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The 5th Workshop IRE on Translational Oncology was held in Rome (Italy) on 27-28 March at the IRCCS Regina Elena National Cancer Institute. This meeting entitled "The New World of RNA diagnostics and therapeutics" highlightes the significant progress in the RNA field made over the last years. Research moved from pure discovery towards the development of diagnostic biomarkers or RNA-base targeted therapies seeking validation in several clinical trials. Non-coding RNAs in particular have been the focus of this workshop due to their unique properties that make them attractive tools for the diagnosis and therapy of cancer.This report collected the presentations of many scientists from different institutions that discussed recent oncology research providing an excellent overview and representative examples for each possible application of RNA as biomarker, for therapy or to increase the number of patients that can benefit from precision oncology treatment.In particular, the meeting specifically emphasized two key features of RNA applications: RNA diagnostic (Blandino, Palcau, Sestito, Díaz Méndez, Cappelletto, Pulito, Monteonofrio, Calin, Sozzi, Cheong) and RNA therapeutics (Dinami, Marcia, Anastasiadou, Ryan, Fattore, Regazzo, Loria, Aharonov)., (© 2023. The Author(s).)

The development of innovative technologies and the advances in the genetics and genomics, have offered new opportunities for personalized treatment in oncology. Although the selection of the patient based on the molecular characteristics of the neoplasm has the potential to revolutionize the therapeutic scenario of oncology, this approach is extremely challenging. The access, homogeneity, and economic sustainability of the required genomic tests should be warranted in the clinical practice, as well as the specific scientific and clinical expertise for the choice of medical therapies. All these elements make essential the collaboration of different specialists within the Molecular Tumor Boards (MTBs). In this position paper, based on experts' opinion, the AIOM-SIAPEC/IAP-SIBioC-SIC-SIF-SIGU-SIRM Italian Scientific Societies critically discuss the available molecular profiling technologies, the proposed criteria for the selection of patients candidate for evaluation by the MTB, the criteria for the selection and analysis of biological samples, and the regulatory and pharmaco-economic issues., (Copyright © 2021. Published by Elsevier B.V.)

In the oncology, the construction, implementation and evaluation of the care pathway must consider the integration of the "histological approach" with the "mutational" one, focused on the identification of specific molecular alterations to which the so-called "agnostic drugs" are targeted. To investigate this issue, a specific Working Group of the MaCroScopio Project (observatory on chronicity) was held in which the leading Italian experts in the oncology and regulatory field participated. From their articles, collected in this dossier, it clearly emerges the need of appropriate tools to manage the intrinsic complexity of the new mutational model and the challenges posed by agnostic drugs; among these Molecular Tumor Board, care pathway and Real-World Data. All this, to promote, for new oncological drugs, the transition from the classic study of the "place in therapy" to the "place in pathway", aimed to build the clinical, regulatory and institutional bases on which mutational oncology is based and make it a reality for all patients who need it.

Introduction: The impact of cancer on basal fertility and ovarian response to stimulation has not yet been clarified. Evidence on this topic is scarce and conflicting. Aim of this study was to assess the impact of breast cancer stage and grade on the number of retrieved mature oocytes during controlled ovarian stimulation for fertility preservation., Methods: Retrospective cohort study evaluating data on 101 stimulation cycles of women with breast cancer undergoing oocyte cryopreservation categorized according to breast cancer stage (low-stage: I; high-stage:II-III) and grade (low-grade: G1-2; high-grade: G3) using the American Joint Committee on Cancer staging system (VIII edition)., Results: High-stage disease was not associated with worse oocyte retrieval outcomes (median 7 vs 7, p = 0.75). High-grade disease patients showed a significantly lower antral follicle count (AFC) compared to low-grade disease patients (10 vs 13, p = 0.03), and required higher doses of FSH (2612 IU vs 2250 IU; p = 0.03) during stimulation. Median number of vitrified oocytes was 6 in low-grade disease patients and 7 in high-grade disease patients (p = 0.35)., Conclusions: Stage and grade of breast cancer do not impact the number of retrieved mature oocytes. However, higher grade of breast cancer is associated with lower AFC at baseline and need for higher doses of gonadotropin during ovarian stimulation., Competing Interests: Declaration of Competing of interest None declared., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

The personalized medicine is in a rapidly evolving scenario. The identification of actionable mutations is revolutionizing the therapeutic landscape of tumors. The morphological and histological tumor features are enriched by the extensive genomic profiling, and the first tumor-agnostic drugs have been approved regardless of tumor histology, guided by predictive and druggable genetic alterations. This new paradigm of "mutational oncology", presents a great potential to change the oncologic therapeutic scenario, but also some critical aspects need to be underlined. A process governance is mandatory to ensure the genomic testing accuracy and homogeneity, the economic sustainability, and the regulatory issues, ultimately granting the possibility of translating this model in the "real world". In this position paper, based on experts' opinion, the AIOM-SIAPEC-IAP-SIBIOC-SIF Italian Scientific Societies revised the new agnostic biomarkers, the diagnostic technologies available, the current availability of agnostic drugs and their present indication., (Copyright © 2021. Published by Elsevier B.V.)

Next Generation Sequencing (NGS) is increasingly used in diagnostic centers for the assessment of genomic alterations to select patients for precision oncology. The Italian Society of Anatomic Pathology and Diagnostic Cytopathology (SIAPEC) through the Molecular Pathology and Predictive Medicine Study Group (PMMP) has been following the progressive development of centers that have adopted NGS technology in diagnostics over time. In July 2017, a study network on massive parallel sequencing was activated in Italy and recognized as the NGS SIAPeC National Network by the SIAPeC Scientific Society Board. Since then, activities have been implemented within the network that provide for alignment of laboratories through diagnostic concordance analysis and monitoring of centers adhering to the Network. Recently, considering the growing need for extended genomic analyses, the PMMP distributed a national survey to assess activities related to the use of genomic diagnostics in oncology within the NGS SIAPEC National Network., Thirty centers participated in the survey. Eighty percent of the centers are laboratories within Pathology Departments. The distribution of laboratories in the country, the diagnostic laboratory/population ratio, the staff dedicated, the type and number of sequencing and mechatronics platforms available, the genomic panels utilized, and the type and number of diagnostic tests carried out in the last year in each center, are reported., The centers were also asked whether they participated in a multidisciplinary Molecular Tumor Board (MTB) for management of patients. Thirty percent of the centers had a MTB that was ratified by regional decree. The professionals most frequently involved in the core team of the MTB are the pathologist, oncologist, molecular biologist, geneticist, pharmacologist, and bioinformatician., The data from this survey indicate that NGS diagnostics in Italy is still heterogeneous in terms of geographical distribution and the characteristics of laboratories and diagnostic test performed. The implementation of activities that favors harmonization, the logistics and the convergence of biological material in reference centers for molecular analyses is a priority for the development of a functional laboratory network., (Copyright © 2021 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology.)

This article summarizes the latest Italian Medical Oncology Association (AIOM) guidelines on the management of cancer-related and chemotherapy-related anemia with a particular attention to the use of erythropoiesis-stimulating agents and iron supplementation.

In the era of personalized medicine, cytopathology reports must be standardized to provide clinicians with clear information regarding relevant diagnostic, prognostic, and predictive tumor features. Since 2010, the international Molecular Cytopathology Meeting has been held annually in Naples, Italy, to disseminate recent breakthroughs and ongoing investigations in the field of modern cytopathology. In particular, the seventh annual meeting, which took place on November 26 through 27, 2018, focused on novel cytological and molecular classifications and novel DNA sequencing techniques, as well as on the possibility of using cytological rather than tissue specimens for lung cancer biomarker testing. The present review aims to update cytopathologists on the more recent achievements in modern cytopathology and to identify key research questions that still remain unanswered., (© 2019 American Cancer Society.)

Aim: This observational study investigates the effectiveness and safety of dabrafenib/trametinib combination in patients with metastatic melanoma., Patients & Methods: Seventy-six patients treated with dabrafenib/trametinib (150 mg twice daily/2 mg once daily) were included., Results: Median progression-free survival was 9 months (95% CI: 7-11) and median overall survival was 14 months (11-16); disease control rate was 72%. Nine patients (12%) experienced a complete response. Of these, seven presented one metastatic site, none had lung or CNS metastasis, and none had elevated baseline lactate dehydrogenase (LDH) levels. Overall, subgroup analysis for patients with adverse prognostic features led to similar results. No new safety signals were reported., Conclusion: Dabrafenib/trametinib combination can be effective and well-tolerated also in a heterogeneous 'real life' population comprising patients with adverse prognostic features.

Background: Leukemia/lymphoma cases reported in 2001 among United Nation soldiers or peacekeepers deployed to the Balkans aroused alert on the exposure to depleted uranium. Recent epidemiological studies carried out in different European countries among peacekeepers who served in the Balkans failed to demonstrate a higher than expected risk of all cancers but, mostly due to their limitations in size and follow up time, leave open the debate on health risk of depleted uranium. The aim of SIGNUM (Study of the Genotoxic Impact in Military Units) was to identify potential genotoxic risk associated with the exposure to depleted uranium or other pollutants in the Italian Army military personnel deployed in Iraq., Methods: Blood and urine samples were collected before and after the deployment from 981 Italian soldiers operating in Iraq in 2004-2005. As, Cd, Mo, Ni, Pb, U, V, W, and Zr were determined in urine and serum. DNA-adducts, 8-hydroxy-2'-deoxyguanine and micronuclei frequency were evaluated in blood lymphocytes. Three different genetic polymorphisms, GSTM1, XRCC1, OGG1 were analyzed., Results: Significant T0-T1 reduction in the total concentration of uranium, increases for Cd, Mo, Ni, Zr, and decreases for As, Pb, W, and V in urine and plasma were observed. Increases in oxidative alterations and in micronuclei frequency, included in the range of values of non-occupationally exposed populations, were observed at the end of the period of employment., Conclusions: Our results did not detect any toxicologically relevant variation of DNA-damage biomarkers related to the deployment in the operational theater., (Copyright © 2015 Elsevier GmbH. All rights reserved.)

With the recent progress in predictive medicine several problems have emerged regarding the ethical aspects of genetic testing. The role of the doctor in communicating the consequences of such testing to the patient has become more important than ever in allowing the potential patient to make an informed decision.

Cripto, the founding member of the EGF-CFC genes, plays an essential role in embryo development and is involved in cancer progression. Cripto is a GPI-anchored protein that can interact with various components of multiple signaling pathways, such as TGF-β, Wnt and MAPK, driving different processes, among them epithelial-mesenchymal transition, cell proliferation, and stem cell renewal. Cripto protein can also be cleaved and released outside the cell in a soluble and still active form. Cripto is not significantly expressed in adult somatic tissues and its re-expression has been observed associated to pathological conditions, mainly cancer. Accordingly, CRIPTO has been detected at very low levels in the plasma of healthy volunteers, whereas its levels are significantly higher in patients with breast, colon or glioblastoma tumors. These data suggest that CRIPTO levels in human plasma or serum may have clinical significance. However, very little is known about the variability of serum levels of CRIPTO at a population level and the genetic contribution underlying this variability remains unknown. Here, we report the first genome-wide association study of CRIPTO serum levels in isolated populations (n = 1,054) from Cilento area in South Italy. The most associated SNPs (p-value<5*10-8) were all located on chromosome 3p22.1-3p21.3, in the CRIPTO gene region. Overall six CRIPTO associated loci were replicated in an independent sample (n = 535). Pathway analysis identified a main network including two other genes, besides CRIPTO, in the associated regions, involved in cell movement and proliferation. The replicated loci explain more than 87% of the CRIPTO variance, with 85% explained by the most associated SNP. Moreover, the functional analysis of the main associated locus identified a causal variant in the 5'UTR of CRIPTO gene which is able to strongly modulate CRIPTO expression through an AP-1-mediate transcriptional regulation.

The Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale Tumori "Fondazione G. Pascale" (INT-Pascale) is the largest Clinical Care and Research Cancer Center in Southern Italy. The mission is prevention, diagnosis, and care of cancer and innovative research in oncology. In 2013, INT-Pascale joined the Organisation of European Cancer Institutes (OECI) accreditation and classification project along with other Italian IRCCS cancer centers. One of the major OECI requirements that a cancer center must fulfill in order to achieve and maintain OECI certification is a strong emphasis in translational and clinical research: increasing the number of patients enrolled in clinical trials, establishing easily accessible databases for operators, and informing all possible stakeholders, including patients. A characterizing theme of INT-Pascale is a strong commitment to clinical experimental studies. In the 2007-2014 period, 440 clinical trials were activated at INT-Pascale; in this period, the number of clinical trials and observational studies has had an increment achieving in 2014, respectively, the share of 60 clinical trials and 35 observational studies activated. Optimization of clinical trials management and dissemination of the clinical research culture at INT-Pascale are main objectives to be achieved through several actions and procedures being implemented as a component of the OECI improvement plan. Participation in the OECI program has represented an important challenge to improve quality and processes related to promoting, prioritizing, and monitoring clinical trials at INT-Pascale.

Background: The risk of many cancers is higher in subjects with a family history (FH) of cancer at a concordant site. However, few studies investigated FH of cancer at discordant sites., Patients and Methods: This study is based on a network of Italian and Swiss case-control studies on 13 cancer sites conducted between 1991 and 2009, and including more than 12 000 cases and 11 000 controls. We collected information on history of any cancer in first degree relatives, and age at diagnosis. Odds ratios (ORs) for FH were calculated by multiple logistic regression models, adjusted for major confounding factors., Results: All sites showed an excess risk in relation to FH of cancer at the same site. Increased risks were also found for oral and pharyngeal cancer and FH of laryngeal cancer (OR = 3.3), esophageal cancer and FH of oral and pharyngeal cancer (OR = 4.1), breast cancer and FH of colorectal cancer (OR = 1.5) and of hemolymphopoietic cancers (OR = 1.7), ovarian cancer and FH of breast cancer (OR = 2.3), and prostate cancer and FH of bladder cancer (OR = 3.4). For most cancer sites, the association with FH was stronger when the proband was affected at age <60 years., Conclusions: Our results point to several potential cancer syndromes that appear among close relatives and may indicate the presence of genetic factors influencing multiple cancer sites.

The 8q24 region is a gene desert, although chromosomal aberrations and somatic amplification involving this region, including translocations involving the protooncogene c-MYC, have been frequently reported in people with cancer. To investigate the role of variants in 8q24 region, the authors analyzed data from a prospective study (n = 10,372 participants who were followed for 11 years) in which a large number of health events (>1,500) occurred (1993-1998). They genotyped all subjects for 5 candidate single nucleotide polymorphisms (rs672888, rs1447295, rs9642880, rs16901979, and rs6983267) that were identified in previous genome-wide scans. Although significant associations with individual single nucleotide polymorphisms were small in magnitude, the authors observed higher increases in the risks of different types of cancer with specific haplotypes, particularly when subjects were homozygous for the haplotype: for breast cancer and homozygotes for haplotype CAGCT, hazard ratio = 3.40, 95% confidence interval: 1.24, 9.21; for prostate cancer and grouped rare haplotypes, hazard ratio = 7.43, 95% confidence interval: 3.00, 18.37; and for brain cancer and homozygotes for haplotype CGGCT, hazard ratio = 13.48, 95% confidence interval: 3.00, 59.53. Significant associations were also observed between haplotypes and deaths from cardiovascular diseases and cerebrovascular diseases; the most stable association was between homozygotes for haplotypes CGTCG and CAGCT and total deaths in men (hazard ratio = 3.5, 95% confidence interval: 1.8, 6.9, and hazard ratio = 2.8, 95% confidence interval: 1.3, 6.4, respectively). In conclusion, the authors have observed a strong pleiotropic effect of the 8q24 region in a large prospective study. This observation can shed light on the mechanisms underlying reported associations between 8q24 variants and disparate chronic diseases.

Training through Research Application Italian iNitiative (TRAIN) is a mobility program financed under the EU action called "Cofinancing of regional, national and international programs" (COFUND) of the European Commission Seventh Framework Program (FP7) - People, and has been designed to encourage the promotion and development of international programs of research through mobility at various stages of research careers. The aim of TRAIN is to improve translational skills in the field of cancer by promoting a three-year international mobility program assigning a total of 51 fellowships subdivided into incoming, outgoing and reintegration fellowships.?The TRAIN proposal has been submitted in February 2009 to the European Commission in reply to the 2008 FP7-PEOPLE-COFUND call and has been successfully evaluated. TRAIN is addressed to postdoctoral scientists or scientists who have at least four years' full-time equivalent research experience and who wish to improve their careers spending one year abroad. The mobility program is open also to non-Italian experienced scientists wishing to spend one year in an Italian research center or private company. Part of the scheme is targeted to experienced Italian scientists who have completed at least three years of research in a foreign country and are interested in returning to Italy.?TRAIN is part of an overall Italian strategy outlined by the International Program of the Italian Cancer Network "Alleanza Contro il Cancro" to promote Italian participation in the building of the European Area for translational cancer research and to enhance the interaction between academy and industry.

Vascular Endothelial Growth Factor (VEGF) is the main player in angiogenesis. Because of its crucial role in this process, the study of the genetic factors controlling VEGF variability may be of particular interest for many angiogenesis-associated diseases. Although some polymorphisms in the VEGF gene have been associated with a susceptibility to several disorders, no genome-wide search on VEGF serum levels has been reported so far. We carried out a genome-wide linkage analysis in three isolated populations and we detected a strong linkage between VEGF serum levels and the 6p21.1 VEGF region in all samples. A new locus on chromosome 3p26.3 significantly linked to VEGF serum levels was also detected in a combined population sample. A sequencing of the gene followed by an association study identified three common single nucleotide polymorphisms (SNPs) influencing VEGF serum levels in one population (Campora), two already reported in the literature (rs3025039, rs25648) and one new signal (rs3025020). A fourth SNP (rs41282644) was found to affect VEGF serum levels in another population (Cardile). All the identified SNPs contribute to the related population linkages (35% of the linkage explained in Campora and 15% in Cardile). Interestingly, none of the SNPs influencing VEGF serum levels in one population was found to be associated in the two other populations. These results allow us to exclude the hypothesis that the common variants located in the exons, intron-exon junctions, promoter and regulative regions of the VEGF gene may have a causal effect on the VEGF variation. The data support the alternative hypothesis of a multiple rare variant model, possibly consisting in distinct variants in different populations, influencing VEGF serum levels.

Background: Type 2 diabetes (T2D) is associated with obesity and has been shown recently to be associated with tumors/cancer. HNF1-beta and JAZF1 genes are associated with T2D and prostate cancer. We have previously shown that CHOP 5'UTR-c.279T>C and +nt30C>T haplotype variants contribute to T2D. CHOP deficiency causes obesity in mice, thus CHOP gene variants may contribute to human obesity. Furthermore, CHOP mediates apoptosis and is implicated in cancer pathogenesis. Hence, we aimed at identifying any potential association of CHOP 5'UTR-c.279T>C and +nt30C>T genotypes and corresponding haplotypes with overweight condition/pre-obesity and tumors/cancer in an Italian dataset., Methods: We recruited from Italy 45 overweight subjects (body mass index (BMI) >or= 25) and 44 control subjects (BMI < 25) as well as 54 cases with at least one cancer or at least one tumor and 43 control subjects without tumors/cancer from the general population. We excluded allelic departure from Hardy-Weinberg equilibrium in cases and control subjects, separately., Results: We assessed the power to detect risk odds ratios by association tests in our datasets. We tested the hypothesis of association of CHOP 5'UTR-c.279T>C and +nt30C>T genotypes and haplotypes with tumors/cancer and, separately, with overweight condition. Both associations were not significant., Conclusion: From our study, we may conclude that CHOP 5'UTR-c.279T>C and +nt30C>T genotypes and corresponding haplotypes are not associated with tumors/cancer and pre-obesity. However, more studies are warranted to establish the role of CHOP variants in tumor/cancer predisposition and in overweight condition.

Background: Cell cycle checkpoint regulation is crucial for prevention of tumor in mammalian cells. Cyclin-dependant kinase 4 (CDK4) is important in cell cycle regulation, as it controls the G1-S phase of the cell cycle. CDK4 has potential mitogenic properties through phosphorylation of target proteins. We aimed at identifying a role of CDK4 IVS4-nt40 G-->A gene variant in benign and/or malignant tumors and in obesity-associated benign and/or malignant tumors in an Italian adult subject dataset., Methods: We recruited 263 unrelated Italian subjects: 106 subjects had at least one benign tumor and 46 subjects had at least one malignant tumor, while 116 subjects had at least two tumors and/or cancers. We collected BMI data for 90% of them: 186 subjects had a BMI>or=30 Kg/m2 and 52 subjects had a BMI >or= 30 Kg/m2. We performed statistical power calculations in our datasets. DNA samples were directly sequenced with specific primers for the CDK4 IVS4-nt40 G-->A variant. Genotype association tests with disease were performed., Results: In our study, no significant association of the CDK4 IVS4-nt40 AA genotype with cancer and/or tumors/cancer are/is detected. However, the CDK4 IVS4-nt40 AA genotype is significantly associated with cancer and tumors/cancer in obese patients., Conclusion: This finding is interesting since obesity is a risk factor for tumors and cancer. This study should prompt further work aiming at establishing the role of CDK4 in contributing to tumor/cancer genetic risk predisposition, as well as its role as a potentially effective therapeutic target gene for obesity-associated tumor/cancer management.

Aim of this work was to assess the predictive value of micronuclei (MN) frequency in peripheral blood lymphocytes (PBL) for the risk of cancer death in disease-free individuals. Blood samples from 1650 subjects selected from the general population of Pisa, Italy, were collected between June 1991 and November 1993. The follow-up until January 2005 recorded a total of 111 deaths (52 for cancer). MN frequency was assessed for 49 cancer cases and 101 matched controls. A significantly higher MN frequency was found in cancer cases (4.7+/-3.4 MN/1000 BN cells) versus controls (1.5+/-1.7; p<0.0001). Donors were stratified in two classes and multivariate logistic regression analysis confirmed that individuals with high MN frequency (>2.5 MN/1000 BN cells) had a significantly increased risk of cancer death (OR=10.7; 95% CI=4.6-24.9; p<0.0001) when compared to individuals with low MN frequency (

Background: Asbestos is the principal etiological factor of malignant mesothelioma (MM), accounting for more than 80% of all tumor cases. However, other co-factors, including genetic susceptibility may play a role in the etiology of this disease, possibly modulating the effects of exposure to asbestos and other carcinogenic mineral fibers. The frequent report of familial clustering was the first indication supporting the involvement of genetic factors. Therefore, we performed an extensive literature search to evaluate existing studies reporting familial cases of MM., Methods: Published reports addressing the issue of familial susceptibility to MM have been searched through PubMed using keywords and free text tools. Eighty-two citations were retrieved and 20 of them actually reported a familial cluster of MM. Three more articles were identified through the references. The probability that the observed familial clusters of mesothelioma could have randomly occurred in exposed families was evaluated with the Family History Score Zi (FHSi)., Results: The result of this analysis suggested that clustering of MM cases in families exposed to asbestos may be explained with the additional contribution of other familial factors. The FHSi allowed to reject the hypothesis of random occurrence of these clusters with a probability of a first type error ranging between 1 per cent and 1 per billion., Conclusions: The evaluation of the published materials supports the hypothesis that - although familial clustering of MM is largely attributable to shared asbestos exposure - the additional contribution of factors dealing with genetic susceptibility may play a role in the etiology of MM.

Background: The Italian external quality assessment scheme in classical cytogenetics was started in 2001 as an activity funded by the National Health System and coordinated by the Italian Public Institute of Health., Objectives: The aim of our work is to present data from the first 4 years of activity, 2001-2004., Methods: Italian cytogenetics public laboratories were enrolled on a voluntary basis, and this nationwide program covered prenatal, postnatal and oncological diagnosis. The scheme is annual and retrospective; a panel of experts reviewed the quality of images and reports in order to assess technical, analytical and interpretative performance., Results: Over the 4-year period, the number of participating laboratories increased: from 36 in 2001, 46 in 2002, 49 in 2003 to 51 in 2004. The overall technical performance was satisfactory. Inadequacy or lack of information in reporting was the most frequent analytical inaccuracy identified in all parts of the scheme. However, the percentage of complete reports increased significantly during the period: by 36% in postnatal diagnosis between 2001 and 2004 (p < 0.001) and by 42% in oncological diagnosis between 2002 and 2004 (p = 0.003)., Conclusions: Our experience reveals that participation in external quality assessment programs has significant advantages, helping to standardize and to assure quality in cytogenetic testing., ((c) 2008 S. Karger AG, Basel)

This population-based study (the largest on this issue conducted in Southern Europe) has examined mortality among the parents of 2622 children diagnosed with cancer in Piedmont during 1967-1994. Parents were followed up from the date of the index child's birth until the end of 2000, yielding a total of 118 090.7 person-years of observation. Standardized mortality ratios (SMRs) were estimated using mortality rates for the whole population of Piedmont as the reference. Among mothers, total mortality was similar to that expected [SMR 1.02, 95% confidence interval (CI) 0.85-1.23, 117 cases]. A reduced risk of mortality was seen in fathers (SMR 0.91, 95% CI 0.81-1.02, 293 cases); this was largely due to causes other than cancer and the reduction in risk disappeared after the index child's death (SMR 0.98, 95% CI 0.84-1.15, 168 cases). Deaths from cancers of the lymphohaematopoietic system were in excess among mothers (SMR=2.13, 95% CI 1.02-3.92, 10 cases) and breast cancer deaths were in excess specifically among mothers of leukaemic children (SMR 2.32, 95% CI 1.16-4.14, 11 cases). Three mothers dying with breast cancer had index children who had been diagnosed with a bone sarcoma. Parental cancer of the respiratory tract was significantly associated with both tumours of the central nervous system and Hodgkin's lymphoma in the index child. The excess risks identified here may be due to genetic factors or due to parental psychological stress consequent to cancer in a child that may lead to increased mortality either through the direct effects of stress or through consequent changes in lifestyle.

Consumption of dairy products seems to increase the risk of cancer at several sites, while intake of cruciferous vegetables could have protective effects. However, these dietary intakes are subject to measurement error, and associations with cancer could be due to confounders. Mendelian randomization has been suggested as a way to overcome confounding by exploiting the random allocation of alleles from parents to offspring. In mid-2006, the authors conducted a study of allele frequencies for the lactase (LCT) and taste receptor, type 2, member 38 (TAS2R38) genes, including 634 volunteers recruited (1992-1998) from the Italian branch of the European Prospective Investigation into Cancer and Nutrition. The authors hypothesized that there would be a lower milk intake among carriers of the LCT CC genotype and a different intake of cruciferous vegetables among carriers of the TAS2R38 variant. Overall, the frequency of the LCT T allele was higher in northern Italy than in southern Italy. Food intake was associated with gene variants. An association was evident for ice cream and LCT variants (p = 0.004); less so for milk intake. In addition, the TAS2R38 variant showed a geographic gradient and an association with cruciferous vegetable intake. These results suggest that the LCT and TAS2R38 variants are good candidates for Mendelian randomization studies of cancer and other health outcomes.

Objective: Our aim was to investigate the reliability of the information on family history of cancer in first-degree relatives in a hospital-based case-control study., Study Design and Setting: We re-interviewed at home 294 controls of an Italian hospital-based case-control study on digestive tract neoplasms using the same questionnaire and compared the responses reported by these patients in the two settings., Results: A satisfactory agreement between the two interviews was reported for family history of any cancer (kappa=0.7) and of cancers of the digestive tract (kappa=0.8). The agreement was apparently higher for esophageal and stomach cancers (kappa>0.8) than for intestinal cancers (kappa=0.6) and lower for lung cancer (kappa=0.5). We found a systematic tendency to report a history of cancer more frequently in the hospital setting than in the home setting., Conclusion: The present study showed a good reliability of data on family history of all cancers, including cancers of the digestive tract, provided by hospital controls through a structured interview-administered questionnaire. It suggests, moreover, that controls in the hospital setting tend to recall more often, and presumably more completely, a family history of cancer.

Frequent consumption of fresh fruit and vegetables, and polymorphisms in the detoxifying enzyme glutathione S-transferase M1 (GSTM1) and other metabolic genes have been shown to modulate cancer risk at some sites. We have shown recently that DNA adducts, a reliable indicator of genotoxic damage and, possibly, of cancer risk, are modulated by plasma levels of selected micronutrients. Here we further investigate the association between DNA adduct levels and consumption of major food groups and foods, and the estimated dietary intake of nutrients, taking into account the possible modifying effect of metabolic polymorphisms, in a larger sample of 634 healthy adults enrolled in a prospective study in Italy. DNA adducts and five polymorphic metabolic genotypes (GSTM1, GSTT1, NAT2, CYP1A1 and MTHFR) were determined in peripheral leukocytes by using 32P-postlabeling technique and PCR methods. DNA bulky adducts (mean: 7.82 +/- 0.40/10(9) nt) were detected in 482/634 samples (76.0%). Overall, DNA adduct levels were significantly and inversely associated with the intake of raw leafy vegetables (P = 0.02), non-citrus fruits (P = 0.04), potassium (P = 0.01) and beta-carotene (P = 0.05). No association was evident with the five genotypes. Stratification by GSTM1 genotype showed strong inverse associations of DNA adduct levels with increasing consumption of all vegetables combined (P = 0.04), leafy vegetables (P = 0.004), raw leafy vegetables (P = 0.002) and fish (P = 0.03) among 307 GSTM1-null subjects; strong inverse associations also emerged with estimated dietary intakes of beta-carotene (P = 0.004), vitamin E (P = 0.004), niacin (P = 0.02) and potassium (P = 0.01). In contrast, no association emerged among 295 subjects with a GSTM1-wild genotype. Overall, statistically significant interactions in predicting DNA adduct levels were observed between the GSTM1-null genotype and consumption of leafy vegetables (P = 0.01), white meat (P = 0.04), and intake of vitamin C (P = 0.04), vitamin E (P = 0.05) and beta-carotene (P = 0.02). Our results suggest that the role of a diet rich in antioxidants in preventing or reducing DNA adduct formation is restricted to subjects lacking the detoxifying activity of GSTM1 isoenzyme (approximately 50% of the general population).

The frequency of cells with structural chromosomal aberrations (CAs) in peripheral blood lymphocytes is the first genotoxicity biomarker that has shown an association with cancer risk. CAs are usually divided into chromosome-type (CSAs) and chromatid-type aberrations (CTAs), with different mechanisms of formation. From a mechanistic point of view, it is of interest to clarify whether the cancer predictivity of CAs is different with respect to CSAs and CTAs. We report here cancer risk for cytogenetically tested, healthy subjects with respect to frequency of CAs, CSAs, and CTAs in peripheral blood lymphocytes, using Nordic (1981 subjects with CA data, 1871 subjects with CSA/CTA data) and Italian (1573 subjects with CA data, 877 subjects with CTA/CSA data) cohorts, with a median follow-up of 17 years. High levels of CAs at test were clearly associated with increased total cancer incidence in the Nordic cohorts and increased total cancer mortality in the Italian cohort. In the Nordic cohorts, significantly elevated cancer risks were observed for subjects with both high CSAs and high CTAs at test, and these variables showed equally strong cancer predictivity. The results of the Italian cohort did not indicate any clear-cut difference in cancer predictivity between the CSA and CTA biomarkers. There was no significant effect modification by age at test, gender, country, or time since test. The results suggest that both DNA double-strand breaks and other initial DNA lesions responsible for CSAs and CTAs are associated with cancer risk.

To determine whether the occurrence of first and second primary malignancies in first-degree relatives of cancer patients aged 0-25 years (probands) differed from that in the general population, a cohort study was carried out on 860 relatives of 265 probands living in the province of Trieste, Italy. During the follow-up period (median duration = 28 years, 25th-75th percentile = 20-34), the relatives developed 103 first primary cancers vs. 88.9 expected for a standardized incidence ratio (SIR) of 1.2 (p = 0.2). Significantly elevated risks were found for melanoma in the parents of probands aged 15-25 years with melanoma (SIR = 15.0, p = 0.002), for hemolymphatic malignancies in the fathers of probands aged 0-14 years with brain tumors (SIR = 13.3, p = 0.0005) and for hemolymphatic cancers in relatives as a whole of probands aged 15-25 years with lymphomas (SIR = 4.5, p = 0.01). During the follow-up period, 7 relatives with a first primary cancer had a subsequent malignancy vs. 4.2 expected for an SIR of 1.7 (p = 0.3). Our results indicate that young cancer patients per se should not to be considered as a factor that usually increases the risk of developing malignant tumors among their first-degree relatives, except when a known cancer family syndrome or predisposition is recognized., (Copyright 2003 Wiley-Liss, Inc.)

Inherited single nucleotide polymorphisms (SNPs) of DNA repair genes may contribute to variations in DNA repair capacity and susceptibility to cancer. We investigated the role of SNPs in three DNA repair genes (X-ray repair cross-complementing group 1-Arg399Gln, exon 10; X-ray repair cross-complementing group 3-Thr241Met, exon 7; and xeroderma pigmentosum-D-Lys751Gln, exon 23) and their combination, in modulating the levels of "bulky" DNA adducts in a population sample of 628 Italian healthy individuals belonging to the prospective European project "European Prospective Investigation into Cancer and Nutrition." DNA-adduct levels were measured as relative adduct level per 10(9) nucleotides by (32)P-post DNA labeling assay in WBCs from peripheral blood. Genotyping was performed by PCR-RFLP analysis or primer extension/denaturing high-performance liquid chromatography technique. We found a dose-response relationship between the number of at-risk alleles and levels of adducts (P = 0.0046). Individuals with at least three variant alleles had a statistically significant odds ratio (OR) for being in the highest tertile of adducts compared with those with undetectable adducts [three alleles, adjusted OR = 5.07, 95% confidence interval (CI) = 1.29-19.9; four alleles, adjusted OR = 5.03, 95% CI = 1.18-21.45; five alleles, adjusted OR = 7.65, 95% CI = 0.94-62.2]. Our study suggests that the combined effect of multiple variant alleles may be more important than the investigation of single SNP in modulating DNA repair capacity.

An increased risk of cancer in healthy individuals with high levels of chromosomal aberrations (CAs) in peripheral blood lymphocytes has been described in recent epidemiological studies. This association did not appear to be modified by sex, age, country, or time since CA test, whereas the role played by exposure to carcinogens is still uncertain because of the requisite information concerning occupation and lifestyle was lacking. We evaluated in the present study whether CAs predicted cancer because they were the result of past exposure to carcinogens or because they were an intermediate end point in the pathway leading to disease. A nested case-control study was performed on 93 incident cancer cases and 62 deceased cancer cases coming from two prospective cohort studies performed in Nordic countries (Denmark, Finland, Norway, and Sweden) and Italy. For each case, four controls matched by country, sex, year of birth, and year of CA test were randomly selected. Occupational exposure and smoking habit were assessed by a collaborative group of occupational hygienists. Logistic regression models indicated a statistically significant increase in risk for subjects with a high level of CAs compared to those with a low level in the Nordic cohort (odds ratio, 2.35; 95% confidence interval, 1.31-4.23) and in the Italian cohort (odds ratio, 2.66; 95% confidence interval, 1.26-5.62). These estimates were not affected by the inclusion of occupational exposure level and smoking habit in the regression model. The risk for high versus low levels of CAs was similar in subjects heavily exposed to carcinogens and in those who had never, to their knowledge, been exposed to any major carcinogenic agent during their lifetime, supporting the idea that chromosome damage itself is involved in the pathway to cancer. The results have important ramifications for the understanding of the role played by sporadic chromosome damage for the origin of neoplasia-associated CAs.

Aims and Background: A cohort study was conducted in order to measure cause-specific mortality among parents of children recorded in the Childhood Cancer Registry of Piedmont. It is the first study carried out on the subject in southern Europe., Methods and Study Design: The study comprised the 740 children resident in Turin and in whom a cancer had been diagnosed in the period 1967-1991. Nominal data were obtained for 723 fathers and 733 mothers. At the end of the follow-up in 1995, 645 fathers were alive, 68 dead and 10 untraceable. Corresponding figures for mothers were 700, 28 and 5. Cause of death was known for 91 of 96 parents., Results: The period of observation of parents started on the birth of the index child, however mortality analyses were restricted to the period after 1965 because of limited availability of local reference rates. Total mortality was lower than expected among fathers (66 observed deaths vs 88.2 expected, P <0.05) and mothers (28 vs 31.4). Fathers showed deficits (not statistically significant) of lung neoplasms (4 vs 9.9), cardiovascular diseases (18 vs 27.1) and hepatic cirrhosis (2 vs 6.6). No statistically significant variations in mortality were observed with time from diagnosis or according to life status of the children. No cancer deaths occurred among the mothers of sarcoma cases whereas 1.9 were expected., Conclusions: The data do not indicate any increase in mortality from cancer or other causes end, on the contrary, show a reduction in mortality which was more evident for the causes related to life style.

Chromosomal aberrations (CAs), sister chromatid exchanges (SCEs), and micronuclei (MN) in peripheral blood lymphocytes have for decades been used as cytogenetic biomarkers to survey genotoxic risks in the work environment. The conceptual basis for this application has been the idea that increased cytogenetic damage reflects an enhanced cancer risk. Nordic and Italian cohorts have been established to evaluate this hypothesis, and analyses presented previously have shown a positive trend between CA frequency and increased cancer risk. We now report on a pooled analysis of updated data for 3541 subjects examined for CAs, 2703 for SCEs, and 1496 for MN. To standardize for interlaboratory variation, the results for the various cytogenetic end points were trichotomized on the basis of the absolute value distribution within each laboratory as "low" (1-33 percentile), "medium" (34-66 percentile), or "high" (67-100 percentile). In the Nordic cohort, there was an elevated standardized incidence ratio (SMR) for all cancer among subjects with high CA frequency [1.53; 95% confidence interval (CI), 1.13-2.05] but not for those with medium or low CA frequency. In the Italian cohort, a SMR in cancer of 2.01 (95% CI, 1.35-2.89) was obtained for those with a high CA frequency level, whereas the SMRs for those with medium or low did not noticeably differ from unity. Cox's proportional hazards models gave no evidence that the effect of CAs on total cancer incidence/mortality was modified by gender, age at test, or time since test. No association was seen between the SCEs or the MN frequencies and subsequent cancer incidence/mortality. The present study further supports our previous observation on the cancer predictivity of the CA biomarker, which seems to be independent of age at test, gender, and time since test. The risk patterns were similar within each national cohort. This result suggests that the frequency of CAs in peripheral blood lymphocytes is a relevant biomarker for cancer risk in humans, reflecting either early biological effects of genotoxic carcinogens or individual cancer susceptibility.

Cytogenetic assays in peripheral blood lymphocytes (PBL) have been used extensively in the last decades to survey human exposure to genotoxic agents. The conceptual basis for this approach has been the hypothesis that the extent of genetic damage in PBL reflects critical events for carcinogenic processes in target tissues. The predictive value of these tests for subsequent cancer risk has been recently evaluated by two cohort studies of cancer mortality and incidence carried out in Italy and in five North European countries. In this paper we report the update of both cohorts. In the new follow-up, a total of 64 cancer deaths out of 2019 subjects in the Italian cohort and 127 new cases of cancer out of 3182 subjects in the Nordic cohort were observed. The cytogenetic endpoints studied were CA (chromosomal aberrations), SCE (sister chromatid exchanges) and MN (micronuclei). In order to take into account the interlaboratory variation of absolute values, the results were trichotomized within each laboratory into three strata: low (1-33 percentile), medium (34-66 percentile), or high (67-100 percentile). The association between chromosomal damage and cancer risk was evaluated through SMR (standardized mortality ratio) for Italy and SIR (standardized incidence ratio) for the Nordic countries. National mortality/incidence cancer rates (age, sex and calendar-year specific) were used as reference. A linear trend of SMRs and SIRs according to CA level was found in both cohorts for the "All Cancers" cause (p < 0.01). In the Italian cohort it was also possible to analyze some specific cancer sites: a significant increase of SMR among subjects with a high level of CA with respect to the general population was found for lung cancers and lymphatic and hematopoietic tissue cancers. Contrariwise, no association between cancer mortality/incidence and SCE or MN frequency was observed. Findings from this study support the existence of an association between CA frequency and cancer risk.

We conducted a population-based cohort study in the province of Trieste, Italy, to assess whether the first-degree relatives of children with malignancies had an increased risk of cancer compared with the general population. We examined cancers occurring in all first-degree relatives of children who experienced malignancies under the age of 15 years between 1971 and 1993 (probands). A cohort of the 394 relatives of the 125 probands contributed 7,939 person-years of observation. Among the relatives as a whole, we found a statistically significant increased risk of developing all malignancies except non-melanoma skin carcinoma (21 observed relatives with cancer and 12.46 expected, for a standardized incidence ratio [SIR] of 1.69), of developing breast cancer (SIR = 3.09) and of developing haemolymphatic system neoplasms (SIR = 4.03). This was mainly due to the excess cancer risk in the relatives of probands with intracranial tumours, who showed a significant 3.1-fold risk for developing all cancers but non-melanoma skin tumours. Our findings and the previously reported steep rise in the incidence of childhood brain tumours in our area may imply that not only genetic factors but also shared environmental agents might be involved in the observed aggregation of cancer in the families of probands with intracranial tumours.

To investigate the existence of an association between the frequency of chromosome aberrations (CA) in non-target tissues and cancer risk, a historical cohort study was carried out in a group of 1455 subjects screened for CA over the last 20 years in Italy. Statistically significant increases in standardized mortality ratio (SMR) for all cancers were found in subjects with medium and high levels of CA in peripheral blood lymphocytes (SMR = 178.5 and SMR = 182.0, respectively) and in subjects with high levels of CA for respiratory tract cancers (SMR = 250.8) and lymphatic and hematopoietic tissue neoplasms (SMR = 548.8). Significant trends in the SMRs were observed for these latter causes of death.

In order to study the familial aggregation of colorectal cancer we investigated the pedigrees of the patients with adenocarcinoma of the large bowel who underwent a surgical operation between november 1990 and october 1992 at the Istituto di Chirurgia Generale e Sperimentale Of Pisa University. For each proband, information was obtained on his/her four grandparents and all their second generation descendants. The final sample included 99 probands and 1455 relatives. Only two cases with diagnosis of familial adenomatous polyposis were excluded. As a control group, we applied the same methodology to the spouses of probands, collecting in the end a sample of 72 families including 1163 individuals. The frequency of both colorectal and extracolonic cancer was higher in the relatives of cases than in the control group, for all the relationships. Among the first degree relatives, the empirical risk of colorectal cancer was 1/30 among the case families and 1/139 among the control families, for a 4.6 fold increase in risk. For cancers at all sites (colorectal excluded), the corresponding risk were 1/8 and 1/12. We computed the posterior probability of dying from cancer for a random individual, given the known affection status of one or more of his/her relatives of specified relationship. For an individual with one first degree relative affected by colorectal cancer the posterior risk of the same tumor was 1/15, compared to a value of 1/70 for the entire control population. Considering all cancers, colorectal excluded, we obtained the result that for a person with at least three affected relatives, one of first, one of second and one of third degree, the probability of dying from colorectal cancer was 6%. The distribution of the number of affected individuals for kindred was highly skewed, with a few families responsible of a large part of the observed familial aggregation. This was true for both the cases of colorectal cancer and for all-site cancer. However, no family fulfilled the criterion of hereditary nonpolyposis colorectal cancer (Lynch syndromes I or II).

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant disorder characterized by susceptibility to large-bowel cancer, frequently with early onset and localized in the right colon. Several tumours of other sites may also occur with increased frequency in these families. During the period 1984-1989, 28 families with HNPCC were identified in our Health Care District through a population-based colorectal cancer registry. Moreover, 61 additional families were selected and classified as having "suspected" HNPCC. The objective of the present study is to report the occurrence of new cases of cancer in the 5- to 6-year follow-up of individuals at risk of tumour development in either HNPCC or "suspected" families. There were 374 family members at risk in HNPCC and 468 in "suspected" families, contributing, respectively, 2,377 and 2,712 persons/year at risk. Thirty-four new tumours developed among HNPCC family members vs. 29.3 expected; however, the occurrence of colorectal cancer in this group was significantly higher than expected, and this excess was particularly evident in the age-groups 41-50 and 51-60. In "suspected" HNPCC, 38 new tumours developed vs. 24.5 expected; at variance with the other group, besides colorectal neoplasms, lung, liver and brain tumours also occurred significantly in excess. Moreover, the increased risk was uniformly distributed among different age-groups. In conclusion, HNPCC family members are at increased risk of developing colorectal cancer, with an earlier onset than the general population; in contrast, high-risk individuals in "suspected" HNPCC families seem to be prone to a broader neoplastic spectrum, and risk of tumours does not seem to be limited to any particular age-group.

Study Objective: The aim was to link individual demographic and medical records into sibships to obtain the sibling distribution of biopsies and cancers, and thereby calculate heritability and recurrence risks in families, thus aiding early diagnosis and prevention of cancers., Design: The 157,823 individual records of the inhabitants of the town of Ferrara in Italy were automatically linked into 106,821 sibships. A 10% sample (10,842 sibships) was then extracted from the distribution of sibships and tabulated, for linkage to medical records., Patients: The biopsy records at the Institute of Pathological Anatomy of the University of Ferrara were manually linked to cancer records and then to sibships. It was possible to construct the distribution of 2062 biopsies and of 829 cancers in sibships., Results: From the distribution of biopsies and tumours in sibships, it was possible to estimate the incidence of tumours in the population (0.052) and in siblings of affected (0.083), and to apply to such distributions current methods for the estimate of heritability (h2 = 0.246) and of recurrence risks of tumours in sibships, age independent., Conclusions: The study shows that the procedure resulting in the estimation of incidences and recurrence risks for tumours could be completely automated, and extended to whole populations and homogeneous subgroups in post industrial cultures.