Consultas de Alto Riesgo de Cáncer Colorrectal
Dr. Antoni CastellsHospital Clínic, Barcelona
69%
2%27%
1%1%
Riesgo medio(esporádico)
Poliposis adenomatosafamiliar
CCHNP
Enfermedad inflamatoriaintestinal
CCR familiar
Epidemiología del cáncer colorrectal
Grupo de Oncología Digestiva-AEG. Eur J Gastroent Hepatol 2004
Factores de riesgo personal
y/o familiar
No
Edad
< 50 años 50 años
AbstenciónCribado
Si
Factor de riesgo personal
Adenoma Enfermedad inflamatoria
intestinal
Vigilancia Vigilancia
Factor de riesgo familiar
PAF CCHNP CCRfamiliar
Cribado
Cribado
Cribado
Clasificación del riesgo de CCR
Atención a la población de alto riesgo
• Diversas neoplasias• Centralizado• Pacientes referidos• Hereditario
• No integración del tratamiento y seguimiento
Modelo tradicional• Cáncer colorrectal• Descentralizado (red)• Enfoque poblacional• Hereditario y familiar, y
premaligno (adenoma)• Integración del tratamiento
y seguimiento
CAR-CCR
Familial adenomatous polyposis (FAP)
• Autosomal dominant disorder• One in 15,000 live births• More than 100 polyps• Diffuse distribution• Onset: 15-20 year-old• Extracolonic manifestations: upper
GI adenomas, congenital hypertrophy of the retinal pigment epithelium, osteomas, and dental anomalies (Gardner syndrome), brain tumor (Turcot syndrome)
• Overall CRC risk ~100% by age 40-50• APC gene mutations (truncanting)
Germline APC gene testing
2934_2935delAA (frameshift at codon 978, termination at codon 983)
• Autosomal dominant disorder• Early onset CRC: <45 years of age• Location in proximal colon• Histology: undifferenciated, signet-ring cell type• Multiple CRC (synchronous, metachronous)• Multiple neoplasms (endometrial, gastric, small
bowel, renal, ovarian, and skin)• Life-time risk of developing CRC: 60-80%• Benefit from periodic colonoscopy examination
(every 1-2 years)
Lynch syndrome – Hereditary non-polyposis colorectal cancer (HNPCC)
DNA mismatch repair (MMR) system
MSH6MSH2
MSH6
MSH2
MSH6
MSH2MLH1 PMS2
Lynch syndrome: pathogenesis
Normalmucosa
Carcinoma
MSH2, MLH1, MSH6, PMS2(germline mutation)
TGF--RII, BAX, IGFIIR
Microsatellite instability
Second hitLoss of protein
expression
N
T
N
T
• 3 relatives with CRC*: one relative should be first-degree relative of the other two, and
• 2 successive generations should be affected, and• 1 tumor should be diagnosed before age 50
• Familial adenomatous polyposis should be excluded
• Tumors should be verified by histopathologicalexamination
Vasen et al. Dis Colon Rectum 1991
Amsterdam criteria
*Vasen et al. Gastroenterology 1999
*Amsterdam II: CRC and/or HNPCC-related neoplasia (endometrial, small bowel, ureter or renal pelvis)
Lynch syndrome identification: limitations
DNA MMRdeficiency
60%
0%20%40%60%80%
100%
Fulfillment ofAmsterdam criteria
Lindor et al. JAMA 2005Llor et al. Clin Cancer Res 2005
Fulfillment of Amsterdam criteria
70%
0%20%40%60%80%
100%
Presence of MMRmutation
Aaltonen et al. N Engl J Med 1998
1. CRC diagnosed <50 yrs.
2. Synchronous CRC, metachronous CRC, or other HNPCC-related cancer (CRC, endometrial, ovarian, gastric, pancreas, biliary tract, small bowel, ureter or renal pelvis, brain), regardless of age.
3. CRC with presence of tumor infiltrating lymphocytes, Crohn’s-like lymphocytic reaction, mucinous/signet-ring differentiation, or medullary growth pattern, diagnosed <60 yrs.
4. One or more first-degree relatives with an HNPCC-related tumor diagnosed <50 yrs.
5. Two or more first- or second-degree relatives with HNPCC-related tumors, regardless of age.
Umar et al. J Natl Cancer Inst 2004
Identification of individuals who should be tested for MSI analysis:
Revised Bethesda guidelines
Performance of selective vs. universal molecular screening
*p<0.001 (McNemar test)
*
Piñol et al. JAMA 2005
*
0% 20% 40% 60% 80% 100%
Overall accuracy
NPV
PPV
Specificity
Sensitivity
Universal (IHC) Rev. Beth. + IHC Rev. Beth. + MSIRevised BethedaMSI Revised BethesdaIHC Universal (IHC)
Jerusalem recommendations1. All patients diagnosed with colorectal cancer before
the age of 70 years should be submitted to MMR testing
2. MMR testing can be done by immunostaining and/or MSI analysis
3. Colorectal cancers exhibiting loss of MLH1 expression should evaluated by means of BRAF (V600E) or MLH1 promoter methylation analysesbefore undergoing germline MLH1 gene testing
Shike y Boland. Gastroenterology 2010
University of Helsinki (n=1,042)
EPICOLON(n=1,222)
C-CFR(n=9,371)
The Ohio State University(n=1,516)
13,151 unrelated CRC probands
10,206 informative, unrelated CRC probands
MMR deficiency(n=1,386)
Mutation (n=289)
No mutation (n=779)
Mutation (n=12)
No mutation (n=1,383)
Lynch(n=312)
No Lynch(n=9,576)
2,945 excludeda
MMR proficiency(n=8,633)
No mutation (n=176)
Mutation (n=11)
Tumor MMR testing (n=10,019
Direct germline MMR gene analysis (n=187)
No germline MMR gene analysis
(n=318)
Germline MMR gene analysis
(n=1,068)
Germline MMR gene analysis
(n=1,395)
No germline MMR gene analysis
(n=7,238)
Moreira et al. JAMA 2012
Diagnostic yield of strategies for Lynch syndrome identification
1,96% 1,90%2,12%
2,23%
0,0%
0,5%
1,0%
1,5%
2,0%
2,5%
Bethesda Jerusalem Selective* Universal
*Selective strategy: tumor MMR testing of CRC patients diagnosed 70 years-old, and in older patients fulfilling the Bethesda guidelines
∆↓ 4.9%
∆↓ 14.6%
∆↓ 12.2%
Moreira et al. JAMA 2012
Cumulative distribution of MMR gene mutations according to the age at CRC diagnosis
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
21-25 26-30 31-35 36-40 41-45 46-50 51-55 56-60 61-65 66-70 71-75 76-80 81-85
Age at CRC diagnosis (years)
Moreira et al. JAMA 2012
Diagnostic yield of strategies for Lynch syndrome identification
1,96% 1,90%2,12%
2,23%
0,0%
0,5%
1,0%
1,5%
2,0%
2,5%
Bethesda Jerusalem Selective* Universal
*Selective strategy: tumor MMR testing of CRC patients diagnosed 70 years-old, and in older patients fulfilling the Bethesda guidelines
∆↓ 4.9%
∆↓ 14.6%
∆↓ 12.2%
Moreira et al. JAMA 2012
Strategies for the identification of Lynch syndrome
4,4% 5,1%6,5%
9,1%
0%
2%
4%
6%
8%
10%
Germline MMR gene analysis
27,0%
57,8%65,2%
100%
0%
20%
40%
60%
80%
100%
Tumor MMR testing
Bethesda Jerusalem Selective* Universal
∆↓ 35% ∆↓ 29%
Moreira et al. JAMA 2012
Serrated polyposis(hyperplastic polyposis syndrome)
Definition (WHO 2010) >5 proximal serrated polyps (at
least, 2 polyps >10 mm), or >20 serrated polyps (any size,
any location), or any serrated polyp in a person
with one FDR with serrated polyposis
Prevalence: 1 in 3,000 screening sigmoidoscopies
Heterogeneous disease: Type 1: multiple SSA (large size and proximal) Type 2: multiple hyperplastic polyps (any location)
Normal mucosa
ACF
MVHP
SSA
SSA-HGD
CRC
Proximal tumors Mutated BRAF CIMP-H MSI-H (MSS) MLH1 loss
Sessile serrated pathway
Goel and Balaguer. Curr CRC Rep 2011
BRAF mutation
p16, IGFBP7, others? methylation
Apoptosis inhibition
Molecular changes
Morphologic changes
MSI-H tumors MSS tumors
MCC / APC methylation and/or
p53, 18q LOH…
MLH1methylation
Endoscopic surveillance in 77 patients with serrated polyposis Multicenter observational study, 1982-2008 27 (35%) patients developed CRC (22 at baseline examination)
Boparai et al. Gut 2010
Serrated polyposis and CRC risk
Cumulative risk: 7% at 5 years
Mucosacolónica
Adenoma Carcinoma
Prevención 3aria o vigilanciaPrevención 1aria
Prevención 2ariao cribado
Prevención del CCR en población de alto riesgo
High-Risk CRC Clinic Community-based center Primary care physician
Community-based screeningof hereditary CRC
Consultas de Alto Riesgo de Cáncer Colorrectal
Dr. Antoni CastellsHospital Clínic, Barcelona