colorectal cancer and hereditary colon cancer syndromes carol … · • understand the diagnostic...

Colorectal Cancer and Hereditary Colon Cancer Syndromes

Carol A. Burke, M.D.

1The screen versions of these slides have full details of copyright and acknowledgements

Carol A. Burke, M.D., FACG, FACP


1

Sanford R. Weiss MD Center for Hereditary Colorectal Neoplasia

Digestive Disease Institute

Cleveland Clinic, Cleveland, Ohio

Objectives

• Review the molecular and genetic basis of sporadic colorectal cancer (CRC)

• Identify the precursor lesions of CRC

2

• Understand the diagnostic features of the hereditary colorectal cancer syndromes

• Development management strategies for your patients with the hereditary cancer syndromes

Colorectal cancer precursors

3

70% Adenomatous Lesions

Chromosomal Instability (CIN) Microsatellite Stable (MSS)

30%Serrated LesionBRAF mutation

CpG Island Methylation (CIMP) Microsatellite Instability (MSI) or MSS




Classification of colorectal polypsAdenomatous Lesions Serrated Lesions

• Tubular

• Tubulovillous

• Villous

• Hyperplastic Polyp– Microvesicular (MVHP)

– Goblet Cell (GCHP)

– Mucin Poor (MPHP)

4

• Sessile Serrated Adenoma/Polyp (SSP/A)– With cytological dysplasia

– Without cytologic dysplasia

• Traditional Serrated Adenoma (TSA)– With conventional dysplasia

– Without conventiona ldysplasia

WHO 2010

Proposed serrated pathway of MSI-H CRC

BRAF mutation+/- methylation

? Additional methylation

Generally slowly progressive or random

5Snover, DC, Human Pathology 2010; accepted 16 June 2010

BRAF mutation+ methylation

Methylation of hMLH1

Usually rapidly progressive

Mutation or methylation of other genes

• 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

Prevention of CRC: recognition of high risk precursor lesions

6

• 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




Detection of polyps

All Adenoma HP SSA/P SSAD CRCNo. 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%

7

Proximal -- 19.1% 3.6% 0.9% 0% 0%

Distal -- 12.1% 10.1% 0.1% 0.1% 0.1%

DetectionVariability

13.5-36.4%

7.7-31.0%

0.0-1.1%

0-0.5% 0-0.7%

P value <0.001 <0.001 0.020 0.823 0.391

• 13 endoscopists, 184-1463 screening colonoscopies/endoscopist

Hetzel J, et al., Am J Gastro; 2010; doi:10.1038/ajg/2010.315

Detection of polyps (2)

> 1 adenoma

> 1 Proximal SSA

Adenoma/ExamProximal

SSA/ExamDetection Variability

17-47% 1-18% 0.22 ± 0.56 –1.20 ± 1.86

0.01 ± 0.11 –0.26 ± 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)

• 15 endoscopists, 56-3189 screening colonoscopies/endoscopist

Proximal Serrated Polyp Detection

8Kahi, et al., Clin Gastroenterol Hepatol 2011; 9:42-46

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

All t l f i k d ti

9

– 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




Hereditary colon cancer syndromes

• Rare

– < 10% of the new cases of colorectal cancer

• Diagnostic Clues:

10

– Early onset of colorectal neoplasia (< 50 years)

– Excessive number of polyps or multiple primary cancers

– Extracolonic benign or malignant tumors

– Multiple relatives, generations affected

Hereditary polyposis syndromes

Autosomal Dominant Autosomal Recessive

• Familial Adenomatous Polyposis (FAP)

Attenuated FAP (aFAP)

• MYH associated Polyposis (MAP)

11

– Attenuated FAP (aFAP)

• Peutz-Jeghers Syndrome (PJS)

• Juvenile Polyposis Syndrome (JPS)

• Cowden Syndrome - PTEN Hamartoma Tumor Syndrome

Parent with mutated gene

Autosomal dominant inheritance

12

Each child has a 50% chance of inheriting gene mutation;If the gene is inherited, disease is present




Parent is carrier with MYH gene mutation

Parent is carrier with MYH gene mutation

Autosomal recessive inheritance (MAP)

13

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

Hereditary polyposis syndromes

Syndrome Polyp Type Gene MutationFAP and attenuated FAP Adenomatous APC

MYH Associated Polyposis Adenomatous MYH

14

Peutz-Jeghers Syndrome Hamartomatous STK11 (aka LKB1)

Juvenile Polyposis Syndrome Hamartomatous SMAD4 or BMPR1A

Cowden Syndrome Hamartomatous PTEN

Adenomatous polyposis syndromes

15

MAP FAP/AFAP

The majority of genotypedadenomatous polyposissyndromes are caused by mutations in either APCor MYH genes




Human chromosomes

APC

MYH

16Adapted fromUS National Library of Medicine

“Red flags” for adenomatous polyposis syndromes

• Multiple lifetime colorectal adenomas

• Early onset colorectal cancer +/- multiple adenomas

17

• Possible extracolonic manifestations

– Duodenal, gastric, thyroid cancers

– Desmoid tumors, osteomas, soft tissue tumors, dental abnormalities, CHRPE

Various presentations of adenomatous polyposis syndromes

• One individual with multiple adenomas and no family history

ff C C

18

• Two or more generations affected with CRC or adenomas

• Only siblings affected




FAPAFAP

MAP

Adenoma number in adenomatous polyposis syndromes

19

0 adenomas 100 adenomas 1000 adenomas

FAPAFAP

Gastroenterology 2001;121:195-7NEJM 2003;348:791-99Gastroenterology 2004;127:444-51Gastroenterology 2004;127:9-16

Familial adenomatous polyposis

• Autosomal dominant

• Affects 1:10,000 individuals

• Due to mutation in APC gene

20

• Due to mutation in APC gene

• High risk of CRC

• Associated with benign and malignant extracolonic tumors

Genetics of FAP• > 825 APC mutations identified

• 70% cases occur in individuals who inherited a mutation

• 30% cases arise de novo

1

211Nieuwenhuis MH; Cr Rev Onc Hem 2007;61:153




FAP: phenotypic variations

• Profuse or classic

– 100% risk of CRC

– APC mutation identified > 90% of cases

• Attenuated

22

– 60% risk of CRC

– APC mutation identified < 40% of cases

• “Gardner’s syndrome”

– Extra-intestinal manifestations

• “Turcot’s syndrome”

– Medulloblastoma, glioma

FAP phenotype is genotype dependant1


FAP colon phenotype is genotype dependant

Genotype Onset of Polyposis

No. polyps

Polyp location

Lifetime CRC Risk

Age at CRC

Profuse 1st-2nd1000s Diffuse 100% 39 yrs

24

Profuse decade 1000s Diffuse 100% 39 yrs

Intermediate 2nd-3rd

decade100s-1000s Diffuse 60-100% > 39 yrs

Attenuated 4th-5th

decade < 100 Right 60% 56 yrs





Extra-intestinal features of FAP

• Desmoid tumors (15%)

• Thyroid carcinoma (2-17%)

• Adrenal adenoma (7-13% )

• Osteomas (50-90%)

Courtesy J. Church MD

25

• Supernumerary teeth (11-27%)

• CHRPE (70-80%)

• Soft tissue tumors (50%)– Lipoma, fibroma,

sebaceous cysts

• Hepatoblastoma (<2%)

Vasen H; Gut 2008;57:704

Gastric features of FAP• Fundic gland polyposis

– Prevalence: 88%LGD: 41%, HGD: 3%: Only in polyps > 10 mm

• Gastric adenomas– Prevalence: 10%

Usually antrum

26

– Usually antrum

• Gastric cancer: rare– Arises from fundic gland polyposis

CHRPE

Bianchi L, Burke CA, et al., Clin Gastro Hep 2007;6:180

Duodenal features of FAP

• Duodenal adenomas: 100%

• Adenomatous papilla: >60%1

– 89% if appearance abnormal

27

– 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

2Groves C, Gut 2002;50:6361Burke C, GIE 1999;49:358




Staging of duodenal polyposis

1 point 2 points 3 points

No. of polyps 1-4 5-20 >20

Polyp size (mm) 1-4 5-10 >10

Histology Tubular TVA Villous

Dysplasia Mild Moderate Severe

28

Dysplasia Mild Moderate Severe

Spigelman AD., Lancet 1989;2: 783

Stage I = 1-4 points, Stage II = 5-6 points, Stage III = 7-8 points, Stage IV = 9-12 points

Number = 3, Size = 1, Histology = 1, Dysplasia = 16 points: Stage = II

Duodenal cancer risk based upon stage of duodenal polyposis

Stage Points Cancer Risk

I 1 4 0%

29

I 1-4 0%

II 5-6 2.3%

III 7-8 2.4%

IV 9-12 36%

Groves C, Gut 2002;50:636

UGI surveillance in adenomatous polyposis syndromes

Stage Interval Method Intervention

0 5 yrs EGD/D

I-II 3 yrs EGD/D

1 EGD/D C l ib 400 BID/

30

III1 yr3 yrs

EGD/DCE

Celecoxib 400 BID/Polyp eradication

IV*6 mo3 yrs

EGD/DCE

Pancreas sparing duodenectomy

Bianchi L, Burke CA, et al., Clin Gastro Hep 2007;6:180

Begin at age 20D=duodenoscopy with bx of papilla; CE=capsule endoscopy* Preferred approach is preventive surgery




Prophylactic duodenal surgery pancreas sparing duodenectomy

31Mackey R, Burke C, et al., J GI Surg 2005;9:1088

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 i N th E

32

in Northern Europeans

• May have extracolonic benign and malignant tumors akin to FAP

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)

33Sieber O, et al., NEJM 2003;348:791

g ( ) ( ) ( )

Polyp Count100-1000>1000

72%28%

100%0%

100%0%

Family Hx CRC

31% 0% 50%

7.5% of APC negative polyposis patients had bi-allelic MYH mutation




MYH associated polyposis• N=152 patients with 3-100 lifetime adenomas

• Seen in genetics clinic for family or personal history of colorectal neoplasia

MYH negativeN=140

Single MutationN=6

Bi-allelic MutationN=6

34Sieber O, et al., NEJM 2003;348:791

Age at Presentation

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

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 No. Patients

GenotypeRelative Risk

AgeYrs (SD)

CRC Location Prox Distal (%)

Family Hx CRC

(%)

N/N 9043 (97.7%)

Ref 59(8.5) 29 71 15

35

Mut/N 198 (2%) 1.07 (0.87-1.31) 59.6(8.4) 36 64 20

Mut/Mut 27 (0.3%) 28.28 (17.6-44.06) 54(7.3)* 59* 41 26T

Y179C/Y179C 4 49.5(6.0) 75 25 25

Y179C/G396D13 52.5(7.5) 77 23 23

G396D/G396D 10 57.9(6.2) 30 70 30

Lubbe, S. J. et al., J Clin Oncol; 27:3975-3980 2009N= No mutation, * = p <0.01, T= trend

Penetrance of biallelic MUTYH mutation

• The estimated penetrances at age 50 and 60 were 19.5% and 43% respectively

• Biallelic mutations are highly penetrant

36Lubbe, S. J. et al., J Clin Oncol; 27:3975-3980 2009

and are incomplete at the age of 60




The odds ratio (OR)of colorectal cancer risk associated

with monoallelic Y179C and G396D mutations

No increased risk of colorectal cancer associated

37Lubbe, S. J. et al., J Clin Oncol; 27:3975-3980 2009

with monoallelic MYH mutations

Polyposis phenotype in MYH CRC

GenotypeNo.

PatientsSynchronous Polyp Number

0 < 3 >3

38

N/N 2640 79% 15% 6%

Mut/N 91 75% 19% 7%

Mut/Mut 14 29% 29% 42%

Lubbe, S. J. et al., J Clin Oncol; 27:3975-3980 2009

MAP phenotype

Age of Diagnosis 45 yrs (24-72)

Colon PhenotypeAttenuated (80%)10-100 adenomas > age 25> 100 adenomas > age 45

39

Polyp distribution Diffuse (50%), Proximal (40%)

CRC50% at time of Diagnosis; Mean age of 48 yrs (29-72)

Extracolonic tumors Duodenal polyposis, thyroid cancer, gastric cancer, renal cell cancer

Aretz S. Int J Ca 2006; 119:807N=392




Colorectal surveillance of adenomatous polyposis syndromes

Procedure Age (yrs) Interval

Classic FAP Sigmoidoscopy* 10-12 1-2 yrs

aFAP/MYH Colonoscopy§ 18-20 1-2 yrs

40

Post operative Sigmoidoscopy Ileoscopy

1 yr

5 yrs

*Annual colonoscopy§ Surgery consultation once adenomas detected

Adenomatous polyposis syndromes surgical guidelines

• Severe polyposis

– Total Colectomy and ileorectal anastomosis

Proctocolectomy and IPAA (if rectal burden high

41

– Proctocolectomy and IPAA (if rectal burden high, > 20 polyps)

• Oligopolyposis (< 100 polyps)

– Colectomy may be necessary depending on polyp burden

Chemoprevention of FAP

• Colorectal polyposis

– Sulindac 150-200 mg BID- 50% reduction

– Celecoxib 400 mg BID- 28% reduction1

FDA approved in adults as an adjunct to endoscopy

42

FDA approved in adults as an adjunct to endoscopy

• Duodenal polyposis

– Celecoxib 400 mg BID1,2

– Significant improvement in polyp burden (blinded video assessment score)

1 Steinbach G, NEJM 2000;342:1947,




N=18 children, 10-14 yrs, 3 month study

Pediatric chemoprevention in FAPPo

lyps 80

100

120 + 39% + 70% - 44% -44%

43Lynch P, et al., Am J Gastro 2010;105: 1437-43

Num

ber o

f P

--

- - --

--

Pre Post Pre Post Pre Post Pre PostPlacebo 4 mg/kg 8 mg/kg 16 mg/kg

020

4060

Genetic testing in adenomatous polyposis syndromes

• ≥10 cumulative adenomas

• CRC <60 yo

D id

44

• Desmoids

• Relatives of known APC or MYH mutations carriers

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

APC and MYH testing should be performed concurrently




Results of APC genetic testing

• Patient with >100 adenomas

– Sequencing - <90%

– Deletion/duplication - 8-10%

46

• Patients with <100 adenomas

– Mutation detection <30%

MYH genetic testing

• Caucasian patients

– MYH mutation panel sequencing

Y179C and G396D

47

• Non-Caucasian patients

– MYH sequencing


– 1 in 120,000 births

– 50% cases are inherited

– 50% of cases are de novo mutations

• Due to mutation in STK11 gene

Peutz-Jeghers syndrome (PJS)

48

• Due to mutation in STK11 gene

– Genetic testing positive in 90% of PJS patients




• Diffuse hamartomatous polyps

– 50% risk of SBO by age 20

• Muco-cutaneous pigmentation

Hallmarks of PJS

49

– Perioral region, digits, genital area

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

50

• > 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

Frequency of polyps in PJS

50

60

70

80

51

%

Giardiello, Gastroenterology 2000;119:1447

0

10

20

30

40

Small intestine Colon Stomach Rectum




• 90% lifetime risk

– 50% by age 50

• Intestinal and extra-intestinal

Cancer risk in PJS

52

• Unusual Gonadal Neoplasms

– Adenoma malignum of the cervix, ovarian sex cord tumors with annular tubules (SCTAT), or large cell calcifying Sertoli cell testicular tumors

Risk of non-GI cancer in PJS

40

50

60

53

%

0

10

20

30

Breast Ovary Lung Cervix Uterus Testis


25303540

Risk of GI cancer in PJS

%

93% by age of 65

54

05

101520

Colon Pancreas Stomach SmallIntestine

Esophagus

%





Endoscopic evaluation in PJS

• Indications

– Surveillance in asymptomatic PJS patients

– Symptomatic PJS patients or evaluation of laboratory or radiographic abnormalities

55

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

Endoscopic surveillance of PJS

• Recommendations

56

– 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;14:159-167, Dunlop MG. Gut 2002;51:21-7; Giardiello, Clin Gastro Hep 2006;4:408-15

Indication for genetic testing in PJS

• Individuals who meet diagnostic criteria of PJS

• Characteristic mucocutaneous pigmentation

• Family history of Peutz-Jeghers syndrome

57

y y g y

• Relative of a known STK11 mutation carrier




Genetic test results in PJS

• Sequencing - 30-69%

• Deletion/duplication - 30%

58

• 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

Juvenile polyposis syndrome (JPS)

59

• Increased risk of GI cancer

Genetics of JPS

• Mutations found in 60% of individuals

– 35% SMAD4 and 25% BMPR1A

• Important SMAD4 genotype-phenotype correlations

– Massive gastric polyposis

60

– Hereditary hemorrhagic telangiectasia

Reported in up to 23% (Aretz S. J Med Gen 2007;44:702)

Warrants screening for visceral AVMS√ Cerebral, pulmonary, mucosal




Cancer risk in JPS

• Lifetime risk of gastrointestinal cancer: 55%

– Hamartoma-adenoma-carcinoma

• Colorectal cancer

– 20% by age 35

61

20% by age 35

– 68% by age 60

• Upper gastrointestinal cancers

– Gastric: 25%

– Small bowel carcinoma: 14-21%

Clinical features JPS

• Bleeding:

– Iron deficiency anemia

– Overt/occult GI bleeding

– Epistaxis

• Diarrhea

62

• 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)

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




GI screening in JPS

Age to begin Frequency

Colonoscopy Teens Q 1-2

EGD 25 yrs Q 1-2

64Burke, CA, Juvenile Polyposis. Cancer of the Colon, Rectum and Anus. 2005:631-636

EGD 25 yrs Q 1 2

CE 25 yrs Q 3-5

Sooner if symptoms are present

Management of JPS

• Gastrectomy for protein losing gastropathy, bleeding or advanced gastric neoplasia

• Total colectomy and IRA for management of difficult t d i ll t l d d l t l

65

to endoscopically control or advanced colorectal or gastric polyp burden

• Screening for HHT in SMAD4 carriers– Aretz S, J Med Gen 2007;44:702

– Gallione CJ, Lancet. 2004; 363: 852-9

Indication for genetic testing in JPS

• Individuals meeting JPS diagnostic criteria

• Family history of juvenile polyposis syndrome

66

• Relative of a known SMAD4 or BMPR1A mutation carrier




Genetic test results in JPS

• SMAD4 and BMPR1A

– Sequencing - 40%

– Deletion/duplication - 14%

67

Deletion/duplication 14%

Cowden’s syndrome

68Courtesy Brandie Leach, CGC

Cowden’s syndrome (2)


– 1 in 200,000 individuals

• Due to mutation in PTEN

– Detected in > 90% of individuals

69

– Detected in > 90% of individuals

• Hallmarks of disease

– Skin findings, macrocephaly

– Hamartomatous polyps

Lipomas, inflammatory, juvenile, ganglioneuromas, adenomas




Clinical manifestations of CS

70Zbuk K, Eng C, Nature Clin Prac GH 2007

Diagnostic criteria for CS

Pathognomonic Criteria (1)

Major Criteria

(>1 incl. macrocephaly)

Minor Criteria

(> 3 minor)

Cerebellar tumors Breast CA Other thyroid lesions

Facial trichilemmomasNon Medullary Thyroid

CaMR (IQ <76)

71

Acral Keratosis Macrocephaly GI hamartomas

Papillomatous papules Endometrial Ca Lipoma, Fibroma

Fibrocystic Breast Dz

Uterine Fibroids

GU abnormalities or tumors esp renal cell Ca

FHx with some criteria counts NCCN Practice Guidelines in Oncology v1.2008

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

72

– 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):1927-33




Frequency of CS features

73Heald B, et al., Gastro 2010: 139(6):1927-33

Management of CS

• Gastrointestinal polyps are one of the leading features of CS

• An increased risk of early onset CRC has been shown

74

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

Summary

• Sporadic CRC is a heterogeneous disease

– Novel molecular and genetic pathways

Adenomatous and serrated precursors

• Develop methods to improve our detection of precursor l i d i th t lit b fit f l

75

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




76

colorectal cancer and hereditary colon cancer syndromes carol … · • understand the diagnostic...

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