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Flashcards in Lynch Syndrome (Abali) Deck (84):
1

Individuals with Lynch syndrome are at an increased risk of

Colorectal cancer (CRC), endometrial cancer, and several other malignancies

2

The majority of lynch syndrome patients are asymptomatic until they present with symptoms of colorectal cancer such as

Gastrointestinal bleeding, abdominal pain, or a change in bowel habits

3

The lifetime risk of CRC in Lynch syndrome is approximately

70%

4

The incidence of CRC is moderately higher in men than in women, and although the age of onset varies by genotype, CRC in Lynch syndrome occurs at a

Younger age than other CRC's (44 years vs 69 years)

5

The mean age at colorectal cancer diagnosis in HNPCC is

44 years

6

The mean age at colorectal cancer diagnosis in HNPCC is 44 years with 70% located

Proximal to the splenic flexure

7

Individuals with Lynch syndrome suffer from increased incidence of

Synchronous and metachronus CRC

8

Cancers occuring within 6 months of the first primary cancer

Synchronous cancers

9

Cancers occuring more than 6 months after the first primary cancer

Metachronous Cancers

10

Is the survival rate in people with CRC from lynch syndrome better or worse than individuals with CRC from a sporadic variant?

Better

11

In Lynch syndrome, colorectal cancer is somewhat more likely to develop on the

Right (Proximal) side of the colon

12

For every 100,000 new cases of CRC in the united states, how many individuals will have lynch syndrome (Hereditary nonpolyposis colorectal cancer: HNPCC)?

Only 3%

(0.1% will have Familial Adenomatous Polyposis: FAP)

13

Lynch syndrome is caused by a germline mutation in

DNA MMR genes

14

Lynch syndrome is caused by a germline mutation in DNA MMR genes resulting in

Microsatellite instability (MSI)

15

The recognition of similar kindreds by Lynch et al10 in 1966 led to the description of a cancer-prone syndrome that included aggregation of colon, gastric, and notably, endometrial cancers, which they termed the

"Cancer Family Syndrome"

16

Lynch syndrome is due to mutations in which MMR genes?

MSH2, MLH1, and MSH6

17

What type of inheritance pattern is seen in HNPCC (Lynch syndrome)?

Autosomal dominant

18

Suggests a clustering of cancers that probably occurred by chance. In other words, there may be a combination of genetic and non-genetic (i.e., environmental) factors that contributed to the development of cancers within a family. 

Familial Cancer

19

Means that an alteration in a single major gene strongly contributes to the development of cancer or cancer-related conditions within the family.  

Hereditary Cancer

20

Why is Lynch syndrome favored as the name over HNPCC?

Because it is associated with more cancers than just CRC

21

Microsatellite instability caused by defects in DNA mismatch-repair genes are either

Inherited as germ-line defects, or somatically acquired

22

What are the three genetic instability pathways that drive colon neoplasia?

Chromosomal instability, Microsatellite instability, and the CpG island methylator phenotype

23

Mutations in which genes account for 90% of patients with Lynch Syndrome?

MSH2 and MLH1

24

Mutations in hMSH2 or hMLH1 usually result in high levels of

Microsatellite instability

25

Mutations in genes such as hMSH6 result in low levels of

Microsatellite instability

26

MMR protein that functions in recognition of mismatch

MSH2

27

Single base mismatches are bound by

MSH2-MSH6 complexes

28

Large insertion/deletion loops are recognized by

MSH2-MSH3 complexes

29

When a mismatch is generate, the recognition complex binds the DNA as a

Heterotetramer

30

When a mismatch is generated, the recognition complex binds the DNA as a heterotetramer. After binding, the complex recruits an

Excision nuclease (from either 5' or 3' direction)

31

In bacteria, the complex is able to recognize which strand to correct because the parental strand is

Methylated

32

One type of error called "slippage" can occur while DNA polymerase is replicating

Microsatellite sequences

33

Defined as short dinucleotide or mononucleotide repeats

Microsatellite sequences

34

Microsatellite sequences are usually within

Non-coding regions

35

Backward slippage causes

Insertion

36

Forward slippage causes

Deletion

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Recruited by MSH2/MSH6 binding to complete the tetramer

MLH1 and PMS2

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Acts as an endonuclease and cleave the newly synthesized strand on either site of the mismatch

MLH1 and PMS2

39

Degrades the section of the strand containing the Mismatch

Exonuclease

40

How can we detect MSI?

PCR using MSI markers and immunohistochemistry

41

Observed by designing PCR primers in sequence flanking the actual repeat and analyzing the PCR products using gel electrophoresis or an automated sequencer that separates the products on the basis of size.

Microsatellites

42

Microstate instability is analyzed by assessing the stability of at least

Five microsatellite loci

43

MSI can be detected either using

Gel electrophoresis or Capillary Electrophoresis

44

Absence of staining of one or more of the MMR gene proteins in the tumor is consistent with a mutation in the gene and suggests the presence of

MSI

45

Lynch syndrome shows and autosomal dominant inheritance with a colon cancer penetratance of

80%

46

Lynch syndrome shows and autosomal dominant inheritance with an endometrial cancer penetratance of

60%

47

What is Amsterdam Criteria I for determining Lynch Syndrome?

At least one familial cancer case diagnosed before age 50

48

What is Amsterdam Criteria II for determining Lynch Syndrome?

Cases span at least two generations

49

Must have Three relatives with an HNPCC associated cancer, one a first degree relative of the other two

Amsterdam Criteria III

50

Says that the Amsterdam Criteria must be met and that the patient is younger than age 50

Bethesda Criteria

51

Amsterdam and Bethesda criteria are met, and there is a population screening of colon and uterine cancer by MSI/IHC

Clinical Criteria for Lynch Syndrome

52

95% of HNPCC tumors have

MSI at multiple loci

53

10-15% of sporadic tumors have

MSI

54

An immunohistochemistry screening for lynch syndrome is abnormal if their are

Specific protein(s) absent in the tumor tissue

55

Which disease has a Lynch like phenotype?

Polymerase proofreading associated polyposis (PPAP)

56

Characterized by an increase in childhood cancers, mainly hematological malignancies and/or brain tumors, as well as early onset CRC's

Constitutional mismatch repair deficiency (CMMR-D)

57

Almost all patients with CMMR-D also show signs reminiscent of

Neurofibromatosis type 1 and coffe-like stains

58

New class of genes that may cause polyposis (polymerase proofreading-associated polyposis) and/or Lynch syndrome esq phenotype

POLE and POLD1 genes

59

Characterized by young onset colon adenomas (

POLE and POLD1 mutations

60

Can be due to either MMR mutations, or APC mutations

Turcot Syndrome

61

Characterized by CNS tumor in addition to colorectal cancer or polyposis

Turcot Syndrome

62

How does Muir Torre differ from classic Lynch Syndrome?

Skin tumors (sebacous or keratocanthomas)

63

Prospective studies show the males with Lynch Syndrome can have a 5x increased risk for

Prostate Cancer

64

The highest risk of lynch syndrome patients for prostate cancer was with

MS2H mutations

65

Classified as: the majority of markers exhibit microsatellite instability

MSI-H (MSI-High)

66

Classified as: only a minority of the markers exhibit microsatellite instability

MSI-L (MSI-Low)

67

Classified as: None of the markers exhibit microsatellite instability

MSS (Microsatellite Stable)

68

Defined as having instability in two or more markers

MSI-H

69

Defined as having instability in one marker

MSI-L

70

Short repetitive sequences consisting of 1-4 base nucleotide of DNA. These repeat sequences can often be read as DNA “fingerprints” for individual human beings.

Microsatellites

71

If a tumor tissue travels less far that normal tissue in gel or capillary electrophoresis, it means that the tumor incurred mutations that

Made the microsatellites larger

72

Under autosomal recessive inheritance, what percentage of children will get the disease?

25%

73

Under autosomal dominant inheritance, what percentage of children will get the disease?

50%

74

Inactivation of MLH1 could be hereditary (as in Lynch syndrome), or it could be due to

Methylation of CpG island (Not lynch syndrome)

75

Mutations in which two MMR proteins typically result in high MSI?

hMSH2 or hMLH1

76

Mutations in which MMR protein typically results in low MSI?

hMSH6

77

Are heterodimers; if one is deleated, the other will likely be deleated as well

MSH2 and MSH6

78

Transcriptionally silences MSH2 through methylation

Mutated EPCAM

79

Amsterdam criteria only picks up about

50% of cases

80

Newer criteria for diagnosing lynch syndrome where the patient already has cancer, and you only have to meet one of the criteria

Bethesda Criteria

81

Patients with CMMR-D experience biallelic inheritance of the MMR gene for PMS2, what does this mean?

They receive two defective copies of the gene

82

If you were to perform immunohistochemistry on a patient with CMMR-D, what would you expect to see?

Lack of PMS2 in both healthy and tumorous cells due to biallelic inheritance

83

The PPAD related genes POLE and POLD1 are characterized by a

Microsatellite stable tendency

84

Turcot syndrome can be seen in FAP and Lynch syndrome. How does in manifest itself in each?

FAP: Medulloblastoma

Lynch: Glioblastoma

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