Percorso diagnostico delle POLIPOSI ADENOMATOSE e AMARTOMATOSE

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1 XVI Congresso nazionale SIGU - Corso post congressuale Eterogeneità genetica nei tumori ereditari: quali test proporre nella pratica clinica Percorso diagnostico delle POLIPOSI ADENOMATOSE e AMARTOMATOSE

2 Familial CRC ~ 15% Hereditary CRC ~ 3% Polyposis ~ 1% Non-polyposis Sporadic CRC FAP ; AFAP MAP 1: > NEW 2013! Peutz-Jeghers 1: < Juvenile Polyposis Hereditary Mixed Polyposis Cowden Syndrome Polymerase proofreading-associated polyposis (PPAP) As yet undiscovered

3 ? Hereditary Colo-Rectal Cancer Polyposis Non-polyposis ADENOMA -> CARCINOMA 5-10 years 3-5 years Hyperproliferation Normal Adenoma: early Adenoma: Adenoma: intermediate late Cancer: curable Cancer: late Only ~ 25% adenomas progress to cancer POLIPI IPERPLASTICI POLIPI AMARTOMATOSI POLIPI INFIAMMATORI.

4 ? Hereditary Colo-Rectal Cancer Polyposis Non-polyposis >

5 Prevalenza di adenomi, adenomi avanzati e cancro in programmi di screening endoscopico Adenomi AD Avanzati Cancro Rettosigmoidoscopia UKFSS-Trial 2002 (55-64 yrs) 12% 5% 0.04%* SCORE I 2002 (55-64 yrs) 11% 3% 0.05%* IST 2008 (55-64 yrs) 13.5% 3% 0.05% Colonscopia Lieberman 2000 ( 50 yrs) 37% 10% 1.0% Regula 2006 (50-66 yrs) 14% 6% 0.9% IST 2008 (55-64 yrs) 26% 8% 1.1% * Rimozione endoscopica: UKFFS: 17% (17/140) SCORE-I: 20% (11/54)

6 QUANTI (e quali) POLIPI fanno una POLIPOSI?? - iperplastici - adenomatosi - amartomatosi (vari sottotipi)

7 Histology Syndrome Gene Adenomatous polyposis FAP ; AFAP MAP APC MUTYH Hyperplastic polyposis Hamartomatous Polyposis Peutz-Jeghers Juvenile Polyposis Cowden Syndrome (BRRS; Proteus s.) STK11/LKB1 SMAD4; BMPR1A PTEN

8 POLIPOSI ADENOMATOSE

9 Poliposi Familiare Adenomatosa (FAP) classica Malattia rara: 1: : (European Medicine Agency) descritta già nel 1700 e 1800 Lockhard-Mummery (1925): rischio di CRC Autosomica dominante ad alta penetranza 20-30% non c è famigliarità ( de novo ) 1987 Linkage 5q21 (no evidenza di eter.gen.) 1991 clonaggio posizionale gene APC Centinaia-migliaia di adenomi colorettali Eta media insorgenza: anni* Eta media diagnosi: 36 anni* Eta media cancro: anni* Rischio di cancro colorettale 100% *serie storiche prima dell endoscopia

10 S. Gardner (1953) manifestazioni colorettali ed extra come FAP desmoidi (8-13%) osteomi cranio e ossa lunghe alterazioni dentarie cisti sebacee ed epidermoidi lipomi, fibromi neoplasie del surrene e vie biliari S. di Turcot (1959) piu rara della S.di Gardner manifestazioni colorettali (ed extra) come FAP neoplasie cerebrali gene APC (medulloblastoma) geni MMR (glioblastoma multiforme) (eterogeneità genetica)

11 DIAGNOSI PERSONS WITH MORE THAN 100 COLORECTAL ADENOMAS HAVE FAP BY DEFINITION American Association of Gastroenterology, 2003

12 FAP attenuata (AAPC o AFAP) (1990) adenomi colorettali multipli ( < 100 ) alta variabilita intra-familiare n. adenomi localizzazione piu frequente a destra alto rischio di cancro colorettale eta di insorgenza piu avanzata quanti adenomi fanno una FAP??

13 CLASSIFICATION OF FAP: A DIAGNOSTIC NIGHTMARE Lynch, Am J Hum Genet 1998 N. adenomi FAP AFAP sporadici Poliposi profusa Poliposi classica Poliposi sparsa Poliposi attenuata Poliposi molto attenuata adenomi

14 Al Tassan et al., Nature Genetics Feb Multiple adenoma CRC Family * * * APC Germline: * E1317Q APC Somatic: 15 of 18 G:C -> T:A transversions

15 MUTYH-Associated Polyposis (MAP) autosomal recessive adenomatous polyposis gene mutato

16 MUTYH Associated Polyposis (MAP) polyposis Adenomas somatic APC Hyperplastic/ serrated polyps (>40%) K-ras CRC : MSI-L CRC without polyposis 42% only 1 syncronous polyp at CRC diagnosis (Croitoru et al, JNCI 2004) 35% no polyp at CRC diagnosis (Cleary et al, Gastroent 2009)

17 276 MAP pts Muir-Torre No desmoids Gastric polyps 11% No osteomas; CHRPE rare

18 Duodenal adenomas 17% HNPCC

19 . Diagnosi molecolare FAP (Familial Adenomatous Polyposis) vs MAP (MYH-ASSOCIATED POLYPOSIS) (DOMINANTE) 90% 10% Profuse Classic > 100 Sparse Attenuated < 100 Multiple? < 20 (RECESSIVO) CRC 40 anni CRC 50 anni

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21 Hyperplastic polyposis

22 May be heterogeneous Hyperplastic polyposis syndrome (HPS) It may have two phenotypes: (1) the presence of at least 30 (but not necessarily large) hyperplastic polyps in a pancolonic distribution, (2) five hyperplastic polyps proximal to the sigmoid colon with at least two being 1 cm in diameter or larger Some examples can meet both definitions. The proximal and large polyps occurring in the second type of hyperplastic polyposis are likely to be sessile serrated adenomas (SSAs). Molecular research in SSAs strongly suggests that these polyps are precursor lesions that may lead to CRC (BRAF, MSI-H). Conceivably, the risks of cancer and the molecular pathway of carcinogenesis may differ, with MSI-H cancers linked more closely to the second category. More research is required into the phenotypic and genotypic diversity of hyperplastic polyposis Genetic predisposition?

23 Hamartomatous polyposis

24 Peutz-Jeghers Syndrome = association of gastrointestinal polyposis and mucocutaneous pigmentation PJ hamartomatous polyps* most common in the small intestine (in order of prevalence: in the jejenum, ileum, and duodenum) but can also occur in the stomach and large bowel * histopathologically: unique finding of mucosa with interdigitating smooth muscle bundles in a characteristic branching tree appearance Adenomas also appear with increased prevalence throughout the gastrointestinal tract chronic bleeding and anemia recurrent obstruction and intussusception requiring repeated laparotomies and bowel resections Age at onset (symptoms) is variable : Laparotomy for bowel obstruction : - median age 10 years - some within the first few years of life 30% by age 10 years 68% by age 18 years

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26 Juvenile Polyposis Syndrome (JPS) predisposition to hamartomatous polyps in the gastrointestinal (GI) tract, specifically in the stomach, small intestine, colon, and rectum The term "juvenile" refers to the type of polyp* rather than to the age of onset of polyps Most individuals with JPS have some polyps by age 20 years Number of polyps: from 4-5 polyps to > 100 over their lifetime If the polyps are left untreated, they may cause bleeding and anemia. Most juvenile polyps are benign; however, malignant transformation can occur Risk of GI cancers in families with JPS ranges from 9% to 50%. Most of this increased risk is attributed to colon cancer, but cancers of the stomach, upper GI tract, and pancreas have been reported. * hamartomas that develop from an abnormal collection of tissue elements normally present at this site: Juvenile polyps show a normal epithelium with a dense stroma, an inflammatory infiltrate, and a smooth surface with dilated, mucus-filled cystic glands in the lamina propria. Muscle fibers and the proliferative characteristics of adenomas are typically not seen in juvenile polyps.

27 Juvenile Polyposis Syndrome (JPS) Two genes are known to be associated with JPS: BMPR1A. ~20% [Sayed et al 2002, Howe et al 2004]. SMAD4. ~ 20% [Howe et al 2004]. Genotype-phenotype correlations in general are poor - some members of families with JPS and the same mutation have a few polyps, whereas others have more than 100; - the age at which polyps develop can vary from the first decade to beyond the fourth decade among affected members of the same family SMAD4 more likely to have a family history of upper-gi polyps SMAD4 or BMPR1A more likely to have more than ten lower GI polyps and a family history of GI cancer [Burger et al 2002, Friedl et al 2002, Sayed et al 2002].

28 PTEN Hamartoma Tumor Syndrome (PHTS) [Includes: Cowden Syndrome, Bannayan-Ruvalcaba-Riley Syndrome (Bannayan-Riley-Ruvalcaba Syndrome, Bannayan-Zonana Syndrome, Riley-Smith Syndrome, Ruvalcaba-Myhre-Smith Syndrome), Proteus Syndrome] Major criteria Breast cancer Epithelial thyroid cancer (non-medullary), especially follicular thyroid cancer Macrocephaly (occipital frontal circumference 97th percentile) Endometrial carcinoma Minor criteria Other thyroid lesions (e.g., adenoma, multinodular goiter) Mental retardation (IQ 75) Hamartomatous intestinal polyps* Fibrocystic disease of the breast Lipomas Fibromas Genitourinary tumors (especially renal cell carcinoma) Genitourinary malformation Uterine fibroids Cancer Risk 25%-50% ~10% 5%-10% CRC risk not increased * PHTS hamartomatous polyps are different in histomorphology from the polyps seen in Peutz Jeghers syndrome

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30 la realtà non è fatta (solo) di situazioni da manuale. Famigliarità comune AFAP FAP HNPCC Altre poliposi

31 CRITERI CLINICI DETECTION RATE

32 Polyposis Non-polyposis adenomi polipi iperplastici amartomi Documentazione istologica completa!! - numero delle lesioni - biopsie non sono rappresentative - non concordanza tra patologi quadri «misti» in alcuni casi revisione istologica da parte di un patologo esperto

33 DD tra poliposi amartomatose per invio al (primo) test genetico Polyposis Non-polyposis amartomi Fenotipo? 1. Storia personale: altri segni clinici /patologie 2. Storia famigliare: suggestiva? 3. Revisione istologica (patologo esperto!!) Expertise personale? (rare e molto rare!!)

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40 Consulenza Genetica Multidisciplinare in Centro Esperto (RETE) MALATTIE RARE

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42 DD tra FAP e MAP per invio al (primo) test genetico Polyposis Non-polyposis adenomi Modello ereditarietà? 1. Verticalità 2. In assenza di verticalità, FH in fratelli/sorelle 3. In casi singoli, consanguineità (nota o presumibile) Fenotipo? 1. Età diagnosi 2. Numerosità degli adenomi 3. Desmoide 4. Polipi iperplastici/serrati Utilità del test? 1. Fratelli/sorelle 2. Figli

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48 DD tra FAP e MAP per invio al (primo) test genetico Polyposis Non-polyposis adenomi >100 ad Verticalità <40 anni Test APC Test APC & MUTYH Altri test?? MSI STK11.. <100 ad Solo fratria / consanguineità >50 anni Test MUTYH

49 POLYMERASE PROOFREADING-ASSOCIATED POLYPOSIS (PPAP) NEW 2013!

50 SM7 WGS in 3 members Previous linkage data from 5 individuals with > early-onset colorectal adenomas 8 shared regions of the genome WGS: 6 non-silent variants in 4 regions shared by the 3 individuals Genotyping in additional affected showed that only shared one of these: POLE c. 1270C>G (p.leu424val)

51 POLE Validation set 12 Casi individuals European ancestry with CRC, enriched for family history of CRC, multiple adenomas and early-onset disease 0 Controlli individuals European ancestry, 2/3 population-based and 1/3 selected for absent personal history of colorectal tumors 3 ogni CRC «enriched» - Dominant inherited trait (highly penetrant)* - All (except one) pedigrees at least 1 individual with: multiple or very large adenomas, multiple CRC or early-onset CRC

52 POLE Affected status: - > 5 colorectal adenomas - > 1 large (>2 cm in diameter) adenoma - >2 colorectal carcinomas - < 40 years of age at diagnosis of CRC

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54 SM6 Previous linkage shared regions of the genome WGS: variants shared by the individuals (common ancestor) SM4 POLD1 c. 1433G>A (p.ser478asn)

55 POLD1 Validation set 1 Casi individuals European ancestry with CRC, enriched for family history of CRC, multiple adenomas and early-onset disease 0 Controlli individuals European ancestry, 2/3 population-based and 1/3 selected for absent personal history of colorectal tumors 1 ogni circa CRC «enriched» - Dominant inherited trait - Endometrial cancer - Brain tumors

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58 POLE L424V and POLD1 S478N variants can be easily tested for and should be considered in any individual with an unexplaned personal or family history of - multiple or large colorectal adenomas and/or - multiple or early-onset colorectal (or endometrial) carcinoma.

59 Le evidenze sui benefici dei nuovi test genetici sono spesso deboli Alti livelli di evidenza di utilità clinica Livelli di evidenza non definiti/ molto bassi anni senza poter applicare in clinica le scoperte sui geni/genoma + ricerca e sviluppo nel settore fortemente disincentivati potenziale rischio di effetti dannosi per gli utenti/pazienti e i sistemi sanitari evidence dilemma

60 Public Health Genomics (PHGen) CONOSCENZA MONDO POLITICO (decisori) Informazioni per scegliere (multidimensionali, multidisciplinari) metodologia HTA (Health Technology Assessment) Aree: - tecnologia - paziente (etico-sciale) - economia - organizzazione