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Practice bulletins > #147 Lynch Syndrome > Flashcards

#147 Lynch Syndrome Flashcards

1
Q

What is the pattern of inheritance of Lynch syndrome?

A

Autosomal dominant

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2
Q

What was the previous name for Lynch syndrome?

A

Hereditary nonpolyposis colorectal cancer

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3
Q

What types (class) of genes are mutated in Lynch syndrome?

A

Mismatch repair genes.

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4
Q

What are the hallmark diseases of Lynch syndrome? What are others included in the spectrum?

A

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

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5
Q

What percentage of uterine cancers are attributable to a hereditary cause?

A

3-5%

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6
Q

What percentage of ovarian cancers are inherited?

A

8-13%

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7
Q

What is the most common cause of hereditary uterine cancer?

A

Lynch syndrome

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8
Q

What is the most common cause of hereditary colorectal cancer?

A

Lynch syndrome

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9
Q

What is the second most common cause of inherited ovarian cancer?

A

Lynch syndrome

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10
Q

What is the prevalence of Lynch syndrome?

A

1 in 600 to 1 in 3,000 individuals

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11
Q

What are the most common genes associated with Lynch syndrome (specific genes)?

A

MLH1, MSH2, MSH6, PMS2

*deletions in EpCAM gene may lead to inactivation of MSH2 and result in Lynch syndrome

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12
Q

What percentage of women with endometrial cancer have Lynch syndrome?

A

2.3%

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13
Q

What percentage of patients with colorectal cancer have Lynch syndrome?

A

2.2%

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14
Q

What percentage of women <50yo with endometrial ca have mutations associated with Lynch syndrome?

A

5-9%

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15
Q

What is the risk of colorectal cancer through age 70 for women with Lynch syndrome?

A

18-61%

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16
Q

What is the general population’s risk for colorectal cancer?

A

1.7%

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17
Q

What is the risk of endometrial cancer through age 70 for women with Lynch syndrome?

A

16-61%

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18
Q

What is the risk of ovarian cancer through age 70 for women with Lynch syndrome?

A

5-10%

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19
Q

What is the risk of ovarian cancer through age 70 in women with BRCA1 mutation?

A

39-46%

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20
Q

What is the risk of ovarian cancer through age 70 in women with BRCA2 mutations?

A

12-20%

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21
Q

True or false: the risk of cancer varies according to the mismatch repair mutation in Lynch syndrome?

A

True

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22
Q

When endometrial cancer is the presenting diagnosis for patient discovered to have Lynch syndrome, what is the median time before diagnosis of colon cancer?

A

11 years

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23
Q

At what age do women with Lynch syndrome typically develop endometrial cancer?

A

Age 47-49

24
Q

At what age do women with Lynch syndrome typically develop ovarian cancer?

A

Age 42-49

25
Q

What ovarian cancer histologies are over represented in Lynch syndrome?

A

clear cell and endometrioid (compared to sporadic ovarian cancer)

26
Q

Does the genetic instability seen in Lynch syndrome affect the coding regions, non coding regions, or both of the DNA?

A

Both coding and non-coding regions

27
Q

What is microsatellite instability?

A

Insertion or deletion of additional nucleotides into or from microsatellite regions (single nucleotide or dinucleotide repeats)

28
Q

What can make it challenging to determine if a tumor is a potential Lynch syndrome-associated tumor?

A

Microsatellite instability can be caused by Lynch syndrome (germline mutation) or noninherited methylation of the MLH1 promoter

29
Q

What percentage of endometrial cancers have noninherited methylation of MLH1 promoter?

A

20-30%

30
Q

What percentage of colon cancers have noninherited methylation of MLH1 promoter?

A

15-20%

31
Q

What is the name of the criteria to identify which individuals should be tested for Lynch syndrome?

A

Bethesda Guidelines

32
Q

What are the Bethesda guidelines?

A
  • 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
33
Q

What are the two methods of testing for a dysfunctional mismatch repair system?

A
  1. Direct germline DNA testing

2. Tumor testing using immunohistochemistry or microsatellite instability testing

34
Q

Does the absence of a deleterious mutation on direct gene screening for Lynch syndrome exclude Lynch syndrome?

A

No

35
Q

Do most centers prefer doing germline DNA testing or testing of a tumor to assess for Lynch syndrome ?

A

Tumor testing

36
Q

On immunohistochemistry of a tumor, if all four mismatch repair proteins are present does it rule out Lynch syndrome?

A

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

37
Q

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?

A

Microsatellite instability testing of the tumor

38
Q

How do you test for microsatellite instability in a tumor?

A

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

39
Q

What will you see on immunohistochemistry for tumor with methylation of the MLH1 promoter?

A

Absence of MLH1 protein, the PMS2 protein, or both proteins

40
Q

What is the assessment of a patient when a potential Lynch syndrome-associated tumor has no MLH 1 protein and methylation of MLH1 promoter?

A

Lynch syndrome is excluded

41
Q

What is your assessment or next step of potential Lynch syndrome-associated tumor has absent MLH1 and no methylation of MLH1 promoter?

A

Possible Lynch syndrome, require germline DNA testing for Lynch syndrome

42
Q

What percentage of Lynch syndrome-associated cases of endometrial and colorectal cancers will not meet the Bethesda guidelines?

A

12-30%

43
Q

According to the SGO, which endometrial cancer patients should be screened for Lynch syndrome?

A

Perform tumor testing on all endometrial or colorectal tumors diagnosed before age 60yo

44
Q

Which women without cancer should be offered hereditary cancer risk assessment for Lynch syndrome?

A
  • 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
45
Q

What should be discussed at a pretest counseling session for germline DNA testing for Lynch syndrome?

A

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

46
Q

What does the federal Genetic Information Nondiscrimination Act of 2008 protect individuals against and what does it not protect against?

A

Protects against health and employment discrimination based on genetic information. Does not apply to other forms of insurance, such as life or disability insurance

47
Q

In Lynch syndrome what are the two heterodimers to test for? What does it mean?

A

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.

48
Q

In endometrial cancer with loss of either MLH1 or PMS2 gene expression, what percentage will not identify a causative mutation w/ germline DNA tests?

A

10-15%

49
Q

In endometrial cancer with loss of either MSH2 or MSH6 gene expression, what percentage don’t have identifiable mutation on germline DNA testing?

A

35-40%

50
Q

What is the recommendation for colonoscopy screening for women with Lynch syndrome?

A

Colonoscopy every 1-2 years, beginning at age 20-25, or 2years -5 before the earliest cancer diagnosis in the family

51
Q

What is the recommendation for screening for women with Lynch syndrome for endometrial cancer?

A

EMB every 1-2 years beginning at age 30-35. Keeping menstrual calendar and evaluation of AUB.

52
Q

What is the recommendation for ovarian cancer screening in Lynch syndrome?

A

Nothing, unclear if screening with TVUS or CA 125 is effective.

53
Q

What is the effect of OCPs on endometrial cancer risk in general population?

A

Decrease risk by up to 50%

54
Q

What can be used for chemoprevention in Lynch syndrome patients to help decrease risk of endometrial cancer?

A

Progesterone-based contraception

55
Q

At what age should risk-reducing surgery be considered in women with Lynch syndrome? What type of surgery?

A

Risk-reducing hysterectomy and salpingo-oophorectomy should be discussed with patient by their early to mid 40s

56
Q

True or false: Endometrial sampling should be performed prior to risk reducing hysterectomy for Lynch syndrome

A

True

57
Q

What chemoprevention options are available for women with Lynch syndrome in regards to reducing risk of colon cancer?

A

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

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