Lynch Syndrome Key Facts

  • ~ 3% of colorectal cancers (CRCs) are due to Lynch syndrome, previously referred to as Hereditary Nonpolyposis Colorectal Cancer (HNPCC)
  • 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 substantial increased risk for CRC:
    • lifetime risk 54-74% males, 30-52% females
    • mean age of onset 42 to 61 years
    • risk for synchronous colorectal cancer 15-20% at 10 years
  • Females with Lynch syndrome have a 28% – 60% lifetime risk for endometrial cancer
  • Lynch syndrome is associated with increased risks for other cancers including small bowel, gastric, ovarian, urinary tract and pancreatic
  • Recommended screening – colonoscopy every 1-2 years beginning at age 25 – has been demonstrated to substantially reduce (> 50%) CRC incidence and mortality

Identification of individuals with Lynch syndrome

  • Clinical criteria (Bethesda, Amsterdam) fail to identify 25% of individuals with Lynch syndrome, and are inconsistently applied
  • Previous studies have demonstrated the clinical utility and cost effectiveness of screening for Lynch syndrome all newly diagnosed CRCs
  • Screening performed on pathology specimens utilizing immunohistochemistry (IHC) for the 4 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 for Lynch syndrome

  • 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 will impact future screening for synchronous CRC and other Lynch syndrome-associated malignancies
  • There is evidence to suggest a diagnosis of Lynch syndrome may impact surgical and chemotherapeutic management decisions
  • Each 1st degree relative of an individual identified with a Lynch syndrome gene mutation has a 50% chance to also carry the mutation
    • Those 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
    • Those 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
  • Screening for Lynch syndrome on all newly diagnosed colorectal cancers has been recommended by the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group, is a Healthy People 2020 Objective, and is currently being performed in 100’s of facilities nationwide.