colorectal bleeding: a multidisciplinary approach torino, 31 marzo-1 aprile 2006 genetic evaluation...
TRANSCRIPT
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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.
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COLORECTAL CANCER DISTRIBUTION
68%
25%
6% 1%SPORADICFAMILIALHNPCCFAP
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COLON CANCER LIFE-TIME RISK
• Average risk US population 6%
• Familial predisposition 12-18%
• Hereditary Syndromes
HNPCC 70-80%
FAP 100%
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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.
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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)
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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
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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
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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.
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Pre-Test evaluation
MSI - Microsatellite Instability test -
IHC - Immunohystochemistry for MLH1, MSH2, MSH6 products -
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GENETIC TEST
• Amsterdam II criteria
• MSI and IHC pre-test evaluation
Affected member of the family Age > 18
Genetic Counseling Informed consent
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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)
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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
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ACCESS CRITERIA
• Classic or attenuated adenomatous polyposis• Familial hystory of polyposis • Extracolic manifestations
Any Affected Subject
Genetic Counseling Informed consent
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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
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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
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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
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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
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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