Introduction To Hereditary Cancer Susceptibility - Amanda Knoth

Front 1

True or False:

Germline mutations cause cancer?

Back 1

False.

They confer a predisposition for cancer.

Front 2

What does it mean when the DNA changes seen in a tumor are somatic?

Back 2

They are acquired and not heritable

Front 3

What is true of germline mutations seen in tumors?

Back 3

These mutations are present from birth, they are heritable
and they are seen in every cell of the body

Front 4

True or False:

All germline mutations are inherited.

Back 4

False, there are de novo germline mutations that could then be passed on.

Front 5

What is the difference between inherited and familial cancers?

Back 5

Inherited cancers (5-10% of all cancers) are due to a single gene and are highliy penetrant, thus they convey high risk for cancer.

In familial cancers (20-30% of all cancers) we don't have a single gene we can point to. Familial cancers can be multi-factorial or they could be related to a single gene with lower penetrance that we haven't found yet. These confer moderate risk.

Front 6

Is the majority of cancer
-inherited
-familial
sporadic

Back 6

sporadic

Front 7

Give the average ages for the following:
-typical sporadic breast cancer
-HBOC (BRCA)
-Li-Fraumeni (P52)

Back 7

- average breast cancer >50
-HBOC < 45
-Li-Fraumeni < 30

Front 8

What is the normal job of tumor suppressor genes

Back 8

Respond to DNA damage, regulate cell division, control apoptosis.

These are the cells "brakes" for tumorgenesis

Front 9

How many alleles of a given gene have to mutate
for a TUMOR SUPPRESSOR gene to result in cancer?
-1
-2

Back 9

2

If "both breaks on the car go out then you can't stop" if both alleles of the tumor suppressor genes go out then you get a tumor.

This type of mutation is referred to as an "inactivating mutation"

Front 10

What is a proto-oncogene

Back 10

the normal function of proto-oncogenes is to regulate cell growth and differentiation. This is the cell's "accelerator" which drives the normal growth process.

Front 11

If one of the alleles for the proto-oncogene becomes an oncogene what happens?

Back 11

The gene is activated and does too much. The cell becomes permanently turned on. This is called an "activating mutation." Only one allele has to be affected.

Front 12

Name 3 kinds of tumor suppressor genes:

Back 12

Caretaker
Gatekeeper
Landscaper

Front 13

What does a caretaker tumor suppressor gene normally do?

Back 13

nucleotide excision repair
base excision repair
recombination pathways
mismatch repair pathways
telomere metabolism

Front 14

What can happen with mutations of tumor suppressor genes known as caretakers?

Back 14

nucleotide changes
translocations

Examples: MLH1, MSH2, MSH6, PMS2, BRCA1, BRCA2

Front 15

What does a tumor suppressor gene known as a gatekeeper normally do?

Back 15

monitor cell division
monitor apoptosis

Front 16

What happens with mutations of the gatekeeper genes?

Back 16

Mutations lead to proliferation of abnormal cells.

Example APC

Front 17

What is the normal function of the tumor suppressor genes known as landscapers?

Back 17

Control the cellular microenvironment.

Front 18

What happens with mutations in the landscaper genes?

Back 18

Stromal environment develops allowing unregulated cell proliferation.

Front 19

What kinds of genes are mutated in Lynch Syndrome?

Back 19

Mismatch repair genes (caretaker genes)

MLH1, MSH2, MSH6, PMS2

Front 20

What kind of gene is the APC gene?
Gatekeeper
Caretaker
Landscaper
Mixed
(A mutation in this gene causes Familal polyposis)

Back 20

Gatekeeper:

APC gene gone wrong can cause FAP which is unchecked growth.

Front 21

What kind of genes are the BRCA genes?

Back 21

mismatch repair genes (caretakers)

Front 22

What kind of gene is the TP53 gene?

Back 22

It has many functions. It doesn't fall into one category. It is a gatekeeper in that it regulates apoptosis, but it also has caretaker functions. It makes the protein p 53.

Front 23

What gene do we see go wrong in chronic mylocytic leukemia?

Back 23

BCR-ABL

This is an acquired mutation in an oncogene.

The ABL gene on chromosome 9 and the BCR gene on chromosome 22 have a translocation.

Front 24

What gene do we see go wrong with hereditary gastrointestinal stromal tumors?

Back 24

c-KIT

This can be an acquired or a germline mutation.

Front 25

In what oncogene do we see a germline mutation in hereditary melanoma?

Back 25

CDK4

Front 26

There are 4 inherited genes that are oncogenes.

The REST of the inherited genes are tumor suppressor genes.

NAME THE 4 INHERITED ONCOGENES

Back 26

-RET (multiple endocrine neoplasia type 2 - causes NEN2)
-MET (hereditary papillary renal cancer)
-CDK4 (hereditary melanoma)
-c-KIT (hereditary gastrointestinal stromal tumors - causes GIST) (this can also be acquired)

Front 27

Which is more common?
to acquire a mutation in a tumor suppressor gene or to inherit one?

Back 27

acquire one

Front 28

Is TP53 more often acquired or inherited

Back 28

Acquired:
-at least 50% of solid tumors will have a mutation in TP53
-Germline mutations in TP53 are very rare

Front 29

Which two cancer syndromes are ALMOST ALWAYS inherited

Back 29

HBOC (BRCA1, BRCA2)
HNPCC (MLH1, MSH2, MSH6, PMS2)

Front 30

What is HNPCC

Back 30

Heriditary Nonpolyposis Colon Cancer (Lynch syndrome)

Front 31

What genetic syndrome is Lhermitte-Duclos disease associated with?

Lhermitte Duclos is a benign neoplasm of the brain- dysplastic gangliocytoma of the cerebellum

Back 31

Cowden

Front 32

The skin disorder Trichilemmoma is pathognomonic for what genetic syndrome?

Back 32

cowden

Front 33

A germline mutation in the oncogene CDK4 is associated with what heritable cancer?

Back 33

Hereditary melanoma

Front 34

A germline mutation in the oncogene RET is associated with what heritable cancer?

Back 34

multiple endocrine Neoplasia (causes MEN2)

Front 35

A germline mutation in the oncogene MET is associated with what herrtible cancer?

Back 35

Hereditary papillary renal cancer

Front 36

A germline mutation in the oncogene c-KIT is associated with what hereditary cancer?

Back 36

Hereditary Gastrointestinal Stromal Tumors (causes GIST - gastro intestinal stromal tumors))

Front 37

An ACQUIRED mutation in the oncogene BCR-ABL is associated with what kind of cancer?

Back 37

Chronic myeloid leukemia.

Front 38

There are only two cancer syndromes that are ALMOST ALWAYS inherited, what are they?

Back 38

The BRCA genes that cause HBOC (Heriditary breast and ovarian cancer)

The genes that cause Lynch (HNPCC - heriditary nonpolyposis colon cancer)

Front 39

What kind of inheritance is displayed by Li-Fraumeni?

Back 39

autosomal dominant with incomplete penetrance

Front 40

What kind of inheritance is displayed by FAP?

Back 40

autosomal dominant with incomplete penetrance

Front 41

Are most cancer syndromes autosomal dominant or autosomal recessive

Back 41

Autosomal dominant

Front 42

Name two autosomal dominant syndromes with maternal imprinting (paternal transmissioin)

Back 42

-SDHD PGL/ PCC syndrome
Beckwith-Weidemann

Front 43

What kind of colon cancer syndrome is an autosomal recessive disorder?

Back 43

MAP
MYH-associated polyposis

Front 44

If you saw
-Wilm's Tumor (nephrpblastoma)
-and hepatoblastoma

What syndrome would you be thinking about?

Back 44

Beckwith-Wiedemann Syndrome

Front 45

In collecting a family history, what information do you want to obtain about AFFECTED relatives?

Back 45

-current age
-age at dx
-(age at death)
-cancer type, location, stage, laterality
-any second cancers - are the metastasis or new primary
-environmental exposures
-ethnicity/ race

Front 46

In collecting a family history what information do you want to obtain about UNAFFECTED relatives?

Back 46

-current age
-health history
-physical findings associated with cancer syndromes
-screening behaviors
-risk reducing surgeries
-risk factors
-(age and cause of death)

Front 47

Someone who has an inherited gene mutation OR a family history suggestive of an inherited mutation (mutation not yet identified) is at what level of risk?
-Average
-Moderate
-High

Back 47

High

Front 48

A person who has a combination of genetic and lifestyle or environmental factors that increase their risk for cancer are at what level of risk?
-Average
-Moderate
-High

Back 48

Moderate

Front 49

What are some family history items suggestive of a cancer predisposition?

Back 49

-younger than expected age of cancer onset
-multiple generations affected
-at least 2 first degree relatives with tumors at the same site
-at least two first degree relatives with a tumor that is part of a familial cancer syndrome
-at least two relatives with rare tumors

Front 50

What is the risk of breast cancer in the general population?

Back 50

1 in 8 (12%)

Front 51

What is the risk for breast cancer if a person has an affected first or second degree relative?

Back 51

20-30% (2-3 x general population)

Front 52

What is the risk of breast cancer for someone who carries the BRCA1or BRCA 2 gene?

Back 52

50-80%

These are dominant mutations

Front 53

What is the risk of colon cancer in the general population?

Back 53

1 in 20 lifetime risk (5%)

Front 54

What is the risk of colon cancer if there is an affected first or second degree relative under the age of 60.

Back 54

10-15% (2-3 x increased risk)