Hereditary non-polyposis colorectal cancer (HNPCC) Lynch syndrome. Síndrome de Lynch: bases clínicas. de Lynch. DNA mismatch repair (MMR) system

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1 Síndrome de Lynch: bases clínicas Dr. Antoni Castells Servicio de Gastroenterología Hospital Clínic,, Barcelona Hereditary non-polyposis colorectal cancer (HNPCC) Lynch syndrome 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: 60-8 DNA mismatch repair (MMR) system Vía mutadora: síndrome de Lynch MSH6 MSH2 MSH2, MLH1, MSH6, PMS2 (mutación germinal) TGF-β-RII, BAX, IGFIIR Carcinoma MSH6 MSH2 MSH6 Inestabilidad N microsatélites T N T MSH2 MLH1 PMS2 Mucosa colónica Pérdida somática del segundo alelo Pérdida expresión proteica 1

2 Síndrome de Lynch: bases clínicas Estrategias de identificación Afectación colorrectal Manifestaciones extracolónicas Síndrome de Lynch: bases clínicas Estrategias de identificación Afectación colorrectal Manifestaciones extracolónicas Clinical definition of HNPCC: Amsterdam II criteria HNPCC identification: limitations Three relatives with CRC and/or HNPCC-associated neoplasia (endometrial, small bowel, ureter or renal pelvis): one relative should be first-degree relative of the other two, and Two successive generations should be affected, and One tumor should be diagnosed before age 50 Familial adenomatous polyposis should be excluded Tumors should be verified by histopathological examination Vasen et al. Gastroenterology 1999 DNA MMR deficiency % Fulfillment of Amsterdam criteria Lindor et al. JAMA 2005 Llor et al. Clin Cancer Res

3 HNPCC identification: limitations Identification of HNPCC patients: revised Bethesda guidelines DNA MMR deficiency % Fulfillment of Amsterdam criteria Lindor et al. JAMA 2005 Llor et al. Clin Cancer Res 2005 Fulfillment of Amsterdam criteria % Presence of MMR mutation Aaltonen et al. N Engl J Med 1998 Identification of individuals who should be tested for MSI analysis: 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 slike 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 HNPCCrelated tumors, regardless of age. Umar et al. J Natl Cancer Inst 2004 The EPICOLON project Prospective, multicenter (25 hospitals), population-based study Personal and family history Tissue sampling Molecular procedures: MSI testing in all cases IHC (MSH2 / MLH1) in all cases Mutational analysis (MLPA / sequencing) in positive cases Patients evaluated: 1,222 Amsterdam II criteria: 1.8% Revised Bethesda guidelines: 23.5% MSH2 / MLH1 gene mutations: 0.9% Piñol et al. JAMA 2005 Lynch syndrome screening strategies Selective strategy Revised Bethesda guidelines IHC N T MSI IHC Universal" strategy Gene testing Gene testing 3

4 Performance of selective vs. universal molecular screening Cost-minimization analysis of selective vs. universal screening Sensitivity Specificity PPV NPV Overall accuracy % Revised Universal Betheda MSI (IHC) Rev. Revised Beth. Bethesda IHC + Rev. Beth. Universal + MSI (IHC) *p<0.001 (McNemar( test) Piñol et al. JAMA 2005 * * Cost ( ) / mutation ,989 10,644 37,956 Rev. Beth Bethesda MSI Rev. Beth Bethesda IHC Universal MSI IHC (IHC) Piñol et al. JAMA 2005 Performance of selective vs. universal molecular screening Screening in general population: MSI / IHC 1,066 CRC patients 23 MMR gene mutation carriers Family history limited to first-degree relatives Gene n Amsterdam criteria Bethesda guidelines New approaches for Lynch syndrome identification: mathematical models Leiden (Wijnen( et al.. NEJM 1998) PREMM 12 (Balmaña et al.. JAMA 2006) MMRpredict (Barnetson et al.. NEJM 2006) MMRpro (Chen et al.. JAMA 2006) Overall 23 3 (13%) 18 (78%) PREMM 12 algorithm MLH1 MSH2 MSH6 PMS (2) 2 (15%) - (-) - (-) 5 (%) 11 (85%) 1 (33%) 1 (5) Hampel et al. NEJM 2005 Log Odds (mutation) = V V V V V V V V V /V 10 - (0.358)V 11 /10 (0.293)V12/10 V 1 = CRC in the proband; V 2 = 2 or more CRC in the proband; V 3 = endometrial cancer in the proband; V 4 = other HNPCC cancer in the proband; V 5 = adenoma in the proband; V 6 = 1 for presence of CRC in 1st degree relative for presence of CRC in 2nd degree relative; V 7 = 2 1st degree relatives with CRC; V 8 = 1 for presence of endometrial cancer in 1st degree relative for presence of endometrial cancer in 2nd degree relative; V 9 = 2 1st degree relatives with endometrial cancer; V 10 = presence of 1st or 2nd degree relative with other HNPCC cancer; V 11 = sum ages of CRC/adenoma; V 12 = sum ages of endometrial cancer 4

5 Strategy for molecular assessment based on the PREMM 1,2 model MMR-deficient colorectal cancer: sporadic vs. inherited Patient with CRC PREMM 1,2 score CpG island methylator phenotype (CIMP): a distinct phenotype associated with MSI and BRAF (V600E) mutation <5% 5-19% >5% >2 CIMP markers: MLH1 p16 p16 MINT1 MINT2 MINT31 No further risk assessment Tumor MMR testing MSH2 and MLH1 genetic testing, if tumor sample is not available Issa JP. Clin Cancer Res 2008 Balaguer et al. Gastroenterology 2008 Detection of MLH1 germline mutation in tumors with MLH1 loss of expression Lynch syndrome identification Strategies not combined with clinical criteria BRAF mutation analysis p16 immunostaining + BRAF mutation analysis MLH1 methylation analysis Strategies combined with clinical criteria (fulfillment of revised Bethesda guidelines) BRAF mutation analysis p16 immunostaining + BRAF mutation analysis MLH1 methylation analysis Se Se Sp Sp PPV PPV NPV NPV Clinical criteria MSI and/or IHC MSI / IHC BRAF and/or methylation analysis Gene testing Gene testing Jerusalem guidelines Non-affected individuals Payá et al. Clin Cancer Res 2009 Clinical criteria 5

6 Síndrome de Lynch: bases clínicas Colorectal tumor multiplicity in Lynch syndrome Estrategias de identificación Afectación colorrectal Manifestaciones extracolónicas Synchronous colorectal cancer 8% 7% 6% 5% 4% 3% 2% 1% 7,4 6,7 p = ,4 MLH1 MSH2 General population Metachronous colorectal cancer (anual rate) 3% 2% 2% 1% 1% 2,1 1,7 p = ,33% MLH1 MSH2 General population Lin et al. Dis Colon Rectum 1998 Anatomic distribution of 1 st and 2 nd CRC in patients with Lynch syndrome Cumulative risk of colorectal cancer in MMR gene mutation carriers MLH1 mutations MSH2 mutations Goecke et al.. J Clin Oncol 2006 Kempers et al. Lancet Oncol

7 Relevance of Lynch syndrome screening Probability of disease-free survival Relevance of Lynch syndrome screening Probability of overall survival a p=0.02 (all) b p=0.03 (mutation +) a p=0.003 (all) b p=0.05 (mutation +) Järvinen et al.. Gastroenterology 2000 Järvinen et al. Gastroenterology 2000 Chromoendoscopy in Lynch syndrome Polyps found on 1 st (standard) and 2 nd (intensive inspection vs. chromoendoscopy) colonoscopies Chromoendoscopy in Lynch syndrome Number of adenomas per subject and procedure time for 1 st and 2 nd colonoscopies by randomization arm Arm 1 Arm 2 Arm 1: intensive inspection Arm 2: chromoendoscopy Stoffel et al.. Cancer Prev Res 2008 Stoffel et al.. Cancer Prev Res

8 High-magnification chromoendoscopy in HNPCC screening: : a back-to to-back" study Segmental vs. total colectomy in Lynch syndrome: a decision model Hurlstone et al. Am J Gastroenterol 2005 Maeda et al.. J Clin Oncol 2010 Síndrome de Lynch: bases clínicas Lifetime risk of extracolonic tumors Estrategias de identificación Afectación colorrectal Manifestaciones extracolónicas Koornstra et al.. Lancet Oncol

9 Phenotype comparison of MLH1 and MSH2 mutation carriers Cumulative risk of endometrial cancer in MMR gene mutation carriers p= % 69% p= % 2 p= % 9% CRC Endometrial Others MLH1 MSH2 Stoffel et al. Cancer Epidemiol Biomarkers Prev 2008 Ramsoekh et al. Hered Cancer Clin Pract 2009 Incidence of endometrial in Lynch syndrome: utility of prophylactic hysterectomy Gastric cancer in Lynch syndrome Cumulative incidence by gender Cumulative incidence for MMR mutation carriers Schmeler et al.. NEJM 2006 Capelle et al. Gastroenterology

10 Surveillance for extracolonic malignancies in Lynch syndrome Pancreatic cancer in Lynch syndrome Koornstra et al.. Lancet Oncol 2009 Kastrinos et al.. JAMA 2009 Surveillance in familial pancreatic cancer Surveillance in familial pancreatic cancer Lesions identified by EUS or CT (n = 14) Lesions unidentified by EUS or CT (n = 13) Canto et al. Clin Gastroenterol Hepatol

11 Acknowledgments Virginia Alonso Francesc Balaguer Sergi Castellví-Bel Miriam Cuatrecasas Mª Dolores Giráldez Meritxell Gironella María López-Cerón Leticia Moreira Jeniffer Muñoz Teresa Ocaña Maria Pellisé Gina Ramírez Cristina Rodríguez Anna Serradesanferm Montserrat Andreu Cristina Alenda Xavier Bessa Ángel Carracedo Rodrigo Jover Xavier Llor Artemio Payá Virgínia Piñol Elisenda Pons Francisco Rodríguez Clara Ruiz Rosa M. Xicola Juan I. Arenas Lidia Argüello Luis Bujanda Carmen Cordero Juan Clofent Joaquín Cubiella Jaime Cuquerella José M. Duque Ferran Fdez-Bañares Ana M. García Dolors González Ángel Lanas Cristina Martín Mercedes Martínez Juan D. Morillas Antonio Naranjo Enrique Quintero Josep M. Reñé Joaquim Rigau Joan Saló Àngels Vilella Síndrome de Lynch: bases clínicas Dr. Antoni Castells Servicio de Gastroenterología Hospital Clínic,, Barcelona 11