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.