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 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 (2p kb, 16 exons)

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 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.

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 CounselingInformed consent

FAP  Colon cancer predisposition syndrome adenomatous colonic polyps develop (classic form); 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 (1p kb, 16 exons)

ACCESS CRITERIA Classic or attenuated adenomatous polyposis Familial hystory of polyposis Extracolic manifestations Any Affected Subject Genetic CounselingInformed consent

SURVEILLANCE CRITERIA IN HNPCC Colonoscopy EXAMS AGE 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 TVUS from years every 1-2 years EGDscopy from years every 1-2 years US + citology from years every 1-2 years

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

HNPCC genes Dominant autosomic inheritance  MSH6 (2p16.3 – 24 kb, 10 exons)  PMS1 (  PMS2 (7p kb, 15 exons)  The syndrome is the result of deficiencies in mismatch repair genes

INCIDENCE OF COLORECTAL CANCER  new pt/year in Italy  new pt/year in Piemonte  670 new pt/year in Torino