Lynch Syndrome (Abali)

Question 1

Individuals with Lynch syndrome are at an increased risk of

Answer 1

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

Question 2

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

Answer 2

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

Question 3

The lifetime risk of CRC in Lynch syndrome is approximately

Answer 3

70%

Question 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

Answer 4

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

Question 5

The mean age at colorectal cancer diagnosis in HNPCC is

Answer 5

44 years

Question 6

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

Answer 6

Proximal to the splenic flexure

Question 7

Individuals with Lynch syndrome suffer from increased incidence of

Answer 7

Synchronous and metachronus CRC

Question 8

Cancers occuring within 6 months of the first primary cancer

Answer 8

Synchronous cancers

Question 9

Cancers occuring more than 6 months after the first primary cancer

Answer 9

Metachronous Cancers

Question 10

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

Answer 10

Better

Question 11

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

Answer 11

Right (Proximal) side of the colon

Question 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)?

Answer 12

Only 3%

0.1% will have Familial Adenomatous Polyposis: FAP

Question 13

Lynch syndrome is caused by a germline mutation in

Answer 13

DNA MMR genes

Question 14

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

Answer 14

Microsatellite instability (MSI)

Question 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

Answer 15

“Cancer Family Syndrome”

Question 16

Lynch syndrome is due to mutations in which MMR genes?

Answer 16

MSH2, MLH1, and MSH6

Question 17

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

Answer 17

Autosomal dominant

Question 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.

Answer 18

Familial Cancer

Question 19

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

Answer 19

Hereditary Cancer

Question 20

Why is Lynch syndrome favored as the name over HNPCC?

Answer 20

Because it is associated with more cancers than just CRC

Question 21

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

Answer 21

Inherited as germ-line defects, or somatically acquired

Question 22

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

Answer 22

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

Question 23

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

Answer 23

MSH2 and MLH1

Question 24

Mutations in hMSH2 or hMLH1 usually result in high levels of

Answer 24

Microsatellite instability

Question 25

Mutations in genes such as hMSH6 result in low levels of

Answer 25

Microsatellite instability

Question 26

MMR protein that functions in recognition of mismatch

Answer 26

MSH2

Question 27

Single base mismatches are bound by

Answer 27

MSH2-MSH6 complexes

Question 28

Large insertion/deletion loops are recognized by

Answer 28

MSH2-MSH3 complexes

Question 29

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

Answer 29

Heterotetramer

Question 30

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

Answer 30

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

Question 31

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

Answer 31

Methylated

Question 32

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

Answer 32

Microsatellite sequences

Question 33

Defined as short dinucleotide or mononucleotide repeats

Answer 33

Microsatellite sequences

Question 34

Microsatellite sequences are usually within

Answer 34

Non-coding regions

Question 35

Backward slippage causes

Answer 35

Insertion

Question 36

Forward slippage causes

Answer 36

Deletion

Question 37

Recruited by MSH2/MSH6 binding to complete the tetramer

Answer 37

MLH1 and PMS2

Question 38

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

Answer 38

MLH1 and PMS2

Question 39

Degrades the section of the strand containing the Mismatch

Answer 39

Exonuclease

Question 40

How can we detect MSI?

Answer 40

PCR using MSI markers and immunohistochemistry

Question 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.

Answer 41

Microsatellites

Question 42

Microstate instability is analyzed by assessing the stability of at least

Answer 42

Five microsatellite loci

Question 43

MSI can be detected either using

Answer 43

Gel electrophoresis or Capillary Electrophoresis

Question 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

Answer 44

MSI

Question 45

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

Answer 45

80%

Question 46

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

Answer 46

60%

Question 47

What is Amsterdam Criteria I for determining Lynch Syndrome?

Answer 47

At least one familial cancer case diagnosed before age 50

Question 48

What is Amsterdam Criteria II for determining Lynch Syndrome?

Answer 48

Cases span at least two generations

Question 49

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

Answer 49

Amsterdam Criteria III

Question 50

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

Answer 50

Bethesda Criteria

Question 51

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

Answer 51

Clinical Criteria for Lynch Syndrome

Question 52

95% of HNPCC tumors have

Answer 52

MSI at multiple loci

Question 53

10-15% of sporadic tumors have

Answer 53

MSI

Question 54

An immunohistochemistry screening for lynch syndrome is abnormal if their are

Answer 54

Specific protein(s) absent in the tumor tissue

Question 55

Which disease has a Lynch like phenotype?

Answer 55

Polymerase proofreading associated polyposis (PPAP)

Question 56

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

Answer 56

Constitutional mismatch repair deficiency (CMMR-D)

Question 57

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

Answer 57

Neurofibromatosis type 1 and coffe-like stains

Question 58

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

Answer 58

POLE and POLD1 genes

Question 59

Characterized by young onset colon adenomas (

Answer 59

POLE and POLD1 mutations

Question 60

Can be due to either MMR mutations, or APC mutations

Answer 60

Turcot Syndrome

Question 61

Characterized by CNS tumor in addition to colorectal cancer or polyposis

Answer 61

Turcot Syndrome

Question 62

How does Muir Torre differ from classic Lynch Syndrome?

Answer 62

Skin tumors (sebacous or keratocanthomas)

Question 63

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

Answer 63

Prostate Cancer

Question 64

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

Answer 64

MS2H mutations

Question 65

Classified as: the majority of markers exhibit microsatellite instability

Answer 65

MSI-H (MSI-High)

Question 66

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

Answer 66

MSI-L (MSI-Low)

Question 67

Classified as: None of the markers exhibit microsatellite instability

Answer 67

MSS (Microsatellite Stable)

Question 68

Defined as having instability in two or more markers

Answer 68

MSI-H

Question 69

Defined as having instability in one marker

Answer 69

MSI-L

Question 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.

Answer 70

Microsatellites

Question 71

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

Answer 71

Made the microsatellites larger

Question 72

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

Answer 72

25%

Question 73

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

Answer 73

50%

Question 74

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

Answer 74

Methylation of CpG island (Not lynch syndrome)

Question 75

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

Answer 75

hMSH2 or hMLH1

Question 76

Mutations in which MMR protein typically results in low MSI?

Answer 76

hMSH6

Question 77

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

Answer 77

MSH2 and MSH6

Question 78

Transcriptionally silences MSH2 through methylation

Answer 78

Mutated EPCAM

Question 79

Amsterdam criteria only picks up about

Answer 79

50% of cases

Question 80

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

Answer 80

Bethesda Criteria

Question 81

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

Answer 81

They receive two defective copies of the gene

Question 82

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

Answer 82

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

Question 83

The PPAD related genes POLE and POLD1 are characterized by a

Answer 83

Microsatellite stable tendency

Question 84

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

Answer 84

FAP: Medulloblastoma Lynch: Glioblastoma