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Lynch Syndrome (Abali) Flashcards

1
Q

Individuals with Lynch syndrome are at an increased risk of

A

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

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2
Q

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

A

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

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3
Q

The lifetime risk of CRC in Lynch syndrome is approximately

A

70%

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4
Q

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

A

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

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5
Q

The mean age at colorectal cancer diagnosis in HNPCC is

A

44 years

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6
Q

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

A

Proximal to the splenic flexure

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7
Q

Individuals with Lynch syndrome suffer from increased incidence of

A

Synchronous and metachronus CRC

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8
Q

Cancers occuring within 6 months of the first primary cancer

A

Synchronous cancers

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9
Q

Cancers occuring more than 6 months after the first primary cancer

A

Metachronous Cancers

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10
Q

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

A

Better

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11
Q

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

A

Right (Proximal) side of the colon

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12
Q

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

A

Only 3%

0.1% will have Familial Adenomatous Polyposis: FAP

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13
Q

Lynch syndrome is caused by a germline mutation in

A

DNA MMR genes

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14
Q

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

A

Microsatellite instability (MSI)

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15
Q

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

A

“Cancer Family Syndrome”

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16
Q

Lynch syndrome is due to mutations in which MMR genes?

A

MSH2, MLH1, and MSH6

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17
Q

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

A

Autosomal dominant

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18
Q

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.

A

Familial Cancer

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19
Q

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

A

Hereditary Cancer

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20
Q

Why is Lynch syndrome favored as the name over HNPCC?

A

Because it is associated with more cancers than just CRC

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21
Q

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

A

Inherited as germ-line defects, or somatically acquired

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22
Q

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

A

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

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23
Q

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

A

MSH2 and MLH1

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24
Q

Mutations in hMSH2 or hMLH1 usually result in high levels of

A

Microsatellite instability

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25
Q

Mutations in genes such as hMSH6 result in low levels of

A

Microsatellite instability

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26
Q

MMR protein that functions in recognition of mismatch

A

MSH2

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27
Q

Single base mismatches are bound by

A

MSH2-MSH6 complexes

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28
Q

Large insertion/deletion loops are recognized by

A

MSH2-MSH3 complexes

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29
Q

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

A

Heterotetramer

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30
Q

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

A

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

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31
Q

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

A

Methylated

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32
Q

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

A

Microsatellite sequences

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33
Q

Defined as short dinucleotide or mononucleotide repeats

A

Microsatellite sequences

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34
Q

Microsatellite sequences are usually within

A

Non-coding regions

35
Q

Backward slippage causes

A

Insertion

36
Q

Forward slippage causes

A

Deletion

37
Q

Recruited by MSH2/MSH6 binding to complete the tetramer

A

MLH1 and PMS2

38
Q

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

A

MLH1 and PMS2

39
Q

Degrades the section of the strand containing the Mismatch

A

Exonuclease

40
Q

How can we detect MSI?

A

PCR using MSI markers and immunohistochemistry

41
Q

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.

A

Microsatellites

42
Q

Microstate instability is analyzed by assessing the stability of at least

A

Five microsatellite loci

43
Q

MSI can be detected either using

A

Gel electrophoresis or Capillary Electrophoresis

44
Q

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

A

MSI

45
Q

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

A

80%

46
Q

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

A

60%

47
Q

What is Amsterdam Criteria I for determining Lynch Syndrome?

A

At least one familial cancer case diagnosed before age 50

48
Q

What is Amsterdam Criteria II for determining Lynch Syndrome?

A

Cases span at least two generations

49
Q

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

A

Amsterdam Criteria III

50
Q

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

A

Bethesda Criteria

51
Q

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

A

Clinical Criteria for Lynch Syndrome

52
Q

95% of HNPCC tumors have

A

MSI at multiple loci

53
Q

10-15% of sporadic tumors have

A

MSI

54
Q

An immunohistochemistry screening for lynch syndrome is abnormal if their are

A

Specific protein(s) absent in the tumor tissue

55
Q

Which disease has a Lynch like phenotype?

A

Polymerase proofreading associated polyposis (PPAP)

56
Q

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

A

Constitutional mismatch repair deficiency (CMMR-D)

57
Q

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

A

Neurofibromatosis type 1 and coffe-like stains

58
Q

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

A

POLE and POLD1 genes

59
Q

Characterized by young onset colon adenomas (

A

POLE and POLD1 mutations

60
Q

Can be due to either MMR mutations, or APC mutations

A

Turcot Syndrome

61
Q

Characterized by CNS tumor in addition to colorectal cancer or polyposis

A

Turcot Syndrome

62
Q

How does Muir Torre differ from classic Lynch Syndrome?

A

Skin tumors (sebacous or keratocanthomas)

63
Q

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

A

Prostate Cancer

64
Q

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

A

MS2H mutations

65
Q

Classified as: the majority of markers exhibit microsatellite instability

A

MSI-H (MSI-High)

66
Q

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

A

MSI-L (MSI-Low)

67
Q

Classified as: None of the markers exhibit microsatellite instability

A

MSS (Microsatellite Stable)

68
Q

Defined as having instability in two or more markers

A

MSI-H

69
Q

Defined as having instability in one marker

A

MSI-L

70
Q

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.

A

Microsatellites

71
Q

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

A

Made the microsatellites larger

72
Q

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

A

25%

73
Q

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

A

50%

74
Q

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

A

Methylation of CpG island (Not lynch syndrome)

75
Q

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

A

hMSH2 or hMLH1

76
Q

Mutations in which MMR protein typically results in low MSI?

A

hMSH6

77
Q

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

A

MSH2 and MSH6

78
Q

Transcriptionally silences MSH2 through methylation

A

Mutated EPCAM

79
Q

Amsterdam criteria only picks up about

A

50% of cases

80
Q

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

A

Bethesda Criteria

81
Q

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

A

They receive two defective copies of the gene

82
Q

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

A

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

83
Q

The PPAD related genes POLE and POLD1 are characterized by a

A

Microsatellite stable tendency

84
Q

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

A

FAP: Medulloblastoma

Lynch: Glioblastoma

BMS (62 decks)

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