Isidro Sánchez-García isg@usal · 2019. 5. 30. · B220. 6 months 8 months 10 months 12 months 14...

Genetic predisposition and prevention in cancer

Isidro Sánchez-García

isg@usal.es

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