Lynch Syndrome Facts

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 20-74% males, 20-52% 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

Cancer Type

General Population Risk

MLH1 and MSH2

MSH6

PMS2

Risk

Mean/Median Age of Onset

Risk

Median Age of Onset

Risk

Mean Age of Onset

Colon

5.5%

40%-80%

44-61 years

10-22%

54

15-20%

61-66

Endometrium

2.7%

25%-60%

48-62 years

16-26%

55

15%

49

Stomach

<1%

1%-13%

56 years

< 3%

63

6%

70-78

Ovary

1.6%

4%-24%*

42.5 years

1-11%

46

6%

42

Hepatobiliary tract

<1%

1.4%-4%%

50-57

None reported

None reported

None reported

Urinary tract

<1%

1%-4%

54-60 years

<1%

65

None reported

Small bowel

<1%

3%-6%

47-49 years

None reported

54

59

Brain/central nervous system

<1%

1%-3%

~50 years

Not reported

Not reported

45

Sebaceous neoplasms

<1%

1%-9%

Not reported

Not reported

Not reported

Not reported

Not reported

*20% risk from JAMA. 2011;305(22):2304-2310 included wide confidence intervals (1-65% for MLH1; 3-52% for MSH2).
┼The combined risk for renal pelvic, stomach, ovary, small bowel, ureter, and brain is 6% to age 70. Gastroenterology. 2008; 135(2):419-428.

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.

Lynch Syndrome fact sheet (PDF)