1. Long-Term Colorectal-Cancer Incidence and Mortality after Lower Endoscopy Supervisor: 邱宗傑 主任 Presented by 郭政裕 總醫師 NEJM, Sep 19, 2013

2. Polyp-Cancer sequency ?

4. Morphology, Anatomic Distribution and Cancer Potential of Colonic Polyps. Annals Surgery 1979;190:679-683.

6. Familiar adenomatous polyposis (FAP) APC mutations (Adenomatous polyposis coli) An inherited cancer-predisposition syndrome more than 100 adenomatous polyps in carriers of the mutant gene, the risk of colorectal cancer by the age of 40 years is almost 100% Kathleen H. Biology Of The APC Tumor Suppressor. J Clin Oncol 2000;18:1967-1979.

8. Animal model: The Apc min mouse – chemical mutagenesis that introduced a chain- terminating mutation at nucleotide 2549 in mApc – develop numerous intestinal adenomas in which the remaining wild-type allele is somatically inactivated during adenoma development Kathleen H. Biology Of The APC Tumor Suppressor. J Clin Oncol 2000;18:1967-1979.

9. Sporadic colorectal adenoma and cancers APC – Somatic mutations and deletions that inactivate both copies of APC are present in most patients Wild-type APC – Mutations of β-catenin  resistent to the β- catenin degradation complex Kathleen H. Biology Of The APC Tumor Suppressor. J Clin Oncol 2000;18:1967-1979.

10. Sanford D. Moleucular Basis of Colorectal Cancer. N Engl J Med 2009;361:2449-60.

13. Methods Study population – Prospective cohort study The Nurses’ Health Study: 121,700 U.S. female nurses (30~55 y/o), since 1976 The Health Professionals Follow-up Study: 51,529 U.S. male health professionals (40~75 y/o), sinc 1986 Exclusion criteria – History of cancer – Ulcerative colitis – Colorectal polyps – Familiar polyposis syndromes – Previous lower endoscopy

14. Observational studies – Enrolled: n=88,902 (31,736 men, 57,166 women) – 1998~2008 – Questionnaire and collect information every 2 year (Low GI endoscopy: sigmoidscopy or colonoscopy) – Incidence analysis in 2010, mortality analysis in 2012

15. Polyps – Adenomatous polyps – Advanced adenoma (≥10 mm, tubulovillus or villous, or high-grade dysplasia) – High-risk adenoma ( numbers ≥ 3) – Colonoscopic polypectomy: excision of comfirmed adenomatous polyps (excluding hyperplastic polyps) – Negative endoscopy: no adenomas or CRCs

16. Molecular analysis – Microsatellite instability status – BRAF (codon 600) – KRAS (codon 12 and 13) – PIK3CA (exons 9 and 20) – DNA methylation (8 CpG island methylator phenotype, CIMP) Specific promotors: MLH1, CACNA1G, CDKN2A, CRABP1, IGF2, NEUROG1, RUNX3, and SOCS1) Long interspersed nucleotide element 1 (LINE-1)

18. Results 88,902 participants, follow-up for 22 years – Received endoscopy vs. without endoscopy – Colorectal cancer: 1815 incident cases (2%)

21. Screen colonscopy interval

22. Surveillance colonoscopy interval after removal of adenomatous polyps

26. Summary Low gastrointestinal endoscopy is associated with a low incidence and low mortality of colorectal cancer Tumor molecular features of the serrated pathway might be involved in the development of cancer within 5 years after colonoscopy