The Department focuses primarily on epidemiological and translationalresearch. This comprises knowledge of lifestyle and genetic risk factors inorder to take preventive action (i.e. from prediction to prevention), andknowledge of inequalities in cancer prevention and treatment for carrying outcorrective actions. Our research relies on extensive interaction betweenresearchers in the fields of basic experimental science, epidemiology, genetics,and clinical medicine. The priorities of the Department are: • promotion of healthy diet and lifestyle: to proceed from large cohortstudies in which the INT has been actively involved for more than 20 years, todietary intervention studies targeting the general population, high-risksubgroups, and cancer patients to minimize the risk of recurrence (facilitiesinclude a hormonal laboratory, a teaching kitchen, and a synergic garden) • environmental and occupational risk factors: this research is moving fromstandard epidemiological designs to the systematic monitoring of occupationalrisk through the linkage of cancer registry data and occupational history files,in addition to forming stronger collaborations with the public agencies that areresponsible for occupational and environmental surveillance in order to estab-lish specific preventive actions • hereditary cancer prevention in high-risk families: to go beyond clinical sur-veillance and prophylactic surgery, and promote research on environmentaland lifestyle factors as well as genetic characteristics that may affect the pene-trance of hereditary cancer genes • in the field of low penetrance cancer genes and polygenic inheritance: toclassify the complex genetics of risk and prognosis of lung and breast cancer • inequalities in survival and cure rates of cancer patients: from the systematicdescription of cancer incidence, prevalence and survival, to research on theinterpretation of survival differences between and within countries, andadvance actions to minimize such inequalities.

UNITS

EPIDEMIOLOGY AND PREVENTIONFranco Berrino (until 30 April)

Marco A. Pierotti (Interim 1st May)

NUTRITIONAL EPIDEMIOLOGY Vittorio Krogh

EVALUATIVE EPIDEMIOLOGY Gemma Gatta

ANALYTICAL EPIDEMIOLOGY Milena Sant

MEDICAL GENETICS Siranoush Manoukian

HEREDITARY DIGESTIVE TRACTTUMORS

Lucio Bertario

MOLECULAR BASIS OF GENETICRISK AND GENETIC TESTING

Paolo Radice

MOLECULAR BASIS OF GENETICRISK, POLYGENIC MODELS

Tommaso Dragani

DIRECTOR OF DEPARTMENT

Franco Berrino (until 30 April)Marco A. Pierotti (Interim 1st May)

PREVENTIVEAND PREDICTIVEMEDICINE DEPARTMENT

61 Scientific Report 2011

62Preventive and Predictive Medicine Department

epidemiology and prevention

HEAD Franco Berrino, MD (until 30 April)Marco A. Pierotti, PhD (Interim 1 May)

RESEARCH STAFFMaria Gaetana Di Mauro, MD Patrizia Pasanisi, MD, MScAnna Villarini, Biol Sci DElisabetta Venturelli, Biol Sci DGiuliana Gargano, Biol Sci DEleonora Bruno, MSc

PSYCHOLOGISTManuela BellegottiMilena Raimondi

DIETICIAN Daniela Del Sette Cerulli

TECHNICIAN Adalberto Cavalleri

ADMINISTRATIVE PERSONNEL Paola Consorti, Curtosi Patrizia, MariaGrazia Guerrini, Maria Larossa

CONSULTANTFranco Berrino, MD (from 1st May)

The Unit has two main research activities: 1) dietary and life-style intervention trials aimed at theprevention and recurrence of breast cancer (BC), and 2) observational studies on the relationship betweenmetabolic and endocrine parameters and the incidenceof BC and BC recurrences. The main ongoing study is the DIANA (DIet andANdrogens)-5 project, a randomized controlled trial totest the efficacy of dietary change and physical activity toprevent or delay the development of recurrences in BCpatients estimated to be at high risk based on hormonalor metabolic profiles. Study design: a) recruitment of2000 patients aged 35-70, operated for BC in the last 5years, without recurrences, in 12 collaborative centers indifferent Italian regions (Lombardy, Piedmont, Emilia,Abruzzo, Campania, Basilicata, and Sicily); b) randomiza-tion in a control group that receives only general lifestylerecommendations for cancer prevention and in an inter-vention group that is helped to change through periodicmeeting, kitchen, fitness courses, and common meals, withdecreasing intensity over 5 years; c) follow-up the cohort

for 5 years; analysis by intention-to-treat and by compli-ance score. By December 2011, 1424 patients wererandomized. Further studies include: • A prospective study on several thousand BC patientsadmitted to INT for primary surgical treatment to testthe prognostic role of androgens in BC progression. Abiological bank of fasting blood samples collected at thetime of diagnosis is available for BC research. • A pilot trial of the effects of caloric restriction andmetformin, a caloric restriction mimetic drug, for preven-tion of BC in 400 peri-or postmenopausal women withanthropometric or metabolic traits of metabolicsyndrome. Factorial design: metformin versus placebo(double-blind) and dietary intervention with kitchencourses and common meals versus dietary recommenda-tions only. The main objective of the trial is to clarify themetabolic and endocrine effects of calorie restriction, andthe epigenetic mechanisms that mediate such an effect. Keywords: diet, breast cancer, metformin

RELEVANT NOTES

Publications

Pasanisi P, Bruno E, Venturelli E, Manoukian S, BarileM, Peissel B, De Giacomi C, Bonanni B, Berrino J,Berrino F. Serum levels of IGF-I and BRCApenetrance: a case control study in breast cancerfamilies. Fam Cancer. 2011; 10: 521-8.

Bakken K, Fournier A, Lund E, Waaseth M,Dumeaux V, Clavel-Chapelon F, Fabre A, Hémon B,Rinaldi S, Chajes V, Slimani N, Allen NE, Reeves GK,Bingham S, Khaw KT, Olsen A, Tjønneland A,

Rodriguez L, Sánchez MJ, Etxezarreta PA, ArdanazE, Tormo MJ, Peeters PH, van Gils CH, Steffen A,Schulz M, Chang-Claude J, Kaaks R, Tumino R, GalloV, Norat T, Riboli E, Panico S, Masala G, GonzálezCA, Berrino F. Menopausal hormone therapy andbreast cancer risk: impact of different treatments.The European Prospective Investigation intoCancer and Nutrition. Int J Cancer. 2011; 128: 144-156.

63 Scientific Report 2011

nutritional epidemiology

HEAD Vittorio Krogh, MD MS

RESEARCH STAFFClaudia Agnoli, Nutrition Tech, ScD, MSc Sara Grioni, Nutrition Tech, BSc Maria Valeria Pala, Agronomy D, PhDSabina Sieri, Biol Sci D, PhD

ADMINISTRATIVE PERSONNEL Alberto Evangelista, Follow-up and DatabaseManager, BSc

The Nutritional Epidemiology Unit is involved in largeprospective studies on the association between diet, hor-mones, nutrition, lifestyle, genetic factors, and cancer risk.The EPIC study (http://epic.iarc.fr) was designed to investi-gate the relationships between diet, lifestyle, genetic, andenvironmental factors and the incidence of cancer andother chronic disease in 10 European countries. The mainpublished results of 2011 are: smoking, heavy alcohol con-sumption, and obesity contributed to sizeable fractions ofhepatocellular carcinoma burden; in western Europe, asignificant proportion of cancer cases are attributable toalcohol consumption, especially consumption higher thanthe recommended upper limits; high concentrations ofserum HDL are associated with a decreased risk of coloncancer ; high levels of glycated hemoglobin are associatedwith an increased risk of pancreatic cancer ; heavy alcoholconsumption is associated with an increased risk of intes-tinal-type non-cardia gastric cancer ; presence in theserum of specific immunoglobulin E is associated withdecreased risk of glioma.

The ORDET study, one of the first prospective Europeanstudies on the role of hORmones and DiET in the eti-ology of cancer, was organized within the EpidemiologyUnits of the INT. The main published results of 2011 are:elevated serum glucose and HOMA-IR are associatedwith increased breast cancer risk, in particular n womendiagnosed after 55 years, for which elevated SHBG levelsare associated with a reduced risk; women who drankmore than 13 g alcohol per day had lower survival thannon-drinkers. The ORDET study is participating in the“Pooling project on circulating level of vitamin D in breastand colorectal cancer”, a collaborative project thatinvolves major European and North American cohortstudies coordinated by Harvard University and funded byNIH. In 2011, the researchers have been involved in thepreparation of data for statistical analysis. Keywords: prospective studies, diet, hormones

RELEVANT NOTES

Collaborations

Epidemiology of endometrial cancer consortium(E2C2).

Endogenous Hormones and Breast CancerCollaborative Group.

The Pooling Project of Prospective Studies of Dietand Cancer.

The Pooling Project on circulating level of vitaminD in Breast and Colorectal Cancer.

IDEFICS Consortium. International Lung CancerConsortium.

Publications

Schütze M, Boeing H, Pischon T, Rehm J, Kehoe T,Gmel G, Olsen A, Tjønneland AM, Dahm CC,

Overvad K, Clavel-Chapelon F, Boutron-Ruault MC,Trichopoulou A, Benetou V, Zylis D, Kaaks R,Rohrmann S, Palli D, Berrino F, Tumino R, Vineis P,Rodríguez L, Agudo A, Sánchez MJ, Dorronsoro M,Chirlaque MD, Barricarte A, Peeters PH, van GilsCH, Khaw KT, Wareham N, Allen NE, Key TJ,Boffetta P, Slimani N, Jenab M, Romaguera D, WarkPA, Riboli E, Bergmann MM. Alcohol attributableburden of incidence of cancer in eight Europeancountries based on results from prospectivecohort study. BMJ. 2011; 342:d1584.

Trichopoulos D, Bamia C, Lagiou P, Fedirko V, TrepoE, Jenab M, Pischon T, Nöthlings U, Overved K,Tjønneland A, Outzen M, Clavel-Chapelon F, KaaksR, Lukanova A, Boeing H, Aleksandrova K, BenetouV, Zylis D, Palli D, Pala V, Panico S, Tumino R,Sacerdote C, Bueno-De-Mesquita HB, Van KranenHJ, Peeters PH, Lund E, Quirós JR, González CA,

Sanchez Perez MJ, Navarro C, Dorronsoro M,Barricarte A, Lindkvist B, Regnér S, Werner M,Hallmans G, Khaw KT, Wareham N, Key T, Romieu I,Chuang SC, Murphy N, Boffetta P, Trichopoulou A,Riboli E. Hepatocellular carcinoma risk factors anddisease burden in a European cohort: a nestedcase-control study. J Natl Cancer Inst. 2011;103(22): 1686-95.

Contributions

Vittorio Krogh is a member of the editorial boardof the International Journal of Public Health.

64Preventive and Predictive Medicine Department

evaluative epidemiology

HEAD Gemma Gatta, MD

RESEARCH STAFFAnnalisa Trama, MD, PhD Roberto Foschi, Math D, MSc

ADMINISTRATIVE PERSONNELFrancesca Rabito, Rossana Berruti

The Unit is principally involved in assessing the burden ofcancer in populations, focusing on rare cancers andtumors diagnosed in children, adolescents, and youngadults (AYA). The project Surveillance of Rare Cancers inEurope (RARECARE) estimated the incidence,prevalence, survival, and mortality of rare cancers andpublished a series of articles in the European Journal ofCancer. In collaboration with the ESO and the ESMO, thefirst training course on rare solid cancers was organizedin Stresa (March 2011). A further important result ofRARECARE was the estimation of cancer prevalence inEurope for common cancers, and a publication is inpreparation. The project “Prostate cancer survival patients in Italy”funded by the AIRC aims at interpreting survival differ-ences within Italy with the application of cure survivalmodels. The project is part of the Prostate Program ofthe INT. The project Rare Cancers in Italy: surveillanceand evaluation of the access to diagnosis and treatment(RITA2) aims at: providing updated cancer burden indica-tors in Italy, describing diagnosis and treatment pathways

for rare cancers, and designing a study for the reciprocalvalidation of the Rete Tumori Rari (RTR) and cancer reg-istries data. In the context of this project, discussionstarted with the RTR and dedicated high resolutionstudies on mesothelioma long-term survival,neuroendocrine tumors, and testicular cancers have beendesigned in collaboration with experts of the INT andcancer registries. The Unit is updating the Italian estimations of incidence,mortality, and prevalence for major cancer sites. A mono-graphic number of the journal Tumori will be ready by theend of 2012. The project, supported by the CCM andACC, is in collaboration with the ISS. From the EURO-CARE study, a new indicator of outcome was estimatedfor childhood and AYA lymphoid leukemia (ALL), namelythe proportion of cured patients. A paper is in prepara-tion presenting the results from ALL across Europeancountries.Keywords: rare cancers, childhood cancer, cancer burden in

population

RELEVANT NOTES

Collaborations

National collaborations:

In the frame work of the project Rare Cancers inItaly: surveillance and evaluation of the access todiagnosis and treatment (RITA2), this Unitcollaborate with the Italian Association of CancerRegistries (AIRTUM), with the clinical rare cancersnetwork (Rete Tumori Rari) coordinated by Dr.Paolo Casali, with the Istituto Superiore di Sanità(ISS) and the Federazione Italiana delle Associazionidi Volontariato in Oncologia (FAVO).

Collaborations have been established with Dr.Filippo de Braud and Dr. Vincenzo Mazzaferro tostudy neuroendocrine tumors, and with Dr. UgoPastorino, Dr. Marina Garassino, and Prof. GiuseppePelosi to study mesothelioma. Within the prostatecancer survival patients in Italy, this Unitcollaborates with the Prostate program of the INT,with 8 population-based Italian cancer registries(Varese, Trento, Bolzano, Reggio Emilia, Genoa,Latina, Naples, and Ragusa) and with the ISS.

International collaborations:

Thanks to the new project on rare cancers(Information network on rare cancers -RARECARENet) supported in the context of theSecond Program of Community Action in the Fieldof Health (2008-2013) of the EU, this Unit hascollaborations with several European partners(University of Edinburgh, Comprehensive CancerCentre in The Netherlands, Institut deCancérologie Gustave Roussy, National OncologyHospital in Bulgaria, National Cancer Registry inIreland, Finland and Slovenia), with the EuropeanCancer Patient Coalition (ECPC), with majorscientific societies (ESSO, ESMO and ECCO), withthe portal for rare diseases in Europe (Orphanet),and with the European initiative Rare CancerEurope. In the framework of the EuropeanPartnership for Action Against Cancer (EPAAC),this Unit works closely with different Europeanexperts with the aim to contribute to thereduction of cancer burden in Europe.

Publications

Gatta G, van der Zwan JM, Casali PG, Siesling S, DeiTos AP, Kunkler I, Otter R, Licitra L, Mallone S, TavillaA, Trama A, Capocaccia R; RARECARE working

group. Rare cancers are not so rare: The rarecancer burden in Europe. Eur J Cancer. 2011; 47:2493-511.

Contributions

Maura Massimino, Felice Giangaspero, Maria LuisaGarrè, Lorenza Gandola, Geraldina Poggi, VeronicaBiassoni, Gemma Gatta, Stefan RutkowskiCollaboration for the recommendations for Wilmstumor in adults.

START chapter on Childhood medulloblastoma.Critical Reviews in Oncology/Hematology. 2011;79: 65-83.

Segers H, van den Heuvel-Eibrink MM, Coppes MJ,Aitchison M, Bergeron C, de Camargo B, Dome JS,Grundy P, Gatta G, Graf N, Grundy P, KalapurakalJA, de Kraker J, Perlman EJ, Reinhard H, Spreafico F,Vujanic G, Warwick AB, Pritchard-Jones K; TheSIOP-RTSG and the COG-Renal TumourCommittee. Management of adults with Wilms’tumor: recommendations based on internationalconsensus. Expert Rev Anticancer Ther. 2011;11(7): 1107-15.

65 Scientific Report 2011

analytical epidemiology

HEAD Milena Sant, MD

RESEARCH STAFFPamela Minicozzi, Mathematics D, MSc

PHD STUDENTS Carmen Tereanu, MD Paolo Bonaiuti, Mathematics D, MSc

ADMINISTRATIVE PERSONNELChiara Margutti

The main activity of the unit consists in the analysis ofcancer survival and in the interpretation of differencesacross countries and over time, within the framework ofthe EUROCARE (European CAncer REgistry basedproject on survival and care of cancer patients) project, acollaborative effort started in the 1990s and now at its5th round, centralizing survival data from 113 Europeancancer registries. To date, the project has produced 4monographs and numerous scientific publications. Theunit coordinates the EUROCARE scientific activities andsecretariat and, in collaboration with the IstitutoSuperiore di Sanità, Rome, contributes to data manage-ment and statistical analyses. The unit is responsible fordata collection, management, and analyses of the EURO-CARE high resolution (HR) studies, designed to explainthe reasons for the survival differences across regions andover time. The cancer registries participating in EURO-CARE HR collect detailed clinical information on tumorstage, diagnostic exams, tumor gene expression,treatment, follow-up, and comorbidity factors influencingsurvival. The HR studies describe, compare, and monitor

patterns of cancer care across Europeancountries/regions, developing indicators of best practice,and analyzing their dissemination in current clinical prac-tice. Presently, studies are in course on breast, colorectal,lung cancer, lymphoma, and melanoma. The Unit isresponsible for HAEMACARE, a project aimed to investi-gate epidemiological and clinical indicators forhematological neoplasms in Europe. The unit collaborateswith the CONCORD project (worldwide study oncancer survival) led by Prof. MP Coleman, LSHTM,London, UK. Dr. Sant is project leader of the EPAAC(European Partnership Against Cancer Action) WorkPackage 4 (Health information), whose major aim is tounify the epidemiologic data produced by populationcancer registries in a European Cancer InformationSystem. In addition to population-based studies, the unitparticipates in a clinical study based at INT investigatingthe prognostic influence of tumor characteristics andmetabolic factors on breast cancer prognosis.Keywords: survival, patterns of care, cancer registries

RELEVANT NOTES

Collaborations

ISS. Centro Nazionale di Epidemiologia,Sorveglianza e Promozione della Salute IARCInternational Agency for Research on CancerLSHTM London School of Hygene and Tropicalmedicine

AIRTUM Associazione italiana dei registri tumori;FRANCIM France-cancer-incidence et mortalité;ENCR European Network of Cancer Registries;ICBP International cancer Benchmark Project, UK;EUROCOURSE Europe Against Cancer:Optimisation of the Use of Registries for ScientificExcellence in Research

EUROCHIP European Cancer Health IndicatorProject EU Joint Research Centre, Ispra

Publications

Marcos-Gragera R, Allemani C, Tereanu C, DeAngelis R, Capocaccia R, Maynadie M, Luminari S,Ferretti S, Johannesen TB, Sankila R, Karjalainen-Lindsberg ML, Simonetti A, Martos MC, Raphaël M,Giraldo P, Sant M; HAEMACARE Working Group.Survival of European patients diagnosed withlymphoid neoplasms in 2000-2002: results of theHAEMACARE project. Haematologica. 2011;96(5): 720-8.

66Preventive and Predictive Medicine Department

medical genetics

HEAD Siranoush Manoukian, MD, PhD

CLINICAL RESEARCH STAFFBernard Peissel, MD, PhD Gaia Roversi, MD, PhD

DATA MANAGERDaniela Zaffaroni, Biol Sci D, PhD

RESIDENTSElisa Cattaneo, MD Giulia Melloni, MD

ADMINISTRATIVE PERSONNELCaterina Spina, Alex Sandra DosSantos Masioli

The consolidated activity of the Medical Genetics Unitoffers genetic counseling for several hereditary predispo-sitions to cancer syndromes. The main focus of the Unit isthe study of hereditary breast and ovarian cancer(HBOC) syndrome, in addition to other inherited predis-positions to cancer such as Li-Fraumeni syndrome andfamilial melanoma. The principal goal of the Unit is toidentify individuals at genetically increased risk of cancerin order to offer a targeted clinical management by pro-viding an integrated and multidisciplinary health careservice. More than 7200 individuals belonging to about3500 different HBOC families have been identified andcharacterized. When available, all relevant data has beencollected in the Medical Genetics HBOC database(including more than 1000 BRCA1 and BRCA2 gene car-riers from over 540 families). Moreover, about 620healthy and 550 affected patients are regularly followed incollaboration with other INT Units. All clinical, genetic,and molecular data of individuals belonging to HBOCfamilies is constantly updated. For all patients treated at

INT and followed by the Medical Genetics Unit, tumorspecimens and blood samples are routinely collected.

The availability of familial, molecular, clinical, and patholog-ical data, as well as biological specimens, is essential forthe following studies: • genetic characterization of HBOC: gene penetrance,survival, disease features, as well as environmental riskfactor modifiers and tumor characteristics • long-term efficacy, health and psychological impact ofclinical and instrumental surveillance, risk reducingoptions and treatment in HBOC individuals • biological and clinical significance of BRCA gene muta-tions of unknown risk • genomic and transcriptome analyses for the identifica-tion of modifier risk factors and new genes involved ingenetic predisposition to HBOCKeywords: hereditary breast and ovarian cancer, cancer predisposition

syndrome, familial and hereditary cancer

RELEVANT NOTES

Collaborations

Breast Cancer Consortium (BCAC) - Consortiumof Investigators of Modifiers of BRCA1/2 (CIMBA)Medical Genetics, Department of Medicine,Surgery and Dentistry, University of Milan

Hereditary Breast Cancer Clinical Study Group -Department of Oncology, A.O. Sacco and A.O.Fatebenefratelli (development of a model for theidentification and management of women at highgenetic risk for breast cancer - PI: Manoukian)

Istituto Superiore Sanità (ISS), Rome - Departmentof Oncology, A.O. Sacco and A.O. Fatebenefratelli(development of a model for the identification andmanagement of women at high genetic risk forbreast cancer)

Cancer Research Institute, Genoa (IST) and CancerInstitute Regina Elena, Rome (IFO) in collaborationwith Psychological Unit of INT

Publications

Manoukian S, Peissel B, Frigerio S, Lecis D, BartkovaJ, Roversi G, Radice P, Bartek J, Delia D. Two newCHEK2 germ-line variants detected in breastcancer/sarcoma families negative for BRCA1,BRCA2, and TP53 gene mutations. Breast CancerRes Treat. 2011; 130(1): 207-15.

Yang XR, Chang-Claude J, Goode EL, et al.Associations of breast cancer risk factors withtumor subtypes: A pooled analysis from the breastcancer association consortium studies. J NatlCancer Inst. 2011; 103(3): 250-63.

Sardanelli F, Podo F, Santoro F, Manoukian S,Bergonzi S, Trecate G, Vergnaghi D, Federico M,Cortesi L, Corcione S, Morassut S, Di Maggio C,Cilotti A, Martincich L, Calabrese M, Zuiani C,Preda L, Bonanni B, Carbonaro LA, ContegiacomoA, Panizza P, Di Cesare E, Savarese A, Crecco M,Turchetti D, Tonutti M, Belli P, Maschio AD; for theHigh Breast Cancer Risk Italian 1 (HIBCRIT-1)

Study. Multicenter surveillance of women at highgenetic breast cancer risk using mammography,ultrasonography, and contrast-enhanced magneticresonance imaging (the high breast cancer riskItalian 1 study): final results. Invest Radiol. 2011;46(2): 94-105.

Contributions

Scientific Committee of the National ItalianNetwork for the Surveillance of the high geneticrisk women (Ministry of Health and IstitutoSuperiore Sanità, Rome)

Members of Italian Society of Human Genetics(S.I.G.U.) and SIGU-Oncological Medical Geneticsgroup

67 Scientific Report 2011

molecular basis of genetic risk, polygenic models

HEAD Tommaso A. Dragani, PhD

RESEARCH STAFFGiacomo Manenti, PhD

POSTDOCTORAL FELLOWSAntonella Galvan, PhD Sara Noci, PhD Elisa Frullanti, PhD Francesca Colombo, PhD

PHD STUDENT Alice Dassano, Biol Sci D

TECHNICIANSFelicia S. Falvella, PhD Angela Pettinicchio

ADMINISTRATIVE PERSONNELSilvia Portincasa

During 2011, our research Unit continued its studies ongenetic susceptibility to lung cancer. In particular, we car-ried out a case-only genome-wide association study(GWAS) using a 620,901 single-nucleotide polymorphism(SNP) array in a first series of 600 lung adenocarcinoma(ADCA) patients and in a replication series of 317 lungADCA patients to identify SNPs associated with clinicalstage. We observed the strongest statistical associationwith rs10278557 (P = 1.1 x 10-5), located in themesenchyme homeobox 2 (MEOX2) gene, and ourresults pointed to the role of germ line variationsinvolving multiple loci in modulating clinical stage and,therefore, prognosis in lung ADCA patients. We have alsocharacterized the mechanism underlying the tumor sup-pressor activity of the MFSD2A gene, and found that a5’-region polymorphism modulates promoter activity ofthis gene, potentially affecting MFSD2A mRNA levels innormal lung and in lung tumors. We carried out meta-

and pooled analyses of the FGFR4 Gly388Arg polymor-phism as a cancer prognostic factor, observing a role forthe variant in modulating outcome in different types ofcancer, thus offering to clinicians a new marker to predictpredisposition to poor survival in cancer patients. Finally,we carried out a pharmacogenomic study on theresponse to opioids for cancer pain in a European seriesof 1008 cancer patients by testing 1 million SNPs. Ourresults indicated that a SNP panel including eight SNPs,with rs12948783, upstream of the RHBDF2 gene,showing the best statistical association (P = 8.1 x 10-9),was significantly associated with pain relief, and may pro-vide a new tool for personalized therapy of cancer pain.Functional annotation analysis of SNP-tagged genes sug-gested the involvement of genes acting on processes ofthe neurologic system. Keywords: genetic susceptibility, pharmacogenomics, polymorphisms

RELEVANT NOTES

Collaborations

Dr. Olga Ibanez, Butantan Institute, Sao Paulo,Brazil.

European Pharmacogenetic Opioid Study (EPOS)consortium, Norwegian University of Science andTechnology (NTNU), Trondheim, Norway.

Publications

Galvan A, Skorpen F, Klepstad P, Knudsen AK,Fladvad T, Falvella FS, Pigni A, Brunelli C, CaraceniA, Kaasa S, Dragani TA. Multiple Loci modulate

opioid therapy response for cancer pain. ClinCancer Res. 2011; 17: 4581-7.

Frullanti E, Galvan A, Falvella FS, Manenti G,Colombo F, Vannelli A, Incarbone M, Alloisio M,Nosotti M, Santambrogio L, Gonzalez-Neira A,Pastorino U, Dragani TA. Multiple genetic locimodulate lung adenocarcinoma clinical staging. ClinCancer Res. 2011; 17: 2410-6.

Contributions

Frullanti E: Second Level Master in MedicalStatistics and Statistical Methods for Epidemiology.University of Milan.

68Preventive and Predictive Medicine Department

molecular basis of genetic risk and genetic testing

HEAD Paolo Radice, Biol Sci D

RESEARCH STAFFDaniela Perotti, PhD

POSTDOCTORAL FELLOWS Laura Caleca, PhD Mara Colombo, PhD Giovanna De Vecchi, Biol Sci D Antonio Fiorino, Biol Sci D Paolo Peterlongo, PhD* Carla B. Ripamonti, MD

PHD STUDENT Irene Catucci, Med Biotech D*

FELLOWS Claudia Foglia, Biol Sci D Sara Ciceri, Med Biotech D

TECHNICIANPatrizia Mondini

ADMINISTRATIVE PERSONNELSilvia Grassi

*c/o FIRC Institute of Molecular Oncology Foundation(IFOM)

This research unit is devoted to the identification andcharacterization of genetic elements associated with pre-disposition to cancer and cancer progression. Our studiesare mainly focused on breast carcinoma and Wilms tumor(WT). The main achievements in 2011 are as follows. • Following the discovery that PALB2 constitutionalmutations predispose to both breast and pancreatic carci-nomas, we screened 62 hereditary breast cancer casesnegative for BRCA gene mutations (BRCAX) and with apersonal and/or familial history of pancreatic cancer. Thefrequency of identified pathogenic mutations (4.8%) wasnot significantly different from that (2.1%) we observed inBRCAX cases unselected for association with othercancer types. • A putative polymorphism (rs12975333) in the miR-125 microRNA, previously reported in association withincreased breast cancer risk, was genotyped in 3145BRCAX cases and 4114 controls from Italy, Spain,Germany, and Australia. None of the examined samplescarried the analyzed variant, ruling out its role in breast

cancer predisposition in the investigated populations. • The occurrence of specific telomere maintenancemechanisms (TMMs) was investigated in 34 WTs.Alternative lengthening of telomeres (ALT) was detectedas the sole TMM in 5 samples and in association withtelomerase activity (TA) in 6 samples; 17 samples exhib-ited TA only and in 6 cases no TMM was found. This is thefirst evidence of the presence of ALT in WT, which wasfound to be the only TMM supporting tumor develop-ment in a subset of cases. • The genetic effects induced by the RPF-1 protein,encoded by the WT-related POU6F2 gene, was investi-gated using a genome-wide approach. Protein-DNAinteractions were validated by band-shift assay of putativeconsensus sequences and functionally characterized onpromoters cloned into reporter vectors. Several regula-tors of embryonic kidney development were founddirectly modulated by RPF-1, suggesting a role for thisfactor in kidney morphogenesis. Keywords: cancer genetics, familial breast cancer, Wilms tumor

RELEVANT NOTES

Collaborations

Fondazione Istituto FIRC di Oncologia Molecolare,Milan Italy

Network Italiano Tumori Eredo-Famigliari (INTEF) -P. Radice, co-coordinator

CONsorzio degli Studi ITaliani sul TumoreEreditario alla Mammella (CONSIT TEAM) - P.Radice, coordinator

Evidence-based Network for the Interpretation ofGermline Mutant Alleles (ENIGMA) - P. Radice,steering committee member

Associazione Italiana di Ematologia ed OncologiaPediatrica (AIEOP) - D. Perotti, Wilms tumorworking group steering committee member

Breast Cancer Consortium (BCAC)

Consortium of Investigators of Modifiers ofBRCA1/2 (CIMBA)

Institut Catala de Oncologia, Barcelona, Spain

Department of Human Genetics, Leiden UniversityMedical Center, Leiden, The Netherlands

Queensland Institute of Medical Research,Brisbane, Queensland, Australia

Publications

Peterlongo P, Catucci I, Pasquini G, Verderio P,Peissel B, Barile M, Varesco L, Riboni M, Fortuzzi S,Manoukian S, Radice P. PALB2 germline mutationsin familial breast cancer cases with personal andfamily history of pancreatic cancer. Breast CancerRes Treat. 2011; 126: 825-8.

Venturini L, Daidone MG, Motta R, Collini P,Spreafico F, Terenziani M, Piva L, Radice P, Perotti D,Zaffaroni N. Telomere maintenance in Wilmstumors: First evidence for the presence ofalternative lengthening of telomeres mechanism.Genes Chromosomes Cancer. 2011; 50: 823-9.

69 Scientific Report 2011

hereditary digestive tract tumors

HEADLucio Bertario, MD

RESEARCH STAFF Paola Sala, Biol Sci DStefano Signoroni, Biol Sci D

ADMINISTRATIVE PERSONNELMariangela Di CeglieOrnella Galuppo

The Unit of Hereditary Digestive Tract Tumors is devotedto the counselling, molecular testing, and clinical manage-ment of individuals with genetic predisposition to themajor hereditary syndromes of gastrointestinal cancer.These include Lynch syndrome or hereditary non-poly-posis colorectal cancer (HNPCC), familial adenomatouspolyposis (FAP) and its phenotypic variant attenuatedFAP, Peutz-Jeghers Syndrome, and hereditary gastriccancer.Individuals with evidence of hereditary susceptibility tocancer are counseled and informed about personal riskand that of their relatives. Depending of the fulfillment ofdefined criteria, individuals who receive geneticcounseling are offered the possibility to undergo molec-ular testing for identification of specific geneticalteration(s) that may be associated with the increasedrisk of cancer in their families. These criteria include per-sonal and family history of cancer, presence of specificclinical phenotypes, and tumor characteristics. The genes

presently screened on a routine basis include: MLH1,MSH2, MSH6, and PMS2, cumulatively referred to asDNA mismatch repair (MMR) genes [HNPCC]; APC andMUTYH [FAP and attenuated FAP]; LKB1 [Peutz-JeghersSyndrome], and CDK1 [gastric cancer]. All tests are performed at the diagnostic laboratorylocated at IFOM (FIRC Institute of Molecular Oncology)in collaboration with the DNA Sequencing Unit of theCogentech Consortium at the IFOM-IEO campus. During2011, more than 300 individuals were screened forgermline mutations in cancer predisposing genes. Thisdiagnostic activity is integrated by several research pro-grams (LILT, Rome; PIO, Bari). At the preclinical level, theyare focused on the identification of genetic markersresponsible for familial aggregations that test negative bythe above described molecular screenings or that influ-ence cancer risk in mutation carriers.Keywords: hereditary cancer, colorectal tumor, polyposis

RELEVANT NOTES

Collaborations

Mallorca European Group for the HereditaryColorectal Cancer

InTEF (Network Nazionale Italiano Tumori Eredo-Famigliari)

Publications

Burn J, Gerdes AM, Macrae F, Mecklin JP, MoesleinG, Olschwang S, Eccles D, Evans DG, Maher ER,Bertario L, Bisgaard ML, Dunlop MG, Ho JWC,Hodgson SV, Lindblom A, Lubinski J, Morrison PJ,Murday V, Ramesar R, Side L, et al. Long-term effectof aspirin on cancer risk in carriers of hereditarycolorectal cancer: an analysis from the CAPP2

randomised controlled trial. Lancet. 2011; 378:2081-7.

Vitellaro M, Bonfanti G, Sala P, Poiasina E, BarisellaM, Signoroni S, Mancini A, Bertario L. Laparoscopiccolectomy and restorative proctocolectomy forfamilial adenomatous polyposis. Surg Endosc. 2011;25: 1866-75.

Contributions

Lucio Bertario, coordinator of the collaborativegroup for the elaboration of guidelines for clinicalmanagement of familial adematous polyposis,Lombardy Region.

Lucio Bertario, president of AIFEG Association(Associazione Italiana per lo Studio della Familiaritàed Ereditarietà dei Tumori Gastrointestinali)