: A Pancreatic Cancer Screening Study in Hereditary High-Risk Individuals. The main goal of this study is to screen and detect pancreatic cancer and precursor lesions in individuals with a strong family history or genetic predisposition to pancreatic cancer.  and magnetic cholangiopancreatography (MRI/MRCP) will be utilized to screen for  pancreatic lesions.

Updated: 10/03/2025

Guidelines

The National Comprehensive Cancer Network (NCCN) provides risk management guidelines for people with  mutations.

Colorectal cancer 

  • Colonoscopy every 1-2 years. Speak with your doctor about whether you should be screened yearly or every two years. Men, people over age 40 and individuals with a personal history of colon cancer or colon may benefit most from yearly screenings. 
    • For people with , or EPCAM:
      • beginning between ages 20-25 (or 2-5 years before the earliest age of colon cancer in the family, if diagnosed before age 25).
    • For people with or PMS2: 
      • beginning between ages 30-35 (or 2-5 years before the earliest age of colon cancer in the family, if diagnosed before age 35).
  • Daily aspirin can decrease the risk of colorectal cancer. The best dose and timing are unknown. Speak with your doctor about the benefits, risks, best timing and dose.

Endometrial and ovarian cancer

  • Be aware of endometrial and ovarian cancer symptoms.
  • Consider endometrial biopsy every 1-2 years beginning between ages 30-35.
  • Discuss the benefits and risks of oral contraceptives.
  • Consider risk-reducing hysterectomy; discuss risk-reducing removal of ovaries and with your doctor (, , and gene mutations).

Stomach and upper GI cancers

  • Begin screening for stomach cancer and other upper GI cancers between ages 30-40 every 2-4 years for those with , , , mutations. Screening should include high-quality upper endoscopy (esophagogastroduodendoscopy, EGD), ideally at the time of colonoscopy.
  • Consider earlier, more frequent screening based on family history of stomach or upper GI cancers.
  • Test for H. pylori at the beginning of screening and treat if the test is positive. 

Other cancers

  • Consider annual cancer screening with testing and digital rectal exam.
  • For people with a family history of urothelial cancer and men with an mutation:
    • Consider annual urinalysis beginning between ages 30-35.
  • For people with a family history of pancreatic cancer:
    • Consider annual cholangiopancreatography (MRCP) and/or endoscopic (EUS) beginning at age 50 or 10 years before the earliest age of exocrine pancreatic cancer in the family.
    • Consider participating in a pancreatic cancer screening study. 
  • Consider annual physical and neurological exams. 

Updated: 09/26/2025