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COLORECTAL BLEEDING: a multidisciplinary approach Torino, 31 marzo-1 aprile 2006

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. COLON CANCER LIFE-TIME RISK.

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COLORECTAL BLEEDING: a multidisciplinary approach Torino, 31 marzo-1 aprile 2006

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  1. COLORECTAL BLEEDING:a multidisciplinary approachTorino, 31 marzo-1 aprile 2006 GENETIC EVALUATION Schena M, Angelini F, Bertetto O. Department of Medical Oncology, COES, Ospedale S. Giovanni Battista, Torino, Italy.

  2. COLORECTAL CANCER DISTRIBUTION

  3. COLON CANCER LIFE-TIME RISK • Average risk US population 6% • Familial predisposition 12-18% • Hereditary Syndromes HNPCC 70-80% FAP 100%

  4. HNPCC • Autosomal dominant hereditary cancer predisposition syndrome • Early onset of CRC (average age 44) • Frequent proximal colon distribution • Fast adenomacarcinoma evolution • Extracolonic cancers: endometrium, ovary, stomach, small bowel,hepatobiliary tract,ureter or renal pelvis, pancreas, brain.

  5. 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)

  6. HNPCC genes Dominant autosomic inheritance • MLH1(3p22.3 – 57 kb, 19 exons) • MSH2(2p21- 80 kb, 16 exons)

  7. 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

  8. GENETIC COUNSELING(minimal access criteria) • No family history (or very small family): 2 HNPCC-related cancers in the same patient Young 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.

  9. Pre-Test evaluation • MSI - Microsatellite Instability test - • IHC -Immunohystochemistry for MLH1, MSH2, MSH6 products -

  10. GENETIC TEST • Amsterdam II criteria • MSI and IHC pre-test evaluation Affected member of the family Age > 18 Genetic Counseling Informed consent

  11. 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)

  12. FAP Genes Dominant autosomic (APC) and recessive (MYH) inheritance • APC (5q22.2 – 100 kb, 15 exons) • MYH (1p34.1- 11 kb, 16 exons)

  13. ACCESS CRITERIA • Classic or attenuated adenomatous polyposis • Familial hystory of polyposis • Extracolic manifestations Any Affected Subject Genetic Counseling Informed consent

  14. SURVEILLANCE CRITERIA IN HNPCC AGE OF START EXAMS FREQUENCY EXAMS COMMENTS Colonoscopy 21 years • every 2 years up to 40 years • afterward yearly COLON CA TVUS from 23-35 years • every 1-2 years ENDOMETRIAL CA OVARIAN CA EGDscopy from 20-35 years • every 1-2 years GASTRIC CA US + citology from 20-35 years • every 1-2 years URETERAL CA

  15. FAP SURVEILLANCE CRITERIA AGE OF START EXAMS FREQUENCY EXAMS COMMENTS Colonoscopy from puberty • yearly • genetic counseling APC research • total colectomy COLON CA Gastro-duodenoscopy from 20-25 years • every 1-3 years GASTRIC CA DUODENAL CA Thyroid exam from 10-12 years • every 12 month THYROID CA

  16. 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

  17. 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

  18. 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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