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Cancer colo-rectal et Génétique

A. KARTHEUSER

K. DAHAN

Ch. SEMPOUX

C. WALON

Ch. VERELLEN-DUMOULIN

 THE IMPACT OF GENETICS IN COLORECTAL NEOPLASIA

HEREDITARY NON POLYPOSIS COLORECTAL CANCER (HNPCC)

• Lynch I
• Lynch II
• Muir-Torre syndrome

HNPCC Lynch I syndrome

• Site-specific
• colorectal cancers

HNPCC Lynch II syndrome

• Colorectal cancer
• Other cancers :

  - endometrium

  - stomach

  - biliary tract

  - urinary tract

  - ovaries

  - brain

  - breast

  - small bowel

  - lung

  - other .....

HNPCC Muir-Torre syndrome

• Subcutaneous gland tumours
• Skin cancers :

  - keratocanthomas

  - basal cell carcinomas

HNPCC: épidémiologie 

• Incidence : > 1/200
• ± 5 % of all CRC
• Penetrance 80-90 %

HNPCC: Critères diagnostiques

"Critères d'Amsterdam"

• > 3 cas, dont 2 premier degré
• > 2 générations
• 1 cancer < 50 ans
• + PAF exclue

HNPCC: Méthodes de diagnostic 

• Sang : Mutations gènes MMR : hMSH2, hMLH1
• Tumeur :

  - Immunohistochimie : protéines hMSH2, hMLH1

  - Instabilité des microsatellites

  - Méthylation promoteurs : «Epigenic silencing »

HNPCC : Clinical surveillance recommendations 

Site

Procedure

Lower age limit (yrs)

Interval (yrs)

WEBER, Lancet, 1996, 348 : 465.

 HNPCC: Risk of cancer

 

Site	Cumulative lifetime risk

HNPCC: Prophylactic surgery

. Recommended :	gene carriers
	with adenomas
	with high degree of dysplasia
	and/or villosity
. Type of surgery :	Colectomy + IRA
	CPT + IPAA

 

HNPCC: Rectal cancer risk after abdominal colectomy  

* Risk of rectal cancer :	12 % at 12 years
* Multivariate analysis :	age at 1st surgical procedure; surveillance or not

RODRIGUEZ et al., Ann. Surg. 1997; 225 : 202-207.

HNPCC: Survival analysis

aaaaaCRCaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa	5-year
	survival rate

PERCESEPE et al., Int. I. Cancer, 1997; 71 : 373-376.

HNPCC 

DNA mismatch repair genes defect

HNPCC 

IMPACT OF GENETICS

. Carcinogenesisaaaaaaaaaa
. At risk screening
. Cancer prevention :
aaaaaaa- colonoscopy :	. from 20-25 years
	. every 2 years
aaaaaaa- surgery :	. TC + IRA
	. TPC + IPAA

CANCER COLORECTAL : Biologie moléculaire

aaaaaaaaaa HNPCC : Hereditary Non Polyposis Colo-rectal Cancer

aaaaaaaaaa - autosomique dominant

aaaaaaaaaa - polypes villeux, dysplasie

aaaaaaaaaa - cancers < 40-45 ans

aaaaaaaaaa - cancers multiples

aaaaaaaaaa - cancers extracoliques

aaaaaaaaaa- pronostic

HNPCC

CANCER COLORECTAL : BIOLOGIE MOLECULAIRE 

. HNPCC : diagnostic génétique

aaaaaaaaaa - hMLH1

aaaaaaaaaa - hMSH2

aaaaaaaaaa - PMS1

aaaaaaaaaa - PMS2

HNPCC 

DNA mismatch repair genes : 

hMSH2	2p16	60 %
hMLH1	3p21	30 %
hPMS1	2q31-33	?
hPMS2	7p22	?
...	...	...

DNA REPAIR IN THE HUMAN 

. 3 x 109 bases / cell

aaaaa1014 cells

aaaaa 1016 division cycles / life

. Estimated replication error rate :

aaaaa 10-10 mut / bp / cell / generation

aaaaaaaaaaaaaaaafl

aaaaa DNA repair enzymes

aaaaa = Proof reading

aaaaaaaaaaaaaaafl

aaaaa < 3 bp mistakes

aaaaa when copying the human genome

SPORADIC COLORECTAL CANCER IN BELGIUM

 

M

F

Total

NCR, 1992

COLORECTAL CANCER 

HEREDITARY NON POLYPOSIS COLORECTAL CANCER (HNPCC) 

Underlying mechanism :

Germline mutations in DNA

mismatch repair genes (MMR)

HEREDITARY NON POLYPOSIS COLORECTAL CANCER (HNPCC) 

DNA mismatch repair genes (MMR) :

h MSH2	h MLH2
h MLH1	h MLH3
h MSH3	PMS1
h MSH6	PMS2

 HEREDITARY NON POLYPOSIS COLORECTAL CANCER (HNPCC)

HEREDITARY NON POLYPOSIS COLORECTAL CANCER (HNPCC)

HEREDITARY NON POLYPOSIS COLORECTAL CANCER (HNPCC)

. Tumour :

- Immunohistochemistry (IH): Proteins hMSH2 and hMLH1

- Microsatellite instability (MSI)

- Promotor methylation : "Epigenic silencing"

. Blood :

- Mutation screening in MMR genes : hMSH2, hMLH1, ...

HEREDITARY NON POLYPOSIS COLORECTAL CANCER (HNPCC)

. Molecular biology has significantly contributed to the understanding of the genetic basis of HNPCC.

. Once the mutation is identified, all at risk family members can easily be tested.

. A close surveillance programme can be offered to proven HNPCC gene carriers including prophylactic surgery when indicated.

HNPCC:SCREENING STRATEGY (I)

HNPCC:SCREENING STRATEGY (II)

HNPCC:STATEGIE DIAGNOSTIQUE (I)

HNPCC:STATEGIE DIAGNOSTIQUE (II)

Auteur: Prof. A. Kartheuser - 26/11/1999