EPIDEMIOLOGIA ANALITICA O INVESTIGATIVA

Diade di Ippocrate

UOMO

AMBIENTE

MALATTIA INFETTIVA

Causa necessaria ma non sufficiente

AGENTE EZIOLOGICO

FATTORI DI RISCHIO

MALATTIE

FR 1

M1

FR 2

INTERAZIONI Effetti additivi Sinergismi Antagonismi

M2

FR 3

M3

FR 4

M4

FATTORI PROTETTIVI

MALATTIE

FP 1

M1

FP 2

M2

FP 3

M3

FP 4

M4

FATTORI DI RISCHIO CANCEROGENO DI NATURA BIOLOGICA, MECCANICA, FISICA E CHIMICA

THE PREVENTION OF INFECTIONASSOCIATED CANCERS

(S. De Flora and P. Bonanni, Carcinogenesis 32, 787-795, 2011)
Pathogen
Hepatitis viruses
HBV HCV HDV 1 1 3

IARC Main asociated cancer Group

Pathogen

IARC Group

Main asociated cancer

4.9% of all cancers Hepatocellular carcinoma Hepatocellular carcinoma 85.5% of all HCCs
None

Infectious agents cause 17% of all cancers worldwide, 26% in developing world, 8% in developed world D.M. Parkin, Int.J.Cancer 15, 3030-44, 2005

HBV INFECTION AND PRIMARY HEPATOCELLULAR CARCINOMA

Insertional mutagenesis, i.e., integration of HBV DNA into the cellular genome, in proximity of genes involved in cell proliferation and/or differentiation Transcriptional transactivation, i.e., induction of cellular oncogenes (e.g., c-mic, c-fos) by HBV gene products (e.g., HBxAg) Deletion or mutation of tumor suppressor genes (e.g.,p53) Liver cirrhosis, with inflammation, necrosis and regeneration Enhanced metabolic activation of chemical hepatocarcinogens (e.g., aflatoxin B1, food pyrolysis products)

Nellepatite B umana (HBV) e animale (WHV) vi un esaltato metabolismo di epatocancerogeni chimici

Rischio relativo
HBV AFB1 HBV + AFB1 7,3 3,4 60,0
DANNO AL DNA E INIZIAZIONE DEL CANCRO

AUMENTATO METABOLISMO DI EPATOCANCEROGENI CHIMICI

O O

AFB1
O O

Trp-P-2

OCH3 CH3 N

In collaborazione con:
1 2

NH2

Catt. Gastroenterologia, ISMI, Universit di Genova Ist. Fisiologia Generale, Universit di Genova 3 Institute for Cancer Research, Philadelphia, PA, USA 4 International Agency for Research on Cancer (IARC), Lyon, France 5 National Cancer Institute (NCI), Bethesda, MD, USA 6 Environmental Protection Agency (EPA), Research Triangle Park, NC, USA 7 Integrated Laboratory Systems, Research Triangle Park, NC, USA

THE PREVENTION OF INFECTIONASSOCIATED CANCERS

(S. De Flora and P. Bonanni, Carcinogenesis 32, 787-795, 2011)
Pathogen
Hepatitis viruses
HBV HCV HDV 1 1 3

IARC Main asociated cancer Group

Pathogen

IARC Group

Main asociated cancer

4.9% of all cancers Hepatocellular carcinoma Hepatocellular carcinoma 85.5% of all HCCs
None Cancers at several sites

Papillomaviruses HPV
HPV type 16 HPV types 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 HPV type 68 HPV types 26, 30, 34, 53, 66, 67, 69, 70, 73, 82, 85, 97 HPV type 5 and 8 HPV type 6 and 11 Other and HPV types
1

Cervical cancer 5.2% of all cancers 2A Cervical cancer 100% of cervix cancers 2B 3 3 Cervical cancer Skin cancer None None 2B

Infectious agents cause 17% of all cancers worldwide, 26% in developing world, 8% in developed world D.M. Parkin, Int.J.Cancer 15, 3030-44, 2005

THE PREVENTION OF INFECTIONASSOCIATED CANCERS

(S. De Flora and P. Bonanni, Carcinogenesis 32, 787-795, 2011)
Pathogen
Hepatitis viruses
HBV HCV HDV 1 1 3

IARC Main asociated cancer Group

Pathogen

IARC Group

Main asociated cancer

4.9% of all cancers Hepatocellular carcinoma Hepatocellular carcinoma 85.5% of all HCCs
None Cancers at several sites

Retroviruses
HTLV-I HTLV-II HIV-I 1 3 1 Adult T-cell leukemia/lymphoma None Kaposis sarcoma, non-Hdgkins lymphoma, Hodgkins lymphoma, cervical cancer, anus cancer, conjunctive cancer Kaposis sarcoma, non-Hodgkins lymphoma Human breast cancer

Papillomaviruses HPV
HPV type 16 HPV types 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 HPV type 68 HPV types 26, 30, 34, 53, 66, 67, 69, 70, 73, 82, 85, 97 HPV type 5 and 8 HPV type 6 and 11 Other and HPV types
1

Cervical cancer 5.2% of all cancers 2A Cervical cancer 100% of cervix cancers 2B 3 3 Cervical cancer Skin cancer None None 2B

HIV-II HERV-K

2B NA

Polyomaviruses
JCV MCV SV40 NA NA NA CNS tumors and colorectal cancer? Skin cancer (Merkel cell carcinoma) Malignant mesothelioma ?

Herpesviruses
EBV or HHV4 1 Burkitts lymphoma, sinonasal angiocentric T-cell lymphoma, immunosuppressor-related nonHodgkins lymphoma, Hodgkins lymphoma, nasopharyngeal carcinoma Kaposis sarcoma, primary effusion lymphoma

Infectious agents cause 17% of all cancers worldwide, 26% in developing world, 8% in developed world D.M. Parkin, Int.J.Cancer 15, 3030-44, 2005

KSHV or HHV8

THE PREVENTION OF INFECTIONASSOCIATED CANCERS

(S. De Flora and P. Bonanni, Carcinogenesis 32, 787-795, 2011)
Pathogen
Hepatitis viruses
HBV HCV HDV 1 1 3

IARC Main asociated cancer Group

Pathogen

IARC Group

Main asociated cancer

4.9% of all cancers Hepatocellular carcinoma Hepatocellular carcinoma 85.5% of all HCCs
None Cancers at several sites

Retroviruses
HTLV-I HTLV-II HIV-I 1 3 1 Adult T-cell leukemia/lymphoma None Kaposis sarcoma, non-Hdgkins lymphoma, Hodgkins lymphoma, cervical cancer, anus cancer, conjunctive cancer Kaposis sarcoma, non-Hodgkins lymphoma Human breast cancer

Papillomaviruses HPV
HPV type 16 HPV types 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 HPV type 68 HPV types 26, 30, 34, 53, 66, 67, 69, 70, 73, 82, 85, 97 HPV type 5 and 8 HPV type 6 and 11 Other and HPV types
1

Cervical cancer 5.2% of all cancers 2A Cervical cancer 100% of cervix cancers 2B 3 3 Cervical cancer Skin cancer None None 2B

HIV-II HERV-K

2B NA

Polyomaviruses
JCV MCV SV40 NA NA NA CNS tumors and colorectal cancer? Skin cancer (Merkel cell carcinoma) Malignant mesothelioma ?

Herpesviruses
EBV or HHV4 1 Burkitts lymphoma, sinonasal angiocentric T-cell lymphoma, immunosuppressor-related nonHodgkins lymphoma, Hodgkins lymphoma, nasopharyngeal carcinoma Kaposis sarcoma, primary effusion lymphoma

Infectious agents cause 17% of all cancers worldwide, 26% in developing world, 8% in developed world D.M. Parkin, Int.J.Cancer 15, 3030-44, 2005

KSHV or HHV8

THE PREVENTION OF INFECTIONASSOCIATED CANCERS

(S. De Flora and P. Bonanni, Carcinogenesis 32, 787-795, 2011)
Pathogen
Hepatitis viruses
HBV HCV HDV 1 1 3

IARC Main asociated cancer Group

Pathogen

IARC Group

Main asociated cancer

4.9% of all cancers Hepatocellular carcinoma Hepatocellular carcinoma 85.5% of all HCCs
None Cancers at several sites

Retroviruses
HTLV-I HTLV-II HIV-I 1 3 1 Adult T-cell leukemia/lymphoma None Kaposis sarcoma, non-Hdgkins lymphoma, Hodgkins lymphoma, cervical cancer, anus cancer, conjunctive cancer Kaposis sarcoma, non-Hodgkins lymphoma Human breast cancer

Papillomaviruses HPV
HPV type 16 HPV types 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 HPV type 68 HPV types 26, 30, 34, 53, 66, 67, 69, 70, 73, 82, 85, 97 HPV type 5 and 8 HPV type 6 and 11 Other and HPV types
1

Cervical cancer 5.2% of all cancers 2A Cervical cancer 100% of cervix cancers 2B 3 3 Cervical cancer Skin cancer None None 2B

HIV-II HERV-K

2B NA

Helicobacter pylori

5.5% of all cancers 1 Gastric cancer, MALT 63.4% of stomach cancers

Polyomaviruses
JCV MCV SV40 NA NA NA CNS tumors and colorectal cancer? Skin cancer (Merkel cell carcinoma) Malignant mesothelioma ?

Herpesviruses
EBV or HHV4 1 Burkitts lymphoma, sinonasal angiocentric T-cell lymphoma, immunosuppressor-related nonHodgkins lymphoma, Hodgkins lymphoma, nasopharyngeal carcinoma Kaposis sarcoma, primary effusion lymphoma

Infectious agents cause 17% of all cancers worldwide, 26% in developing world, 8% in developed world D.M. Parkin, Int.J.Cancer 15, 3030-44, 2005

KSHV or HHV8

Culture Helicobacter pylori PCR

Antibiotic resistance assay rRNA

vacA genotypes cagA

It is an extremely valuable study which could affect, positively, millions of human beings
Gastric mucosa (119 subjects) Gender - Age Stage of gastritis Gastric dysplasia Enteroid metaplasia DNA extraction

GSTM1 genotypes OGG1

8-oxo-dG

THE PREVENTION OF INFECTIONASSOCIATED CANCERS

(S. De Flora and P. Bonanni, Carcinogenesis 32, 787-795, 2011)
Pathogen
Hepatitis viruses
HBV HCV HDV 1 1 3

IARC Main asociated cancer Group

Pathogen

IARC Group

Main asociated cancer

4.9% of all cancers Hepatocellular carcinoma Hepatocellular carcinoma 85.5% of all HCCs
None Cancers at several sites

Retroviruses
HTLV-I HTLV-II HIV-I 1 3 1 Adult T-cell leukemia/lymphoma None Kaposis sarcoma, non-Hdgkins lymphoma, Hodgkins lymphoma, cervical cancer, anus cancer, conjunctive cancer Kaposis sarcoma, non-Hodgkins lymphoma Human breast cancer

Papillomaviruses HPV
HPV type 16 HPV types 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 HPV type 68 HPV types 26, 30, 34, 53, 66, 67, 69, 70, 73, 82, 85, 97 HPV type 5 and 8 HPV type 6 and 11 Other and HPV types
1

Cervical cancer 5.2% of all cancers 2A Cervical cancer 100% of cervix cancers 2B 3 3 Cervical cancer Skin cancer None None 2B

HIV-II HERV-K

2B NA

Helicobacter pylori Schistosomes

S. haematubium S. japonicum S. mansoni

5.5% of all cancers 1 Gastric cancer, MALT 63.4% of stomach cancers

1 2B 3 Urinary bladder cancer Colorectal and liver cancers None

Polyomaviruses
JCV MCV SV40 NA NA NA CNS tumors and colorectal cancer? Skin cancer (Merkel cell carcinoma) Malignant mesothelioma ?

Liver flukes
Opistorchis viverrini Opistorchis felineus Chlonorchis sinensis 1 3 1 Cholangiocarcinoma None Cholangiocarcinoma

Herpesviruses
EBV or HHV4 1 Burkitts lymphoma, sinonasal angiocentric T-cell lymphoma, immunosuppressor-related nonHodgkins lymphoma, Hodgkins lymphoma, nasopharyngeal carcinoma Kaposis sarcoma, primary effusion lymphoma

Infectious agents cause 17% of all cancers worldwide, 26% in developing world, 8% in developed world D.M. Parkin, Int.J.Cancer 15, 3030-44, 2005

KSHV or HHV8

PREVENZIONE DEI TUMORI ASSOCIATI CON INFEZIONI O INFESTAZIONI CRONICHE

Eradicazione di infezioni (es. H. pylori, HART) o infestazioni Vaccini contro virus (es. HBV, HPV, FLV, ecc.)

Prevention of HBV infection

HBV

AFB1

Regulations

PRIMARY PREVENTION OF HEPATOCELLULAR CARCINOMA

Avoidance of exposure Chemoprevention

Trp-P-2
Health education

Diet

Drugs

S. De Flora et al, Cancer Res. 47, 40528, 1987; Carcinogenesis 10, 10991106, 1989 A.Izzotti et al, Chem.-Biol. Int. 97, 273285, 1995 A. Camoirano et al, Cancer Epid. Biol. Biom. 10, 775783, 2001

AMBIENTE E TUMORI

Sostenibilit ambientale

AMBIENTE
"insieme degli elementi che, nella complessit delle loro relazioni costituiscono le condizioni di vita dell'uomo" (EU, 1973)

Luomo, come tutti gli esseri viventi, interagisce continuamente con lambiente che pu divenire causa di effetti negativi sul suo stato di salute. Lequilibrio del rapporto uomo-ambiente (come risultato dinamico!) stato fortemente influenzato dai progressi socio-economici e tecnico-scientifici avvenuti nellutlimo secolo.

AMBIENTE E TUMORI
(a) distribuzione geografica

NUMERO DEI CASI DI CANCRO RELATIVI A 16 SITI ANATOMICI

PAESI SVILUPPATI
333 454,6 347,9 389,2 96,1 106,2
STOMACO POLMONE MAMMELLA COLON - RETTO CERVICE UTERINA BOCCA - FARINGE

PAESI IN VIA DI SVILUPPO

336,4 205,9 224,2 182,9 369,5 272,3 253,6 191,6 121,8 58,6 71,2 105,5 45,3 67,2 47,4 67,1

56,8 59,6 116,1 177,2 148,2 82,7 103,5

ESOFAGO FEGATO LINFOMI PROSTATA VESCICA LEUCEMIE

CORPO UTERO

70,4 90 52,9

OVAIO PANCREAS LARINGE

500

400

300

200

100

100

200

300

400

500

NUMERO DI CASI (X 1000)

CANCRO DEL POLMONE

CANCRO DELLO STOMACO

CANCRO DELLA MAMMELLA

AMBIENTE E TUMORI
(a) (b) (c) distribuzione geografica gruppi di popolazione popolazioni migranti

TUMORI IN DIVERSE GENERAZIONI DI EMIGRATI GIAPPONESI CONFRONTATI CON LA POPOLAZIONE STATUNITENSE

Giappone

1a

2a

3a

Bianchi U.S.

Stomaco Colon e retto Mammella Prostata

++++ + + +

+++

++

+ ++++ ++++ ++++

+++ ++++ ++++ ++ ++ ++ ++++ + +++

MORTALITA PER CANCRO DELLA MAMMELLA IN DONNE ITALIANE MIGRANTI IN AUSTRALIA (19621971)

Mortalit (dati standardizzati)

1,6 1,4 1,2 1,0 0,8 0,6 0,4 0,2 0

0-5 6 - 16 17 +

donne australiane

Anni di residenza

AMBIENTE E TUMORI
(a) (b) (c) (d) (e) distribuzione geografica gruppi di popolazione popolazioni migranti variazioni nel tempo rimozione fattori di rischio

INCREASING CONSUMPTION OF CIGARETTES IS FOLLOWED BY A STEEP RISE IN DEATHS FROM LUNG CANCER
Annual per capita consumption of cigarettes

5000

Men Women
Smoking Lung cancer

200

4000

150

3000 100 2000 Smoking 50 1000 Lung cancer 0

1900 1920 1940 1960

0
1980

Lung cancer deaths in England and Wales show a close correlation with the number of cigarettes smoked in earlier years. Source: J. Cairns.

Annual lung cancer deaths per 100,000 population

MORTALITA PER TUMORI POLMONARI (DATI STANDARDIZZATI PER 100.000)

90 80 70 60 50
ITALIA USA

Maschi

UNGHERIA

UK

40 30
GIAPPONE

30

USA

20 10 0
1965-69 70-74 75-79 80-84 85-89 92

Femmine
20 10 0
1965-69 70-74 75-79 80-84 85-89

UK

UNGHERIA GIAPPONE ITALIA

92

INTERAZIONI GENE-AMBIENTE