Cancer - Childhood Onset
Li-Fraumeni Syndrome (LFS)
*germline mut in what gene
*cancers when
*penetrance?
*common? - ANSWER: TP53 mutations
childhood cancers
nearly 100% penetrance
SUPER rare (but not as rare as once thought)
Cancers associated with LFS
Li-FRAUMENi S (6 things) - ANSWER: L = Leukemia
Frauline = women = breast cancer under 31y
A = adrenalcortical carcinoma (most peds)
U = plexUs = choroid plexus tumor (+ other brain)
MEN = prostate cancer
S = Sarcoma (childhood, normally super rare, but common in LFS)
Most common cancer in LFS women? - ANSWER: Breast cancer
Role of TP53 in genome - ANSWER: "guardian" of the genome
If something is going on, will shut down (cell cycle arrest) or explode (apoptosis)
Classic TP53 mutations - ANSWER: LOF by dominant negative
DNA binding domain mutations
Are somatic vs germline TP53 muts similar or different - ANSWER: Similar
*makes things tricky
Classic LFS is caused by what type of TP53 muts - ANSWER: Full penetrance TP53
germline muts
*LOF, dominant negative
LTR of cancer with LFS
<30 you cancer risk with LFS - ANSWER: 90% LTR
50% <30 y
What cancers in LFS are seen under 31 yrs
*hypodiploid seen in what age - ANSWER: Breast, brain, leukemia, sarcoma,
adrenocortical, choroid plexus
*<21 yrs
,LFS screening (frequency and age to start) - for adults
*general
*breast
*brain
*soft tissue and bone
*GI
*Melanoma - ANSWER: Gen: complete physical every 6 mo,
Breast: awareness, clinical exam 2xyear from 20yrs on, annual MRI (age 20-75),
consider rrBM
Brain: annual brain MRI (18yrs on)
Soft tissue/bone: annual whole body MRI, ultrasound of pelvis every 12 months (all 18
yrs on)
GI: upper endoscopy and colonoscopy every 2-5 yrs from 25 yrs on
Melanoma: annual derm exam (18 yrs on)
LFS screening for peds - ANSWER: Begin at birth or when dx
- neuro exam /6mo
- US abdomen & pelvis then MRI at 10y /annual
- brain MRI /anually
- blood labs for leukemia /6 mo until 10y, then annual
- whole body MRI at 1y annual for sarcoma
Classic LFS criteria (clinical) for dx
Three criteria and/or what - ANSWER: 1. proband with sarcoma dx prior to 45 yrs
2. FDR with any cancer dx prior to 45 yrs
3. FDR or SDR with any cancer dx prior to 45 yrs or sarcoma dx at any age
*three criteria and/or dx of TP53 mutation
What % with classic LFS clinical dx criteria have a TP53 mutation? - ANSWER: 60-80%
Phenotypic LFS - ANSWER: No TP53 variant
Meets LFS criteria
LFS carrier criteria - ANSWER: P/LP germline TP53 variant (or mosaic) + no hx of
cancer + LFS in family
Classic LFS criteria - ANSWER: P/LP germline TP53 variant (or mosaic) + meeting
clinical LFS criteria and/or any cancer <18 yrs
Attenuated LFS criteria - ANSWER: P/LP germline TP53 variant (or mosaic) + hx of
cancer not meeting TP53 critiera + no cancer <18 yrs
Different classifiations for LFS based on what - ANSWER: on different TP53 mutations
Breast cancer and TP53
TP53 mutation accounts for what % of BC (breast cancer) age <31?
, Of premenopausal women? (<50yrs)
Median age of BC in LFS women
HER and ER in LFS BC? - ANSWER: ~5-8% <31
~4-5% <50
*30-35 yrs = median age
Over half HER2+ and most are ER+
XX individuals with LFS (and attenuated LFS) have what LTR of Breast cancer? -
ANSWER: 80-90%
Prostate (PrCa) and TP53/LFS
What % of LFS men have PrCa?
What % of LFS men >50 yrs develop PrCa?
LFS men have what fold increase risk of PrCa vs general public?
median age of onset?
What % of PrCa patients have TP53 mut?
PrCa patients have what fold increase of having TP53 mut vs general public?
Associated with what trends of disease
Most Tp53 muts are what - ANSWER: *20% of LFS adult males have PrCA
*51% of LFS men >50 yrs develop PrCa
*21.2 fold increase
*med age onset 56 yrs
0.4-0.8%
7 fold increase risk
Young onset and high grade and stage
*non classical LFS mutations
Mutational spectrum in (PrCa?) LFS patients is skewed to what risk - ANSWER: lower
risk TP53 muts
With TP53 mut, want to avoid what treatment? - ANSWER: Radiation!
*chemo is also potentially oncogenic
What's the biggest offender in mosaicism? - ANSWER: TP53
*b/c almost every panel has TP53 and it's often picked up at mosaic levels
Causes of mosaic test result (from blood test) - ANSWER: 1. Technical error
2. Abnormal clonal expansion (ACE)
3. True post-zygotic somatic mosaicism
4. Massive ammounts of circulating tumor DNA
Causes of Abnormal clonal expansion (ACE)
*mosaic that's not germline (de novo) or post-zygotic - ANSWER: Age related clonal
hematopoiesis of indeterminate potential (CHIP)
post-chemo clonal expansions
hematological malignancy
Li-Fraumeni Syndrome (LFS)
*germline mut in what gene
*cancers when
*penetrance?
*common? - ANSWER: TP53 mutations
childhood cancers
nearly 100% penetrance
SUPER rare (but not as rare as once thought)
Cancers associated with LFS
Li-FRAUMENi S (6 things) - ANSWER: L = Leukemia
Frauline = women = breast cancer under 31y
A = adrenalcortical carcinoma (most peds)
U = plexUs = choroid plexus tumor (+ other brain)
MEN = prostate cancer
S = Sarcoma (childhood, normally super rare, but common in LFS)
Most common cancer in LFS women? - ANSWER: Breast cancer
Role of TP53 in genome - ANSWER: "guardian" of the genome
If something is going on, will shut down (cell cycle arrest) or explode (apoptosis)
Classic TP53 mutations - ANSWER: LOF by dominant negative
DNA binding domain mutations
Are somatic vs germline TP53 muts similar or different - ANSWER: Similar
*makes things tricky
Classic LFS is caused by what type of TP53 muts - ANSWER: Full penetrance TP53
germline muts
*LOF, dominant negative
LTR of cancer with LFS
<30 you cancer risk with LFS - ANSWER: 90% LTR
50% <30 y
What cancers in LFS are seen under 31 yrs
*hypodiploid seen in what age - ANSWER: Breast, brain, leukemia, sarcoma,
adrenocortical, choroid plexus
*<21 yrs
,LFS screening (frequency and age to start) - for adults
*general
*breast
*brain
*soft tissue and bone
*GI
*Melanoma - ANSWER: Gen: complete physical every 6 mo,
Breast: awareness, clinical exam 2xyear from 20yrs on, annual MRI (age 20-75),
consider rrBM
Brain: annual brain MRI (18yrs on)
Soft tissue/bone: annual whole body MRI, ultrasound of pelvis every 12 months (all 18
yrs on)
GI: upper endoscopy and colonoscopy every 2-5 yrs from 25 yrs on
Melanoma: annual derm exam (18 yrs on)
LFS screening for peds - ANSWER: Begin at birth or when dx
- neuro exam /6mo
- US abdomen & pelvis then MRI at 10y /annual
- brain MRI /anually
- blood labs for leukemia /6 mo until 10y, then annual
- whole body MRI at 1y annual for sarcoma
Classic LFS criteria (clinical) for dx
Three criteria and/or what - ANSWER: 1. proband with sarcoma dx prior to 45 yrs
2. FDR with any cancer dx prior to 45 yrs
3. FDR or SDR with any cancer dx prior to 45 yrs or sarcoma dx at any age
*three criteria and/or dx of TP53 mutation
What % with classic LFS clinical dx criteria have a TP53 mutation? - ANSWER: 60-80%
Phenotypic LFS - ANSWER: No TP53 variant
Meets LFS criteria
LFS carrier criteria - ANSWER: P/LP germline TP53 variant (or mosaic) + no hx of
cancer + LFS in family
Classic LFS criteria - ANSWER: P/LP germline TP53 variant (or mosaic) + meeting
clinical LFS criteria and/or any cancer <18 yrs
Attenuated LFS criteria - ANSWER: P/LP germline TP53 variant (or mosaic) + hx of
cancer not meeting TP53 critiera + no cancer <18 yrs
Different classifiations for LFS based on what - ANSWER: on different TP53 mutations
Breast cancer and TP53
TP53 mutation accounts for what % of BC (breast cancer) age <31?
, Of premenopausal women? (<50yrs)
Median age of BC in LFS women
HER and ER in LFS BC? - ANSWER: ~5-8% <31
~4-5% <50
*30-35 yrs = median age
Over half HER2+ and most are ER+
XX individuals with LFS (and attenuated LFS) have what LTR of Breast cancer? -
ANSWER: 80-90%
Prostate (PrCa) and TP53/LFS
What % of LFS men have PrCa?
What % of LFS men >50 yrs develop PrCa?
LFS men have what fold increase risk of PrCa vs general public?
median age of onset?
What % of PrCa patients have TP53 mut?
PrCa patients have what fold increase of having TP53 mut vs general public?
Associated with what trends of disease
Most Tp53 muts are what - ANSWER: *20% of LFS adult males have PrCA
*51% of LFS men >50 yrs develop PrCa
*21.2 fold increase
*med age onset 56 yrs
0.4-0.8%
7 fold increase risk
Young onset and high grade and stage
*non classical LFS mutations
Mutational spectrum in (PrCa?) LFS patients is skewed to what risk - ANSWER: lower
risk TP53 muts
With TP53 mut, want to avoid what treatment? - ANSWER: Radiation!
*chemo is also potentially oncogenic
What's the biggest offender in mosaicism? - ANSWER: TP53
*b/c almost every panel has TP53 and it's often picked up at mosaic levels
Causes of mosaic test result (from blood test) - ANSWER: 1. Technical error
2. Abnormal clonal expansion (ACE)
3. True post-zygotic somatic mosaicism
4. Massive ammounts of circulating tumor DNA
Causes of Abnormal clonal expansion (ACE)
*mosaic that's not germline (de novo) or post-zygotic - ANSWER: Age related clonal
hematopoiesis of indeterminate potential (CHIP)
post-chemo clonal expansions
hematological malignancy
