What does it mean to have a genetic predisposition to a cancer?
- A genetic predisposition (sometimes also called genetic susceptibility) is an
increased likelihood of developing a particular cancer based on a person's genetic
makeup.
- A genetic predisposition results from specific genetic variations that are often
inherited from a parent.
- These genetic changes contribute to the development of a disease but do not
directly cause it.
- Some people with a predisposing genetic variation will never get the disease
while others will, even within the same family.
- In people with a genetic predisposition, the risk of disease can depend on multiple
factors in addition to an identified genetic change. These include other genetic
factors (sometimes called modifiers) as well as lifestyle and environmental factors.
Individualized genomic patient analyses:
the context of the familial background (trio-calling)
Leukemia. 2019 Apr 9. doi: 10.1038/s41375-019-0459-z.
What does it mean to have a genetic predisposition to a cancer?
- A genetic predisposition (sometimes also called genetic susceptibility) is an
increased likelihood of developing a particular cancer based on a person's genetic
makeup.
- A genetic predisposition results from specific genetic variations that are often
inherited from a parent.
- These genetic changes contribute to the development of a disease but do not
directly cause it.
- Some people with a predisposing genetic variation will never get the disease
while others will, even within the same family.
- In people with a genetic predisposition, the risk of disease can depend on multiple
factors in addition to an identified genetic change. These include other genetic
factors (sometimes called modifiers) as well as lifestyle and environmental factors.
cancer
Environmental?????
Pre-cancer
clone
Healthy
carrier
a person's genetic makeup
cannot be altered
TODAY, how do we prevent disease risk in people with a genetic
predisposition?
Prophylactic mastectomy versus surveillance
for the prevention of breast cancer in women's BRCA carriers
Familial breast cancer. BRCA1 mutation carriers have a 54-85% risk of
developing breast cancer during their lifetime
Hunger and Mullighan, NEJM 2015Textbook of Pediatrics
Arthur Schlossmann 1893
Therapeutic developments of childhood ALL
cancer
environmental-
dependent?
Pre-cancer
clone
Healthy
carrier
A person's genetic makeup
cannot be altered
Why are we not able to prevent disease risk in people with a genetic
predisposition?
Written on his blackboard at time of his death, in 1988
HSC
Normal B cell development
What drives the conversion of a preleukemic clone
into a full-blown leukemic clone?
BO
NE
MA
RR
OW
PE
RIP
HE
RY
Pro B cell Pre B cell Immature B cell Matue B cell Memory B cell Plasma cell
pB-ALL childhood leukemia development
Preleukemic
clone
pB-ALL
Hematopoietic stem cell/
lymphoid progenitor
1st GENETIC
SUSCEPTIBILITY2nd HIT
Oncogenic event
Healthy carrier
10,75% of Sca1-ETV6-
RUNX1 mice exposed to
infections developed pB-
ALL
Pax5+/- or Sca1-ETV6-RUNX1 miceE0 E0-21 Birth PN0-21 Month1 Month2 Month4
Disease mouse
or
2 years old
-----
--FACS
analysis
Histological
analysis
Pax5+/- mice Pax5+/- mice
E0 E0-21 Birth PN0-21 Month1 Month2 Month4
Disease mouse
or
2 years old-----
--
Week 5-21:
Move to conventional
facility
FACS
analysis
Histological
analysis
NO pB-ALL
development
Sca1-ETV6-RUNX1 mice Sca1-ETV6-RUNX1 mice
E0 E0-21 Birth PN0-21 Month1 Month2 Month4
Disease mouse
or
2 years old-----
--
Week 5-21:
Move to conventional
facility
FACS
analysis
Histological
analysis
22% of
Pax5+/- mice exposed to
infections developed pB-
ALL
10,75% of
Sca1-ETV6-RUNX1 mice
exposed to infections
developed pB-ALL
2nd hit:
inactivating Kdm5c
mutations
2nd hit:
activating Jak3
mutations
Cancer Research. 2017 Aug 15;77(16)
Cancer Discov. 2015 Dec;5(12)
Infection triggers B-cell Precursor Acute Lymphoblastic Leukemia under a
genetic susceptibility
SPECIFIC PATHOGEN-
FREE facility (SPF)
CONVENTIONAL facility
(CF)
EXPOSURE TO
INFECTION
Interplay between predisposition, exposure andmisregulated immune response in childhood ALL
„life-style“
Geneticpredisposition
InnateImmunity
Adaptive Immunity
Bacteria,Virus,
Parasites
Prevention is better than cure
Leukemia rates in children and young adults
Is leukemia a preventable disease?
What occurs first, infection or the second hit in
infection mediated leukemias?
pB-ALL
Infection exposure
Is leukemia a preventable disease?
Preleukemic
clone
Healthy carrier
Infection
exposure
A
Infection is inducing the clonal
expansion of an already transformed
cell
What occurs first, infection or the second hit in infection mediated leukemias?
2nd hit
Preleukemic clone
Healthy carrier
pB-
ALL
Infection
exposure
A
Infection is inducing the clonal
expansion of an already transformed
cell
What occurs first, infection or the second hit in infection mediated leukemias?
2nd hit
Preleukemic clone
Healthy carrier
pB-
ALL
Infection
exposure
B
Infection is inducing the acquisition of
the second hit
2nd hit
Preleukemic clone
Healthy carrier
pB-
ALL
Infection
exposure
A
Infection is inducing the clonal
expansion of an already transformed
cell
What occurs first, infection or the second hit in infection mediated leukemias?
2nd hit
Preleukemic clone
Healthy carrier
pB-
ALL
Infection
exposure
B
Infection is inducing the acquisition of
the second hit
2nd hit
Preleukemic clone
Healthy carrier
pB-
ALL
It could be preventableDifficult to prevent
Infection
exposure
A
Infection is inducing the clonal
expansion of an already transformed
cell
What occurs first, infection or the second hit in infection mediated leukemias?
2nd hit
Preleukemic clone
Healthy carrier
pB-
ALL
Infection
exposure
B
Infection is inducing the acquisition of
the second hit
2nd hit
Preleukemic clone
Healthy carrier
pB-
ALL
pB-ALLHealthy carrier
healthy diseased
6 months 8 months 10 months 12 months 14 months
Regular bleeding to track disease development
Jak3V670A
pB-ALLHealthy carrier
healthy diseased
IgM
B220
6 months 8 months 10 months 12 months 14 months
Regular bleeding to track disease development
Jak3V670A
IgM
B220
Infection induces the acquisition of the second hit
in pB-ALL under a Pax5 genetic susceptibility
Role of the gut microbiome in infection-driven leukemias
Homeostasis DysbiosisG
ut
Gu
tm
icro
bio
me
Pax5+/-WT
T-Cells B-Cells
Gut-associated
lymphoid tissue
Gut-associated
lymphoid tissue
Healthy pB-ALL
Peripheral
lymphoid tissue
Peripheral
lymphoid tissue
21,95 %
- Decrease of B-cells in peripheral
blood and in Peyer’s patches
- Increase of proB and preB cells
- Different gut microbiome
HomeostasisDysbiosis
Gu
tG
ut
mic
rob
iom
e
Role of the gut microbiome in infection-driven leukemias
Pax5+/- Pax5+/- _ ABWT
T-Cells B-Cells
Gut-associated
lymphoid tissue
Gut-associated
lymphoid tissue
Gut-associated
lymphoid tissue
Healthy pB-ALL
Peripheral
lymphoid tissue
Peripheral
lymphoid tissue
Peripheral
lymphoid tissue
21,95 %
- Decrease of B-cells in peripheral
blood and in Peyer’s patches
- Increase of proB and preB cells
- Different gut microbiome
Antibiotic treatment
HomeostasisDysbiosis
Gu
tG
ut
mic
rob
iom
e
Role of the gut microbiome in infection-driven leukemias
Pax5+/- Pax5+/- _ ABWT
T-Cells B-Cells
Gut-associated
lymphoid tissue
Gut-associated
lymphoid tissue
Gut-associated
lymphoid tissue
Healthy pB-ALL
Peripheral
lymphoid tissue
Peripheral
lymphoid tissue
Peripheral
lymphoid tissue
21,95 %
- Decrease of B-cells in peripheral
blood and in Peyer’s patches
- Increase of proB and preB cells
- Different gut microbiome
Antibiotic treatment
HomeostasisDysbiosis
Gu
tG
ut
mic
rob
iom
e
Role of the gut microbiome in infection-driven leukemias
Pax5+/- Pax5+/- _ ABWT
T-Cells B-Cells
Gut-associated
lymphoid tissue
Gut-associated
lymphoid tissue
Gut-associated
lymphoid tissue
Healthy pB-ALL
Peripheral
lymphoid tissue
Peripheral
lymphoid tissue
Peripheral
lymphoid tissue
21,95 %
- Decrease of B-cells in peripheral
blood and in Peyer’s patches
- Increase of proB and preB cells
- Different gut microbiome
Antibiotic treatment
HomeostasisDysbiosis
Gu
tG
ut
mic
rob
iom
e
The depletion of the gut microbiome influence the incidence of the disease in genetically predisposed carriers
Pax5+/- Pax5+/- _ ABWT
T-Cells B-Cells
Gut-associated
lymphoid tissue
Gut-associated
lymphoid tissue
Gut-associated
lymphoid tissue
Healthy pB-ALLpB-ALL
Peripheral
lymphoid tissue
Peripheral
lymphoid tissue
Peripheral
lymphoid tissue
RR=2,8
62,96 %21,95 %
- Decrease of B-cells in peripheral
blood and in Peyer’s patches
- Increase of proB and preB cells
- Different gut microbiome
- Depletion of the gut microbiome
influence the incidence of the disease
- Decrease T cells in Peyer’s patches
Antibiotic treatment
Some members of Salamanca-Dusseldorf-Madrid team