Developing universal 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.

Screening for Lynch Syndrome on all newly diagnosed colorectal cancers is recommended by the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group, is a Healthy People 2020 Objective. It is already performed in hundreds of facilities nationwide.


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.


What type of screening is recommended?

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.


Impact of screening

  • Referral of patients with abnormal screen results for genetic counseling and molecular testing for germline MMR mutations allows for diagnostic confirmation for the patient and accurate testing for family members.
  • Identification of a CRC patient with Lynch Syndrome affects future screening for synchronous CRC and other Lynch Syndrome-associated malignancies.
  • Evidence suggests a diagnosis of Lynch Syndrome may affect surgical and chemotherapeutic management decisions.
  • First-degree relatives who test negative for the identified mutation are no longer at increased risk for CRC or other Lynch Syndrome-related malignancies, nor are their children at risk for Lynch Syndrome.
  • Relatives who test positive for the familial mutation require colonoscopy every one to two years beginning at age 25, in addition to screening for non-colonic cancers.