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COLORECTAL BLEEDING:a multidisciplinary approach
Torino, 31 marzo-1 aprile 2006
GENETIC EVALUATION
Schena M, Angelini F, Bertetto O.Department of Medical Oncology, COES,
Ospedale S. Giovanni Battista, Torino, Italy.
COLORECTAL CANCER DISTRIBUTION
68%
25%
6% 1%SPORADICFAMILIALHNPCCFAP
COLON CANCER LIFE-TIME RISK
• Average risk US population 6%
• Familial predisposition 12-18%
• Hereditary Syndromes
HNPCC 70-80%
FAP 100%
HNPCC
Autosomal dominant hereditary cancer predisposition syndrome
Early onset of CRC (average age 44)
Frequent proximal colon distribution
Fast adenoma carcinoma evolution
Extracolonic cancers: endometrium, ovary, stomach, small bowel,hepatobiliary tract,ureter or renal pelvis, pancreas, brain.
HNPCC
Five different genes of DNA mismacth repair system:
MLH1, MSH2, MSH6, PMS1, PMS2
Germline inactivating mutation
Microsatellite instability (MSI)Loss of specific protein (IHC)
HNPCC genes Dominant autosomic inheritance
MLH1 (3p22.3 – 57 kb, 19 exons)
MSH2 (2p21- 80 kb, 16 exons)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
AMSTERDAM CRITERIA II
Three family members with HNPCC-related cancer (colon, endometrium, small bowel, kidney-renal pelvis, ureters), two first degree relatives
At least two successive generations affected
One relative diagnosed at less than age 50
GENETIC COUNSELING(minimal access criteria)
No family history (or very small family):2 HNPCC-related cancers in the same patientYoung age of onset (< 50 years old)
Families with two first-degree relatives affected:One with young age of onset (< 50 years old)Colon adenoma at young age (< 40 years old)
Families with three first or two-degree relatives affected at any age.
Pre-Test evaluation
MSI - Microsatellite Instability test -
IHC - Immunohystochemistry for MLH1, MSH2, MSH6 products -
GENETIC TEST
• Amsterdam II criteria
• MSI and IHC pre-test evaluation
Affected member of the family Age > 18
Genetic Counseling Informed consent
FAP
Colon cancer predisposition syndrome -100-1000 adenomatous colonic polyps develop (classic form); 20-100 adenomatous polyps (attenuated form)
Mean age of 16 years (range 7-36 years)
By age 35 years, 95% of individuals have polyps; incidence of colon cancer is 100%
Extracolic manifestations are variably present (polyps of the gastric fundus and duodenum, osteomas, dental anomalies,retinic spots,soft tissue tumors and associated cancers)
FAP Genes Dominant autosomic (APC) and
recessive (MYH) inheritance
APC (5q22.2 – 100 kb, 15 exons)
MYH (1p34.1- 11 kb, 16 exons) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
ACCESS CRITERIA
• Classic or attenuated adenomatous polyposis• Familial hystory of polyposis • Extracolic manifestations
Any Affected Subject
Genetic Counseling Informed consent
SURVEILLANCE CRITERIA IN HNPCC
Colonoscopy
EXAMSAGE OF START
EXAMS FREQUENCY COMMENTS
COLON CA
ENDOMETRIAL CA OVARIAN CA
GASTRIC CA
URETERAL CA
21 years
every 2 years up to 40 years
afterward yearly
TVUSfrom 23-35 years
every 1-2 years
EGDscopyfrom 20-35 years
every 1-2 years
US + citology
from 20-35 years
every 1-2 years
FAP SURVEILLANCE CRITERIA
Colonoscopy
EXAMSAGE OF START
EXAMS FREQUENCY COMMENTS
COLON CA
GASTRIC CA DUODENAL CA
THYROID CA
from puberty
yearly genetic counseling
APC research total colectomy
Gastro-duodenoscop
y
from 20-25 years
every 1-3 years
Thyroid examfrom 10-12 years
every 12 month
CONCLUSION
• Genetic syndromes are rare but show high lifetime risk of CRC with early onset
• The role of gastroenterologist and surgeon that manage colorectal bleeding is crucial to disclose family with high genetic risk
• Members of these families should be addressed to genetic counseling.
www.rigenio.it
HNPCC genes Dominant autosomic inheritance
MSH6 (2p16.3 – 24 kb, 10 exons)
PMS1 (
PMS2 (7p22.1- 36 kb, 15 exons)
The syndrome is the result of deficiencies in
mismatch repair genes
INCIDENCE OF COLORECTAL CANCER
35-40.000 new pt/year in Italy
3.300 new pt/year in Piemonte
670 new pt/year in Torino
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