Lynch syndrome

Symptoms

What are the cancer risks associated with Lynch syndrome in carriers of an MLH1, MSH2, or EPCAM mutation?

Both men and women have a 40-80% risk to develop colorectal cancer and a 1-13% risk to develop stomach cancer by age 70. Furthermore, by age 70, both men and women have up to a 4% risk of hepatobiliary tract cancer, up to a 4% risk of urinary tract cancer, a 3-6% risk of cancer of the small intestine, up to a 3% risk of brain/ central nervous system cancer, and up to a 6% risk of pancreatic cancer.

Women also have a 25-60% risk to develop uterine cancer and a 4-24% risk to develop ovarian cancer by age 70.

References
  • National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology. Genetic/familial high-risk assessment: colorectal. V2.2015. http://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf
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What are the cancer risks associated with Lynch syndrome in carriers of an MSH6 mutation?

What are the cancer risks associated with Lynch syndrome in carriers of a PMS2 mutation?

What are the main symptoms of Lynch syndrome?

Are there earlier onset or later onsets of Lynch syndrome?

What kind of family history is suspicious for Lynch syndrome?

Is there one or two characteristic "odd" or "unusual" symptom or clinical feature of Lynch syndrome?

Variable expression or incomplete penetrance in Lunch syndrome?

Do women with Lynch syndrome have an increased risk for breast cancer?

Do men with Lynch syndrome have an increased risk for prostate cancer?

What are the cancer risks associated with Lynch syndrome in carriers of an MSH6 mutation?

Both men and women have a 10-22% risk to develop colorectal cancer and a 3% risk or less to develop stomach cancer by age 70. Women have a 16-26% risk to develop uterine cancer and a 1-11% risk to develop ovarian cancer by age 70.

In general, for MSH6 mutation carriers, the risk of other cancers is low. Additional risks may depend on an individual's personal and family history of cancer.

References
  • National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology. Genetic/familial high-risk assessment: colorectal. V2.2015. http://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf
What are the cancer risks associated with Lynch syndrome in carriers of a PMS2 mutation?

Both men and women have a 15-20% risk to develop colorectal cancer and women have a 15% risk to develop uterine cancer by age 70. The combined risk for other cancers, which includes renal pelvic, stomach, ovarian, small intestine, ureter, and brain cancers is 6% by age 70.

References
  • National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology. Genetic/familial high-risk assessment: colorectal. V2.2015. http://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf
What are the main symptoms of Lynch syndrome?

The main symptom or feature of Lynch syndrome is an increased risk to develop cancer. In general, people with Lynch syndrome have an increased risk to develop colorectal (colon/rectal), uterine (endometrial), ovarian, and stomach cancer. Cancers of the small intestine, urinary tract, brain/central nervous system, liver, biliary tract, and pancreas are also associated with Lynch syndrome. Sebaceous neoplasms, or small growths on the skin, may also be seen with Lynch syndrome. These skins findings can be either benign (non-cancerous) or malignant (cancerous).

References
Are there earlier onset or later onsets of Lynch syndrome?

Lynch syndrome is an adult-onset condition, which means this condition is typically not seen in children. People with Lynch syndrome can develop cancer at any age in adulthood. That being said, some people with Lynch syndrome may never develop cancer.

In general, individuals who carry a mutation (change) in MLH1 or MSH2 tend to develop cancer earlier compared to people who carry a mutation in MSH6 or PMS2. Nevertheless there is still variability and overlap in the ages of onset. For example, the average age of onset for colorectal cancer for people who carry a mutation in MLH1 or MSH2 is 44-61 years of age, as compared to 54 years of age for MSH6 mutation carriers and 61-66 years of age for PMS2 mutation carriers.

References
  • Kohlmann W, Gruber SB. Lynch Syndrome. 2004 Feb 5 [Updated 2018 Apr 12]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1211/
What kind of family history is suspicious for Lynch syndrome?

Families that have had multiple diagnoses of cancer, particularly colon, uterine, ovarian, and stomach cancers, may have Lynch syndrome. In general, we expect to see these diagnoses at younger ages than usual. For colon or uterine cancer, a diagnosis before age 50 is younger than expected in the general population.

Amsterdam II Criteria can be used to identify individuals at risk for Lynch syndrome based on personal and family history. These criteria can be remembered by the 3-2-1 rule and include:

  • Three or more family members, one of whom is a first-degree relative (parent, sibling, child) of the other two, with a confirmed diagnosis of a Lynch syndrome-related cancer (colorectal, uterine, small intestine, ureter, or renal-pelvis)
  • Two successive generations affected
  • One or more cancers diagnosed before age 50 years

About 50% of people who meet Amsterdam II Criteria are found to have a change (mutation) in a gene associated with Lynch syndrome. However, because these criteria are so strict, approximately 68% of people with Lynch syndrome will not meet Amsterdam II criteria.

A genetic counselor can help you understand whether your family may have a mutation in a gene associated with Lynch syndrome. To find a local genetic counselor visit the Find a Genetic Counselor website.

References
  • Kohlmann W, Gruber SB. Lynch Syndrome. 2004 Feb 5 [Updated 2018 Apr 12]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1211/
  • http://www.cancer.net/cancer-types/lynch-syndrome
  • National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology. Genetic/familial high-risk assessment: colorectal. V2.2015. http://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf
  • Vasen HF. Clinical diagnosis and management of hereditary colorectal cancer syndrome. J Clin Oncol 2000;18:18S-92S.
  • Barnetson RA, Tenesa A, Farrington SM, et al. Identification and survial of carriers of mutations in DNA mismatch-repair genes in colon cancer. N Engl J Med 2006;354:2751-2763.
Is there one or two characteristic "odd" or "unusual" symptom or clinical feature of Lynch syndrome?

There are some findings in a personal and family history that can be considered red flags for Lynch syndrome.

  • Colon or uterine cancer diagnosed at a young age
  • Diagnosis of two or more cancers, including colon, ovarian, uterine, and stomach cancers, in the same person
  • Several family members with colon, ovarian, uterine, stomach, and/or other cancers associated with Lynch syndrome
  • Multiple generations affected with cancer

Up to 9% of patients with Lynch syndrome have sebaceous neoplasms, which are small growths on the skin. Sebaceous neoplasms are rare in the general population.

References
  • Kohlmann W, Gruber SB. Lynch Syndrome. 2004 Feb 5 [Updated 2018 Apr 12]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1211/
Variable expression or incomplete penetrance in Lunch syndrome?

Not every person with Lynch syndrome will develop cancer in his or her lifetime. In other words, Lynch syndrome is not completely penetrant. This condition also has variable expression, which means that not every person who develops cancer will develop the same type of cancer. Knowing there is an increased risk for developing certain types of cancer will help healthcare providers offer appropriate screening and risk reduction options.

References
  • Kohlmann W, Gruber SB. Lynch Syndrome. 2004 Feb 5 [Updated 2018 Apr 12]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1211/
Do women with Lynch syndrome have an increased risk for breast cancer?

Some evidence suggests that women with Lynch syndrome may have an increased risk for breast cancer. However at this time there is not enough evidence to support increased breast cancer screening above what is recommended for the general population. Further studies are needed to better understand the association between Lynch syndrome and the risk for breast cancer.

References
  • http://www.cancer.net/cancer-types/lynch-syndrome
  • Kohlmann W, Gruber SB. Lynch Syndrome. 2004 Feb 5 [Updated 2018 Apr 12]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1211/
Do men with Lynch syndrome have an increased risk for prostate cancer?

Some evidence suggests that men with Lynch syndrome may have an increased risk for prostate cancer. However at this time there is not enough evidence to support increased prostate cancer screening above what is recommended for the general population. Further studies are needed to better understand the association between Lynch syndrome and the risk for prostate cancer.

References
  • http://www.cancer.net/cancer-types/lynch-syndrome
  • Kohlmann W, Gruber SB. Lynch Syndrome. 2004 Feb 5 [Updated 2018 Apr 12]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1211/
  • Haraldsdottir S, Hampel H, Wei L, et al. Prostate cancer incidence in males with Lynch syndrome. Genet Med 2014; 16:553-557.

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