Colorectal Cancer and Hereditary Colon Cancer Syndromes Carol A. Burke, M.D.

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1 Colorectal Cancer and Hereditary, FACG, FACP Sanford R. Weiss MD Center for Hereditary Colorectal Neoplasia Digestive Disease Institute Cleveland Clinic, Cleveland, Ohio 1 Objectives Review the molecular and genetic basis of sporadic colorectal cancer (CRC) Identify the precursor lesions of CRC Understand the diagnostic features of the hereditary colorectal cancer syndromes Development management strategies for your patients with the hereditary cancer syndromes 2 Colorectal cancer precursors 70% Adenomatous Lesions Chromosomal Instability (CIN) Microsatellite Stable (MSS) 30% Serrated Lesion BRAF mutation CpG Island Methylation (CIMP) Microsatellite Instability (MSI) or MSS 3 1

Classification of colorectal polyps Adenomatous Lesions Tubular Tubulovillous Villous Serrated Lesions Hyperplastic Polyp Microvesicular (MVHP) Goblet Cell (GCHP) Mucin Poor (MPHP) Sessile

Proposed serrated pathway of MSI-H CRC BRAF mutation +/- methylation Generally slowly progressive or random?

2010 5 Prevention of CRC: recognition of high risk precursor lesions Colonoscopy with polypectomy has been shown in some, but not all, studies to be associated with a decrease in the incidence

2 Classification of colorectal polyps Adenomatous Lesions Tubular Tubulovillous Villous Serrated Lesions Hyperplastic Polyp Microvesicular (MVHP) Goblet Cell (GCHP) Mucin Poor (MPHP) Sessile Serrated Adenoma/ Polyp (SSP/A) With cytological dysplasia Without cytologic dysplasia Traditional Serrated Adenoma (TSA) With conventional dysplasia Without conventiona ldysplasia WHO Proposed serrated pathway of MSI-H CRC BRAF mutation +/- methylation Generally slowly progressive or random? Additional methylation BRAF mutation + methylation Methylation of hmlh1 Usually rapidly progressive Mutation or methylation of other genes Snover, DC, Human Pathology 2010; accepted 16 June Prevention of CRC: recognition of high risk precursor lesions Colonoscopy with polypectomy has been shown in some, but not all, studies to be associated with a decrease in the incidence of CRC Emerging data demonstrates an overall and left sided CRC mortality reduction with colonoscopy which does not extend to protection in the right colon Lack of protective benefit from colonoscopy may be due to missed lesions, incomplete resection or diversity in biology/morphology 6 2

Detection of polyps All Adenoma HP SSA/P SSAD CRC No. patients 7192 1595 844 46 15 13 No. polyps 4535 2513 1279 61 18 14 Prevalence -- 22.2% 11.7% 0.6% 0.2% 0.2% Proximal -- 19.1% 3.6% 0.9% 0% 0% Distal -- 12.

391 13 endoscopists, 184-1463 screening colonoscopies/endoscopist Hetzel J, et al., Am J Gastro; 2010; doi:10.1038/ajg/2010.

3 Detection of polyps All Adenoma HP SSA/P SSAD CRC No. patients No. polyps Prevalence % 11.7% 0.6% 0.2% 0.2% Proximal % 3.6% 0.9% 0% 0% Distal % 10.1% 0.1% 0.1% 0.1% Detection Variability % % % 0-0.5% 0-0.7% P value <0.001 < endoscopists, screening colonoscopies/endoscopist Hetzel J, et al., Am J Gastro; 2010; doi: /ajg/ > 1 adenoma Detection Variability Detection of polyps (2) 15 endoscopists, screening colonoscopies/endoscopist > 1 Proximal SSA 17-47% 1-18% Adenoma/Exam 0.22 ± ± 1.86 Proximal SSA/Exam 0.01 ± ± 0.68 Adenoma and proximal serrated polyp detection rates were strongly correlated, expressed as proportion of colonoscopies with at least 1 adenoma or proximal serrated polyp (Pearson correlation coefficient.86, P.0001) Proximal Serrated Polyp Detection Kahi, et al., Clin Gastroenterol Hepatol 2011; 9: Detection of high risk patients Identification of an individual with a hereditary CRC Syndrome (HCCS) is important Individuals are at increased risk of other cancers Allows management plan for risk reduction Helps patients understand their risk of cancer Allows coping with responses of knowing risk HCC risk extends to other family members 9 3

4 Hereditary colon cancer syndromes Rare < 10% of the new cases of colorectal cancer Diagnostic Clues: Early onset of colorectal neoplasia (< 50 years) Excessive number of polyps or multiple primary cancers Extracolonic benign or malignant tumors Multiple relatives, generations affected 10 Hereditary polyposis syndromes Autosomal Dominant Familial Adenomatous Polyposis (FAP) Attenuated FAP (afap) Peutz-Jeghers Syndrome (PJS) Juvenile Polyposis Syndrome (JPS) Cowden Syndrome - PTEN Hamartoma Tumor Syndrome Autosomal Recessive MYH associated Polyposis (MAP) 11 Autosomal dominant inheritance Parent with mutated gene Each child has a 50% chance of inheriting gene mutation; If the gene is inherited, disease is present 12 4

5 Autosomal recessive inheritance (MAP) Parent is carrier with MYH gene mutation Parent is carrier with MYH gene mutation Each child has a 25% chance of inheriting both MYH gene mutations (affected), a 50% chance of inheriting at least one MYH gene mutation, and a 25% chance of inheriting no MYH gene mutations 13 Hereditary polyposis syndromes Syndrome Polyp Type Gene Mutation FAP and attenuated FAP Adenomatous APC MYH Associated Polyposis Adenomatous MYH Peutz-Jeghers Syndrome Hamartomatous STK11 (aka LKB1) Juvenile Polyposis Syndrome Hamartomatous SMAD4 or BMPR1A Cowden Syndrome Hamartomatous PTEN 14 Adenomatous polyposis syndromes MAP FAP/AFAP The majority of genotyped adenomatous polyposis syndromes are caused by mutations in either APC or MYH genes 15 5

6 Human chromosomes MYH APC Adapted from US National Library of Medicine 16 Red flags for adenomatous polyposis syndromes Multiple lifetime colorectal adenomas Early onset colorectal cancer +/- multiple adenomas Possible extracolonic manifestations Duodenal, gastric, thyroid cancers Desmoid tumors, osteomas, soft tissue tumors, dental abnormalities, CHRPE 17 Various presentations of adenomatous polyposis syndromes One individual with multiple adenomas and no family history Two or more generations affected with CRC or adenomas Only siblings affected 18 6

Adenoma number in adenomatous polyposis syndromes MAP AFAP FAP 0 adenomas 100 adenomas 1000

Gastroenterology 2004;127:9-16 19 Familial adenomatous polyposis Autosomal dominant Affects

malignant extracolonic tumors 20 Genetics of FAP > 825 APC mutations identified 70% cases occur

7 Adenoma number in adenomatous polyposis syndromes MAP AFAP FAP 0 adenomas 100 adenomas 1000 adenomas Gastroenterology 2001;121:195-7 NEJM 2003;348: Gastroenterology 2004;127: Gastroenterology 2004;127: Familial adenomatous polyposis Autosomal dominant Affects 1:10,000 individuals Due to mutation in APC gene High risk of CRC Associated with benign and malignant extracolonic tumors 20 Genetics of FAP > 825 APC mutations identified 70% cases occur in individuals who inherited a mutation 30% cases arise de novo 1 1 Nieuwenhuis MH; Cr Rev Onc Hem 2007;61:

FAP: phenotypic variations Profuse or classic 100% risk of CRC APC mutation identified > 90% of cases Attenuated

syndrome Medulloblastoma, glioma 22 FAP phenotype is genotype dependant 1 1 Nieuwenhuis MH; Cr Rev Onc Hem

8 FAP: phenotypic variations Profuse or classic 100% risk of CRC APC mutation identified > 90% of cases Attenuated 60% risk of CRC APC mutation identified < 40% of cases Gardner s syndrome Extra-intestinal manifestations Turcot s syndrome Medulloblastoma, glioma 22 FAP phenotype is genotype dependant 1 1 Nieuwenhuis MH; Cr Rev Onc Hem 2007;61: FAP colon phenotype is genotype dependant Genotype Profuse Intermediate Attenuated Onset of Polyposis No. polyps Polyp location Lifetime CRC Risk Age at CRC 1 st -2 nd 1000s Diffuse 100% 39 yrs decade 2 nd -3 rd decade 4 th -5 th decade 100s- 1000s Diffuse % > 39 yrs < 100 Right 60% 56 yrs 1 Nieuwenhuis MH; Cr Rev Onc Hem 2007;61:

Extra-intestinal features of FAP Desmoid tumors (15%) Thyroid carcinoma (2-17%) Adrenal adenoma (7-13% ) Osteomas (50-90%) Supernumerary teeth (11-27%) CHRPE (70-80%) Soft tissue tumors (50%) Lipoma,

9 Extra-intestinal features of FAP Desmoid tumors (15%) Thyroid carcinoma (2-17%) Adrenal adenoma (7-13% ) Osteomas (50-90%) Supernumerary teeth (11-27%) CHRPE (70-80%) Soft tissue tumors (50%) Lipoma, fibroma, sebaceous cysts Hepatoblastoma (<2%) Vasen H; Gut 2008;57:704 Courtesy J. Church MD 25 Fundic gland polyposis Prevalence: 88% Gastric features of FAP LGD: 41%, HGD: 3%: Only in polyps > 10 mm Gastric adenomas Prevalence: 10% Usually antrum Gastric cancer: rare Arises from fundic gland polyposis CHRPE Bianchi L, Burke CA, et al., Clin Gastro Hep 2007;6: Duodenal features of FAP Duodenal adenomas: 100% Adenomatous papilla: >60% 1 89% if appearance abnormal 54% if appearance normal Periampullary/Duodenal cancer: 2-36% 2 When occurs, all die of malignant disease Cancer risk based upon stage of duodenal polyposis 1 Burke C, GIE 1999;49:358 2 Groves C, Gut 2002;50:

10 Staging of duodenal polyposis 1 point 2 points 3 points No. of polyps >20 Polyp size (mm) >10 Histology Tubular TVA Villous Dysplasia Mild Moderate Severe Stage I = 1-4 points, Stage II = 5-6 points, Stage III = 7-8 points, Stage IV = 9-12 points Spigelman AD., Lancet 1989;2: 783 Number = 3, Size = 1, Histology = 1, Dysplasia = 1 6 points: Stage = II 28 Duodenal cancer risk based upon stage of duodenal polyposis Stage Points Cancer Risk I 1-4 0% II % III % IV % Groves C, Gut 2002;50: UGI surveillance in adenomatous polyposis syndromes Stage Interval Method Intervention 0 5 yrs EGD/D I-II 3 yrs EGD/D III 1 yr EGD/D Celecoxib 400 BID/ 3 yrs CE Polyp eradication IV* 6 mo 3 yrs EGD/D CE Pancreas sparing duodenectomy Begin at age 20 D=duodenoscopy with bx of papilla; CE=capsule endoscopy * Preferred approach is preventive surgery Bianchi L, Burke CA, et al., Clin Gastro Hep 2007;6:

Prophylactic duodenal surgery pancreas sparing duodenectomy Mackey R, Burke C, et al.

adenomas and CRC Due to bi-allelic mutations in the MYH gene Y179C and G396D account for

akin to FAP 32 MYH associated polyposis N=107 APC negative patients with FAP Negative

(30-70) Polyp Count 100-1000 >1000 Family Hx CRC 72% 28% 100% 0% 100% 0% 31% 0% 50% 7.

11 Prophylactic duodenal surgery pancreas sparing duodenectomy Mackey R, Burke C, et al., J GI Surg 2005;9: MYH associated polyposis (MAP) Autosomal recessive syndrome of adenomas and CRC Due to bi-allelic mutations in the MYH gene Y179C and G396D account for >80% of mutations in Northern Europeans May have extracolonic benign and malignant tumors akin to FAP 32 MYH associated polyposis N=107 APC negative patients with FAP Negative (N=95) Single Mutation (N=4) Bi-allelic Mutation (N=8) Age 30 (7-72) 31 (30-54) 48 (30-70) Polyp Count >1000 Family Hx CRC 72% 28% 100% 0% 100% 0% 31% 0% 50% 7.5% of APC negative polyposis patients had bi-allelic MYH mutation Sieber O, et al., NEJM 2003;348:

12 MYH associated polyposis N=152 patients with lifetime adenomas Seen in genetics clinic for family or personal history of colorectal neoplasia Age at Presentation MYH negative N=140 Single Mutation N=6 Bi-allelic Mutation N=6 56 (18-77) 64 (25-72) 56 (45-59) Polyp Count 7 (3-100) 4 (3-12) 55 (18-100) Synchronous CRC 19 (14%) 2 (33%) 3 (50%) Family Hx CRC 66 (47%) 4 (67%) 5 (83%) 33% of individuals with > 15 adenomas had bi-allelic MYH mutations Sieber O, et al., NEJM 2003;348: CRC risk associated with MYH Population-based study of 9,268 CRC patients and 5,064 controls Tested for Y179C and G396D MUTYH mutations Genotype N/N No. Patients 9043 (97.7%) Genotype Relative Risk Age Yrs (SD) CRC Location Prox Distal (%) Family Hx CRC (%) Ref 59(8.5) Mut/N 198 (2%) 1.07 ( ) 59.6(8.4) Mut/Mut 27 (0.3%) ( ) 54(7.3)* 59* T Y179C/Y179C Y179C/G396D (6.0) (7.5) G396D/G396D (6.2) N= No mutation, * = p <0.01, T= trend Lubbe, S. J. et al., J Clin Oncol; 27: Penetrance of biallelic MUTYH mutation The estimated penetrances at age 50 and 60 were 19.5% and 43% respectively Biallelic mutations are highly penetrant and are incomplete at the age of 60 Lubbe, S. J. et al., J Clin Oncol; 27:

13 The odds ratio (OR) of colorectal cancer risk associated with monoallelic Y179C and G396D mutations No increased risk of colorectal cancer associated with monoallelic MYH mutations Lubbe, S. J. et al., J Clin Oncol; 27: Polyposis phenotype in MYH CRC Genotype No. Patients Synchronous Polyp Number 0 < 3 >3 N/N % 15% 6% Mut/N 91 75% 19% 7% Mut/Mut 14 29% 29% 42% Lubbe, S. J. et al., J Clin Oncol; 27: MAP phenotype Age of Diagnosis 45 yrs (24-72) Colon Phenotype Attenuated (80%) adenomas > age 25 > 100 adenomas > age 45 Polyp distribution Diffuse (50%), Proximal (40%) CRC Extracolonic tumors 50% at time of Diagnosis; Mean age of 48 yrs (29-72) Duodenal polyposis, thyroid cancer, gastric cancer, renal cell cancer N=392 Aretz S. Int J Ca 2006; 119:

14 Colorectal surveillance of adenomatous polyposis syndromes Procedure Age (yrs) Interval Classic FAP Sigmoidoscopy* yrs afap/myh Colonoscopy yrs Post operative Sigmoidoscopy Ileoscopy 1 yr 5 yrs *Annual colonoscopy Surgery consultation once adenomas detected 40 Adenomatous polyposis syndromes surgical guidelines Severe polyposis Total Colectomy and ileorectal anastomosis Proctocolectomy and IPAA (if rectal burden high, > 20 polyps) Oligopolyposis (< 100 polyps) Colectomy may be necessary depending on polyp burden 41 Chemoprevention of FAP Colorectal polyposis Sulindac mg BID- 50% reduction Celecoxib 400 mg BID- 28% reduction 1 FDA approved in adults as an adjunct to endoscopy Duodenal polyposis Celecoxib 400 mg BID 1,2 Significant improvement in polyp burden (blinded video assessment score) 1 Steinbach G, NEJM 2000;342:1947, 42 14

15 Pediatric chemoprevention in FAP N=18 children, yrs, 3 month study Number of Polyps % + 70% - 44% -44% Pre Post Pre Post Pre Post Pre Post Placebo 4 mg/kg 8 mg/kg 16 mg/kg Lynch P, et al., Am J Gastro 2010;105: Genetic testing in adenomatous polyposis syndromes 10 cumulative adenomas CRC <60 yo Desmoids Relatives of known APC or MYH mutations carriers 44 Genetic testing for adenomatous polyposis syndromes (2) Up to 34% of APC negative FAP patients have biallelic MYH mutations APC and MYH testing should be performed concurrently 45 15

Results of APC genetic testing Patient with >100 adenomas Sequencing - <90% Deletion/duplication - 8-10% Patients with <100

Non-Caucasian patients MYH sequencing 47 Peutz-Jeghers syndrome (PJS) Autosomal dominant 1 in 120,000 births 50% cases are

16 Results of APC genetic testing Patient with >100 adenomas Sequencing - <90% Deletion/duplication % Patients with <100 adenomas Mutation detection <30% 46 MYH genetic testing Caucasian patients MYH mutation panel sequencing Y179C and G396D Non-Caucasian patients MYH sequencing 47 Peutz-Jeghers syndrome (PJS) Autosomal dominant 1 in 120,000 births 50% cases are inherited 50% of cases are de novo mutations Due to mutation in STK11 gene Genetic testing positive in 90% of PJS patients 48 16

17 Hallmarks of PJS Diffuse hamartomatous polyps 50% risk of SBO by age 20 Muco-cutaneous pigmentation Perioral region, digits, genital area 49 Diagnostic criteria for PJS > 3 hamartomatous polyps in GI tract or > 1 GI hamartoma and pigmentation or > 1 GI hamartoma and family history of PJS or Family history of PJS and typical pigmentation World Health Organization Classification of Tumours, Peutz-Jeghers Syndrome Diagnostic Criteria 50 Frequency of polyps in PJS % Small intestine Colon Stomach Rectum Giardiello, Gastroenterology 2000;119:

18 Cancer risk in PJS 90% lifetime risk 50% by age 50 Intestinal and extra-intestinal Unusual Gonadal Neoplasms Adenoma malignum of the cervix, ovarian sex cord tumors with annular tubules (SCTAT), or large cell calcifying Sertoli cell testicular tumors 52 Risk of non-gi cancer in PJS % Breast Ovary Lung Cervix Uterus Testis Giardiello, Gastroenterology 2000;119: Risk of GI cancer in PJS % % by age of 65 Colon Pancreas Stomach Small Esophagus Intestine Giardiello, Gastroenterology 2000;119:

Endoscopic evaluation in PJS Indications Surveillance in asymptomatic PJS patients Symptomatic PJS patients or evaluation of laboratory or radiographic abnormalities At risk first degree relatives

19 Endoscopic evaluation in PJS Indications Surveillance in asymptomatic PJS patients Symptomatic PJS patients or evaluation of laboratory or radiographic abnormalities At risk first degree relatives who meet phenotypic criteria when family mutation not identified To establish phenotype in at risk first degree relatives when genetic testing not performed in affected family member 55 Endoscopic surveillance of PJS Recommendations EGD and capsule endoscopy every other year starting at age 10 or sooner if symptoms are present Enteroscopy to clear small intestine of all polyps > 1 cm in size to minimize SBO Colonoscopy every 2-3 years from the age of 25 Parsi M, Burke CA. GI Clinics NA 2004;14: , Dunlop MG. Gut 2002;51:21-7; Giardiello, Clin Gastro Hep 2006;4: Indication for genetic testing in PJS Individuals who meet diagnostic criteria of PJS Characteristic mucocutaneous pigmentation Family history of Peutz-Jeghers syndrome Relative of a known STK11 mutation carrier 57 19

Genetic test results in PJS Sequencing - 30-69% Deletion/duplication - 30% 58 Juvenile polyposis syndrome (JPS) Autosomal dominant 1 in 120,000 births < 50% of

cancer 59 Genetics of JPS Mutations found in 60% of individuals 35% SMAD4 and 25% BMPR1A Important SMAD4 genotype-phenotype correlations Massive gastric

20 Genetic test results in PJS Sequencing % Deletion/duplication - 30% 58 Juvenile polyposis syndrome (JPS) Autosomal dominant 1 in 120,000 births < 50% of individuals have a family history Due to mutations in SMAD4 or BMPR1A Hallmarks of disease Colonic and gastric polyps >>>> proximal SB Increased risk of GI cancer 59 Genetics of JPS Mutations found in 60% of individuals 35% SMAD4 and 25% BMPR1A Important SMAD4 genotype-phenotype correlations Massive gastric polyposis Hereditary hemorrhagic telangiectasia Reported in up to 23% (Aretz S. J Med Gen 2007;44:702) Warrants screening for visceral AVMS Cerebral, pulmonary, mucosal 60 20

Cancer risk in JPS Lifetime risk of gastrointestinal cancer: 55% Hamartoma-adenoma-carcinoma Colorectal

14-21% 61 Clinical features JPS Bleeding: Iron deficiency anemia Overt/occult GI bleeding Epistaxis

polyposis symptom onset: in first or second decade, mean 18.

21 Cancer risk in JPS Lifetime risk of gastrointestinal cancer: 55% Hamartoma-adenoma-carcinoma Colorectal cancer 20% by age 35 68% by age 60 Upper gastrointestinal cancers Gastric: 25% Small bowel carcinoma: 14-21% 61 Clinical features JPS Bleeding: Iron deficiency anemia Overt/occult GI bleeding Epistaxis Diarrhea Gastric outlet obstruction or protein losing gastropathy AVMs and vascular ectasias Colonic polyposis symptom onset: in first or second decade, mean 18.5 years (9 mos - 67 yrs) 62 Diagnostic criteria of JPS > 5 juvenile polyps of the colon or Juvenile polyps throughout GI tract or > 1 juvenile polyp with family history of JPS 63 21

22 GI screening in JPS Age to begin Frequency Colonoscopy Teens Q 1-2 EGD 25 yrs Q1-2 CE 25 yrs Q 3-5 Sooner if symptoms are present Burke, CA, Juvenile Polyposis. Cancer of the Colon, Rectum and Anus. 2005: Management of JPS Gastrectomy for protein losing gastropathy, bleeding or advanced gastric neoplasia Total colectomy and IRA for management of difficult to endoscopically control or advanced d colorectal l or gastric polyp burden Screening for HHT in SMAD4 carriers Aretz S, J Med Gen 2007;44:702 Gallione CJ, Lancet. 2004; 363: Indication for genetic testing in JPS Individuals meeting JPS diagnostic criteria Family history of juvenile polyposis syndrome Relative of a known SMAD4 or BMPR1A mutation carrier 66 22

Genetic test results in JPS SMAD4 and BMPR1A Sequencing - 40% Deletion/duplication - 14% 67 Cowden s syndrome Courtesy Brandie Leach, CGC 68 Cowden s syndrome (2) Autosomal dominant 1 in 200,000

23 Genetic test results in JPS SMAD4 and BMPR1A Sequencing - 40% Deletion/duplication - 14% 67 Cowden s syndrome Courtesy Brandie Leach, CGC 68 Cowden s syndrome (2) Autosomal dominant 1 in 200,000 individuals Due to mutation in PTEN Detected in > 90% of individuals Hallmarks of disease Skin findings, macrocephaly Hamartomatous polyps Lipomas, inflammatory, juvenile, ganglioneuromas, adenomas 69 23

24 Clinical manifestations of CS Zbuk K, Eng C, Nature Clin Prac GH Diagnostic criteria for CS Major Criteria Pathognomonic Minor Criteria (>1 incl. Criteria (1) (> 3 minor) macrocephaly) Cerebellar tumors Breast CA Other thyroid lesions Facial trichilemmomas Non Medullary Thyroid Ca MR (IQ <76) Acral Keratosis Macrocephaly GI hamartomas Papillomatous papules Endometrial Ca Lipoma, Fibroma Fibrocystic Breast Dz Uterine Fibroids FHx with some criteria counts GU abnormalities or tumors esp renal cell Ca NCCN Practice Guidelines in Oncology v GI polyps in CS 127 PTEN mutation carriers, mean age 34.6 yrs 64/69 (93%) had GI polyps 24/64 both UGI and LGI polyps 2/64 only UGI polyps 38/64 only LGI polyps 13% had CRC; all < 50 years of age Colon polyps: hamartomas, hyperplastic, ganglioneuromas, adenomas, inflammatory Heald B, et al., Gastro 2010: 139(6):

Frequency of CS features Heald B, et al.

features of CS An increased risk of early onset CRC has been shown in PTEN positive patients -

other at risk organs in this population 74 Summary Sporadic CRC is a heterogeneous disease Novel

detection of precursor lesions and improve the mortality benefit of colonoscopy Hereditary colon

25 Frequency of CS features Heald B, et al., Gastro 2010: 139(6): Management of CS Gastrointestinal polyps are one of the leading features of CS An increased risk of early onset CRC has been shown in PTEN positive patients - SIR 224 Consideration should be given to high risk CRC screening in addition to surveillance of other at risk organs in this population 74 Summary Sporadic CRC is a heterogeneous disease Novel molecular and genetic pathways Adenomatous and serrated precursors Develop methods to improve our detection of precursor lesions and improve the mortality benefit of colonoscopy Hereditary colon cancer syndromes are rare but their relative contribution to the CRC burden is high when not identified Patient with HCCS warrant specialized management 75 25

26 76 26

Pathology reports, related operative reports and consult letters must be provided with a request for assessment.

Pathology reports, related operative reports and consult letters must be provided with a request for assessment. Page 1 of 6 Polyposis Syndromes Inherited risk for colorectal cancer is associated with a number of polyposis syndromes (genes), some of which are well-defined and others are less common. Identification