Li Fraumeni

Question 1

Li Fraumeni is a

Answer 1

very rare inherited cancer susceptibility syndrome

Question 2

presentation of Li-Fraumeni syndrome?

Answer 2

childhood cancer
early on set breast cancer
elevated risk for wide range of cancers
sarcoma
premenosaul breast cancers
adrenocortical tumors
leukemias
lymphomas

Question 3

Li Fraumeni must have

Answer 3

more than one family member with cancer susceptibility syndrome

Question 4

LFS is associated with

Answer 4

mutation of tumor suppressor p53 (~70%)

Question 5

p53 is known as the

Answer 5

guardian of genome
somatic mutations occur in over 50% of all human tumors
Most frequent mutation in solid tumors

Question 6

Over _____ different mutations in p53 genes

Answer 6

250

some mutations are more common in families, other are more common in sporadic tumors
different properties of each mutation may in part explain clinical heterogeneity

Question 7

Li-Fraumeni Like syndrome

Answer 7

only 40% associated with p53 mutations

Question 8

What is the clinical benefit of identifying the molecular basis of LFS?

Answer 8

1. clinical recognition of LFS can be complicated, identification of a mutation provides diagnostic certainty
2. an informed clinician can avoid delay in diagnosis of any second tumor
3. radiation should be avoided wherever possible
4. prenatal diagnosis may be offered to families

Question 9

LFS inheritance

Answer 9

autosomal dominant

Question 10

diagnostic criteria for LFS?

Answer 10

1. pro band with sarcoma diagnosed before 45 AND
2. first degree relative with any cancer under 45 AND
3. first or second degree relative with any cancer under 45 or a sarcoma at ANY age

Question 11

diagnostic criteria for Li-Fraumeni Like Syndome (LFL)

Answer 11

1. pro band with any childhood cancer or sarcoma brain tumor, adrenal cortical tumor diagnosed before 45 AND
2. 1st or 2nd egree relative with typical LFS cancer (sarcoma, breast cancer, brain tumor, adrenal cortical tumor, leukemia) at any age AND
3. 1st or 2nd degree relative with any cancer under the age of 60 years

Question 12

How is testing conducted for LFS or LFL?

Answer 12

1. direct sequencing of entire gene of p53
2. some groups only sequence the hot spots
3. other groups sequence the entire p53 messenger RNA
4. if there are no detectable p53 mutations they may go on to other genes like hChk2 or PTEN

Question 13

two hit model of knudson

Answer 13

1 hit: premalignant
germline p53 point mutation

2 hit: carcinoma
amplification of HER2

Question 14

what are the common ways cancer associated hits can occur

Answer 14

1. point mutations may give oncogene activation or tumor suppressor inactivation
2. amplifications and deletions
3. epigenetic silencing by methylation (CDKN2A)
4. insertion of a retrovirus containing an oncogene

Question 15

hits may be on

Answer 15

different genes

Question 16

hit 1:

hit 2:

Answer 16

p53 mutant

Li Fraumeni patient developed EGFR mutant

lung cancer after whole body radiation

Question 17

p53 protects us from

Answer 17

carcinogens

Question 18

____ most prevalent carcinogen

Answer 18

UV

Question 19

if p53 is not functional,

Answer 19

dna damage can occur and accumulate

Question 20

___% of solid tumors have lost the function or expression of p53

Answer 20

50%

Question 21

if regulates the expression of a huge number of other genes:

Answer 21

1. p53 is transcription factor
2. p53 regulates microRNAs as well as protein coding genes
3. p53 is target of conventional chemotherapy and specific rationally designed drugs are now available that can activate p53 without DNA damage

Question 22

In the case of Li-Fraumeni syndrome, the first hit is often a

Answer 22

loss of function in the tumor suppressor p53 (70% of cases).

Question 23

DNA damage is recognized by a

Answer 23

sensor molecule such as Rad 17 which binds the damaged DNA.

Question 24

The ATM/ATR molecules transduce the signal by

Answer 24

phosphorylating CHK1/CHK2 which in turn activates p53 through phosphorylation.

Question 25

P53 binds DNA and activates transcription of

Answer 25

such as p21, Gadd45, Bax and Fas.

Question 26

P21 is a signal for

Answer 26

cell cycle arrest in G1

Question 27

Gadd45 is a signal for

Answer 27

cell cycle arrest in G2.

Question 28

Fas and Bax signal the cell to

Answer 28

commit suicide through apoptosis.