Facts about Lynch Syndrome

  • Approximately 3% of colorectal cancers (CRCs) are due to Lynch Syndrome.
  • Lynch Syndrome is caused by autosomal dominantly inherited mutations in the mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2.
  • Individuals with Lynch Syndrome have a substantial increased risk of developing colorectal cancer. For males, the lifetime risk is 20%-74%, and for females, the risk is 20%-52%. The risk for a second primary colorectal cancer is 15%-20% at 10 years.
  • The mean age of onset 42 to 61 years.
  • Females with Lynch Syndrome have a 28%- 60% lifetime risk for endometrial cancer.
  • First-degree relatives of individuals identified with a Lynch Syndrome gene mutation have a 50% chance to carry the mutation.

Tumor screening for Lynch Syndrome

Lynch Syndrome (previously referred to as hereditary nonpolyposis colorectal cancer, HNPCC) is an inherited disorder that increases the risk for colorectal, endometrial, and many other types of cancer. The Lynch Syndrome Screening Network promotes universal tumor screening of all individuals with newly diagnosed colorectal and endometrial cancers to identify those who are more likely to have Lynch Syndrome. The network recommends such screening because these individuals are at high risk for second primary cancers, their relatives are at risk and could benefit from genetic testing, and the screening tests are cost-effective.

Recommended screening

Clinical criteria (Bethesda, Amsterdam) fail to identify 25% of individuals with Lynch Syndrome, and are inconsistently applied. Screening performed on pathology specimens utilizing immunohistochemistry (IHC) for the four MMR proteins, and/or molecular microsatellite instability (MSI) testing can identify 95% of Lynch Syndrome-associated CRCs. While 15%-20% of CRCs will demonstrate abnormal IHC and/or MSI results, additional reflex testing can differentiate somatic vs. germline events.

Screening Methods

Three algorithms are available for Lynch Syndrome screening. All involve the testing of tumor tissue.

MSI: Approximately 90% of colon tumors from individuals with Lynch Syndrome demonstrate microsatellite instability (MSI), whereas only approximately 15% of sporadic colon tumors do. Thus, MSI testing is useful in determining the likelihood of Lynch Syndrome.

IHC: Tumors from individuals with Lynch Syndrome are likely to demonstrate loss of mismatch repair protein expression. The pattern of loss observed can provide information about which gene is not functioning properly. As a result, immunohistochemistry (IHC) testing can be helpful both in providing information about the likelihood of Lynch Syndrome and in directing testing for a germline mutation to a specific gene.

MSI and IHC: When used alone, MSI and IHC may miss some cases of Lynch Syndrome. For example, MSI alone may not detect cases of Lynch Syndrome because of MSH6 mutations since MSH6-related tumors are sometimes MSS. On the other hand, IHC alone may not detect cases of Lynch Syndrome because of mutations that result in full length, but dysfunctional, protein.

There is no consensus on whether MSI, IHC, or both is the ideal screening tool for Lynch Syndrome. Some centers start with MSI testing and then perform IHC on tumors that demonstrate microsatellite instability to help direct genetic testing. Others use IHC as the sole screening tool. Some centers perform both tests simultaneously to provide as much information as possible.

More detailed information on MSI, IHC, and MSI and IHC testing, along with supplemental materials, is provided in the sections for each algorithm.

PowerPoint presentation on Lynch syndrome tumor screening