#147 Lynch Syndrome Flashcards
What is the pattern of inheritance of Lynch syndrome?
Autosomal dominant
What was the previous name for Lynch syndrome?
Hereditary nonpolyposis colorectal cancer
What types (class) of genes are mutated in Lynch syndrome?
Mismatch repair genes.
What are the hallmark diseases of Lynch syndrome? What are others included in the spectrum?
Hallmark: Colorectal, endometrial, ovarian cancers
Other tumors: gastric, small bowel, hepatobiliary, renal pelvis, ureter, some types of breast cancers, certain brain tumors, sebaceous skin tumors
What percentage of uterine cancers are attributable to a hereditary cause?
3-5%
What percentage of ovarian cancers are inherited?
8-13%
What is the most common cause of hereditary uterine cancer?
Lynch syndrome
What is the most common cause of hereditary colorectal cancer?
Lynch syndrome
What is the second most common cause of inherited ovarian cancer?
Lynch syndrome
What is the prevalence of Lynch syndrome?
1 in 600 to 1 in 3,000 individuals
What are the most common genes associated with Lynch syndrome (specific genes)?
MLH1, MSH2, MSH6, PMS2
*deletions in EpCAM gene may lead to inactivation of MSH2 and result in Lynch syndrome
What percentage of women with endometrial cancer have Lynch syndrome?
2.3%
What percentage of patients with colorectal cancer have Lynch syndrome?
2.2%
What percentage of women <50yo with endometrial ca have mutations associated with Lynch syndrome?
5-9%
What is the risk of colorectal cancer through age 70 for women with Lynch syndrome?
18-61%
What is the general population’s risk for colorectal cancer?
1.7%
What is the risk of endometrial cancer through age 70 for women with Lynch syndrome?
16-61%
What is the risk of ovarian cancer through age 70 for women with Lynch syndrome?
5-10%
What is the risk of ovarian cancer through age 70 in women with BRCA1 mutation?
39-46%
What is the risk of ovarian cancer through age 70 in women with BRCA2 mutations?
12-20%
True or false: the risk of cancer varies according to the mismatch repair mutation in Lynch syndrome?
True
When endometrial cancer is the presenting diagnosis for patient discovered to have Lynch syndrome, what is the median time before diagnosis of colon cancer?
11 years
At what age do women with Lynch syndrome typically develop endometrial cancer?
Age 47-49
At what age do women with Lynch syndrome typically develop ovarian cancer?
Age 42-49
What ovarian cancer histologies are over represented in Lynch syndrome?
clear cell and endometrioid (compared to sporadic ovarian cancer)
Does the genetic instability seen in Lynch syndrome affect the coding regions, non coding regions, or both of the DNA?
Both coding and non-coding regions
What is microsatellite instability?
Insertion or deletion of additional nucleotides into or from microsatellite regions (single nucleotide or dinucleotide repeats)
What can make it challenging to determine if a tumor is a potential Lynch syndrome-associated tumor?
Microsatellite instability can be caused by Lynch syndrome (germline mutation) or noninherited methylation of the MLH1 promoter
What percentage of endometrial cancers have noninherited methylation of MLH1 promoter?
20-30%
What percentage of colon cancers have noninherited methylation of MLH1 promoter?
15-20%
What is the name of the criteria to identify which individuals should be tested for Lynch syndrome?
Bethesda Guidelines
What are the Bethesda guidelines?
- Pt w/ endometrial or colorectal cancer before 50yo
- pt with endometrial or ovarian cancer with synchronous or metachronous colon or other Lynch tumor at any age
- pt with colorectal cancer with tumor-infiltrating lymphocytes, peritumoral lymphocytes, Crohn-like lympocytic reaction, mucinous/signet-ring differentiation, or medullary growth pattern before 60yo
- Pt with endometrial or colorectal cancer and a first degree relative with Lynch associated tumor before 50yo
- Patients with colorectal or endometrial cancer at any age with 2 or more first or 2nd degree relatives with Lynch associated tumor, regardless of age
What are the two methods of testing for a dysfunctional mismatch repair system?
- Direct germline DNA testing
2. Tumor testing using immunohistochemistry or microsatellite instability testing
Does the absence of a deleterious mutation on direct gene screening for Lynch syndrome exclude Lynch syndrome?
No
Do most centers prefer doing germline DNA testing or testing of a tumor to assess for Lynch syndrome ?
Tumor testing
On immunohistochemistry of a tumor, if all four mismatch repair proteins are present does it rule out Lynch syndrome?
Rule out Lynch syndrome in almost all cases. The exception is if a deleterious mutation allows the production of a full-length but nonfunctional mismatch repair protein
If tumor testing comes back negative for Lynch syndrome (presence of all four mismatch repair proteins), but clinical picture is highly suspicious, what is the next step?
Microsatellite instability testing of the tumor
How do you test for microsatellite instability in a tumor?
Compare tumor tissue to normal tissue. Use a panel of five microsatellites and compare the two. If no microsatellite instability is detected, essentially rules out presence of Lynch
What will you see on immunohistochemistry for tumor with methylation of the MLH1 promoter?
Absence of MLH1 protein, the PMS2 protein, or both proteins
What is the assessment of a patient when a potential Lynch syndrome-associated tumor has no MLH 1 protein and methylation of MLH1 promoter?
Lynch syndrome is excluded
What is your assessment or next step of potential Lynch syndrome-associated tumor has absent MLH1 and no methylation of MLH1 promoter?
Possible Lynch syndrome, require germline DNA testing for Lynch syndrome
What percentage of Lynch syndrome-associated cases of endometrial and colorectal cancers will not meet the Bethesda guidelines?
12-30%
According to the SGO, which endometrial cancer patients should be screened for Lynch syndrome?
Perform tumor testing on all endometrial or colorectal tumors diagnosed before age 60yo
Which women without cancer should be offered hereditary cancer risk assessment for Lynch syndrome?
- those with first degree relative w/ colorectal/endometrial ca <60 or identified at risk
- May be reasonable to offer testing for >1st degree if paucity of female relatives, or multiple people who had TAH/BSO, few people reaching advanced age
- If family member with known mutation in DNA mismatch repair gene irrespective of degree of relatedness
What should be discussed at a pretest counseling session for germline DNA testing for Lynch syndrome?
discussion of possible outcomes (pos, neg, uninformative including variants of unknown significance). Options for surveillance, chemoprevention, and risk-reducing surgery. Possible psychologic and familial implications
What does the federal Genetic Information Nondiscrimination Act of 2008 protect individuals against and what does it not protect against?
Protects against health and employment discrimination based on genetic information. Does not apply to other forms of insurance, such as life or disability insurance
In Lynch syndrome what are the two heterodimers to test for? What does it mean?
MLH1 and PMS2. MSH2 and MSH6. Loss of PMS2 protien could indicate abnormal MLH1 or PMS2 gene function. Loss of MSH6 protein could indicate loss of MSH2 or MSH6.
In endometrial cancer with loss of either MLH1 or PMS2 gene expression, what percentage will not identify a causative mutation w/ germline DNA tests?
10-15%
In endometrial cancer with loss of either MSH2 or MSH6 gene expression, what percentage don’t have identifiable mutation on germline DNA testing?
35-40%
What is the recommendation for colonoscopy screening for women with Lynch syndrome?
Colonoscopy every 1-2 years, beginning at age 20-25, or 2years -5 before the earliest cancer diagnosis in the family
What is the recommendation for screening for women with Lynch syndrome for endometrial cancer?
EMB every 1-2 years beginning at age 30-35. Keeping menstrual calendar and evaluation of AUB.
What is the recommendation for ovarian cancer screening in Lynch syndrome?
Nothing, unclear if screening with TVUS or CA 125 is effective.
What is the effect of OCPs on endometrial cancer risk in general population?
Decrease risk by up to 50%
What can be used for chemoprevention in Lynch syndrome patients to help decrease risk of endometrial cancer?
Progesterone-based contraception
At what age should risk-reducing surgery be considered in women with Lynch syndrome? What type of surgery?
Risk-reducing hysterectomy and salpingo-oophorectomy should be discussed with patient by their early to mid 40s
True or false: Endometrial sampling should be performed prior to risk reducing hysterectomy for Lynch syndrome
True
What chemoprevention options are available for women with Lynch syndrome in regards to reducing risk of colon cancer?
600mg daily aspirin for more than 2 years may reduce colorectal cancer incidence, but data on long-term adverse events and effect on mortality not available
