Personalizing Patient Care

Detecting and managing hereditary colorectal cancer syndromes in your practice

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ABSTRACTHereditary syndromes account for 5% to 10% of cases of colorectal cancer. In clinical practice, patients with these syndromes need to be identified to ensure that they and their families receive genetic counseling and testing and appropriate risk-reducing treatment. Genetic testing can offer a precise diagnosis. It allows for risk stratification and focused management and surveillance.


  • Hereditary colorectal cancer syndromes carry a substantial risk of intestinal and extraintestinal tumors.
  • Affected patients need increased cancer surveillance and may benefit from prophylactic surgery.
  • Identifying these patients in clinical practice begins by assessing a patient’s personal and family health history.
  • Patients suspected of having hereditary colorectal cancer syndromes should be referred for genetic counseling and, if appropriate, for genetic testing.



Hereditary colorectal cancer syndromes account for 5% to 10% of cases of colorectal cancer.

Identifying these patients in clinical practice begins by assessing a patient’s personal and family health history. An accurate and comprehensive family history should cover three generations and include ethnic background, ages and causes of death of relatives, and any diagnosis of cancer, including age at onset and history of polyps.

Red flags for a hereditary colorectal cancer syndrome in the personal or family history are:

  • Early age of onset of cancer (eg, colorectal cancer before age 50)
  • More than 10 colorectal adenomas
  • Synchronous (ie, occurring at the same time) or metachronous (occurring at different times) primary cancers
  • Multiple relatives in successive generations with the same or related cancers (eg, colon or endometrial cancer)
  • A family member with a known hereditary colorectal cancer syndrome (Table 1).

Any of these red flags should prompt a referral for genetic counseling.


Many hereditary syndromes are associated with a higher risk of colorectal cancer. Generally, they can be divided into two categories (Table 2): polyposis syndromes (in which patients have numerous colorectal polyps) and nonpolyposis syndromes (with few or no polyps).

These two main types are subclassified on the basis of the histology of most of the polyps detected: adenomatous, hamartomatous, serrated, or mixed types.

In this review, we will address the three most common of these syndromes: Lynch syndrome (hereditary nonpolyposis colorectal cancer), familial adenomatous polyposis, and MYH-associated polyposis. However, as noted in Table 2, other hereditary colorectal cancer syndromes exist, and suspicion of these conditions should prompt a referral for further evaluation.


Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, predisposes people to a variety of cancers.

Colorectal cancer is the most common type of cancer associated with Lynch syndrome. Recent research suggests that the cumulative risk of developing colorectal cancer by age 80 is 42% for all patients with Lynch syndrome.1 The median age at onset is 45 years.1 For patients who undergo segmental resection of their initial cancer, the cumulative risk of metachronous colorectal cancer (ie, a new tumor arising later) is 16% at 10 years, 41% at 20 years, and up to 62% after 30 years.2

Endometrial cancer occurs in 17% to 57% of women with Lynch syndrome by age 70, with a median age at onset of 49 years.1

Other extracolonic cancers in Lynch syndrome include cancers of the:

  • Stomach (1%–10% risk by age 70 years)
  • Ovaries (1%–20% risk)
  • Hepatobiliary tract (1%–2% risk)
  • Urinary tract (1%–12% risk)
  • Small bowel (1%–2% risk)
  • Brain (1%–8% risk)
  • Skin (sebaceous adenomas, adenocarcinomas, and keratoacanthomas).1,3,4

Earlier studies reported higher rates of associated cancer than those shown here. However, their data were largely derived from registries and may be overestimates. The numbers shown above are from population-based studies.

Genetics of Lynch syndrome

Lynch syndrome is caused by a germline mutation in the MLH1, MSH2, MSH6, PMS2, or EPCAM genes.5 These genes code for proteins that are responsible DNA mismatch repair—one of the cell’s proofreading mechanisms during DNA replication.

These mutations are inherited in an autosomal dominant manner. Though de novo mutations in these genes have been reported, they are rare and the exact frequency with which they occur is unknown.6

In whom should Lynch syndrome be suspected?

Lynch syndrome can be suspected on the basis of family history and clinical criteria.

In 1991, the same group of experts who coined the term “hereditary nonpolyposis colorectal cancer” developed family history criteria for it1:

  • At least three relatives with histologically confirmed colorectal cancer, one of whom is a first-degree relative of the other two
  • At least two successive generations involved
  • At least one of the cancers diagnosed before age 50
  • Familial adenomatous polyposis is excluded.

Known as the Amsterdam criteria, these were to be used in collaborative studies of families with hereditary colorectal cancer.7 In 1999, these criteria were broadened to include extracolonic cancers and became known as the Amsterdam II criteria (Table 3).8

Patients whose families meet the Amsterdam II criteria or who have molecular pathologic evidence of Lynch syndrome (see below) are appropriate candidates for genetic counseling and testing.


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