However, data from EUROCARE and recent trends in cancer incidence of some tumour types, clearly shown room for improvement in prevention and control of cancer in Spain (Borras et al, Ann Oncol 2010). This improved effort should include as a cornerstone research on the key issues relevant in cancer epidemiology and prevention as well as in health services research. Priorities should be focused on five main research areas:

• Impact of cancer: Population based cancer registries covers only 20% of the Spanish population nowadays. Then, there is a clear need of statistical methodologies aimed at projecting the cancer cases from the existing registries as well as assessing the future impact of cancer in our country. Specific statistical tools are required using a Bayesian perspective. Also, analysis of the existing cancer registries, although with a partial coverage, could be extremely useful in order to assess the future impact of cancer (Cleries, 2012). The groups in this program cover three cancer registries as well as the coordination of the unique National Registry of Childhood Tumours. Finally, survival and mortality trends could be analyzed, as it has been done, in order to provide policy maker with updated trends to set priorities for prevention and control of cancer.
• Genetic and molecular epidemiology of cancer. During the last decades, many genes have been associated with cancer susceptibility. Several groups from the program carry-out outstanding research on the identification of new genetic variants through both candidates and agnostic approaches, such as genome-wide association studies (GWAS). In this regard, assessing high-penetrance alleles in relatives with a family history of cancer provides clues of altered genetic pathways in a particular cancer. Furthermore, there are established evidences of the importance of gene-environmental interactions in cancer aetiology. This field is now being extended through the inclusion of epigenomics and metabolomics markers towards a better knowledge of the mechanisms of carcinogenesis, identification of new molecular biomarkers for risk, diagnosis, prognosis, and prediction of response to treatment Bochud and Malats, 2012; Gutierrez et al, 2012).
• Infections and cancer. Several infectious agents, mainly viruses and bacteria, are considered to be causes of specific cancers in humans, the population attributable fraction being of about 16.1 % of new cancer cases worldwide (de Martel, 2008). The groups included in the Program cover the three most important agents: human papillomaviruses (Bosch, 2011), Helicobacter pylori, and hepatitis B and C viruses, aimed of application of existing public health methods for infection prevention, such as vaccination, development of new vaccines, identification of virulent factors and interaction with host factors and inflammatory response.
• Life style and environmental factors and cancer risk. Diet, smoking, alcohol and obesity are the most important contributing factors to cancer risk. The fact that between 80 to 90 % of all cancer cases are due to lifestyle and environmental `modifiable' factors provides major opportunities for preventing cancer. Results based on large epidemiological studies conducted by the groups included in this program, among others, using questionnaires and biological markers of exposure, contributed to scientific evidence for appropriate public health prevention activities aimed at reducing the global cancer burden.
• Cancer prevention and control: Relevant scientific knowledge susceptible to be applied in prevention of cancer would be useless if not applied. Thus the identification of barriers, coverage and factors associated with not effective application of the known as effective strategies for cancer prevention, including screening and early detection, should be a key target in research. The same could be said for the needed assessment of the gap between what it is known to be effective therapy and what it is applied in clinical practice through the so called patterns of cancer care studies. All this knowledge should be also made available in a usable way to health policy makers in order to be included in cancer control strategies, if feasible.

These areas of research and intervention have been selected according to the experience in research of the groups included in this program as well as the priorities that could be reasonably achieved in the framework of this RTICC time plan.

The global objectives of this program are fourfold:

1. To improve knowledge on the frequency and the geographical and demographic distribution, and to assess the incidence, survival and mortality trends of the most important tumours in Spain, with special focus on lung, colorectal and breast as well as childhood cancer.
2. To establish a multidisciplinary platform supporting a) the assessment of the contribution of inherited genetic and epigenetic factors in the aetiology of specific cancer sites; b) the identification of new molecular biomarkers of risk, diagnosis, prognosis, and prediction of response to treatment for specific cancers; and c) omics data integration in the risk and prognosis models of cancer.
3. To identify nutritional, lifestyle, infectious, and environmental risk factors associated with the major cancer types, as well as their interaction with genetic susceptibility with special focus on gastrointestinal, gynaecologic and urogenital tumours.
4. To evaluate the feasibility and implementation of preventive and treatment strategies, including primary prevention, screening and patterns of care in breast, lung, sarcoma and childhood cancers.

Globally, the groups involved in this program have shown a relevant record in excellence of research as measured by publications in international journal of high impact, citations and competitive grants, as summarized in the previous section. Finally, this program represents an extension of the epidemiology program in the previous Network of the IS Carlos III which was very well evaluated by external reviewers, indicating the quality of the research carried out.

It is well known that the meaning and relevance of innovation and transfer of technology in the field of epidemiology and prevention of cancer is different of that of laboratory research. Even though, some groups in this program have been active in innovation as shown by different indicators such as the work done in designing innovative strategies for cancer prevention like the case of HPV vaccination, identification of new biomarkers which have allowed for patents approved or the public private partnership in several activities. The groups of C. Lazaro and G. Capellá have a long-time commitment to innovation in the field of molecular diagnosis of cancer where new advances in the analysis of the tumors are being streamed into the clinical routine. The use of screening techniques such as hypermethylation of MLH1 in tumor biopsies (Gausachs et al, 2012) or functional analysis of variants of unknown significance (VUS) (Borras et al, 2012) is recent examples. Currently, they are implementing the high-throughput next generation sequencing in the routine clinical setting with promising results.

The group of G Capellá filed a patent on a panel of methylation markers for early noninvasive diagnosis of colorectal cancer in stool DNA. The validation of this marker is just finished in the diagnostic setting and in the evaluation of risk of dysplasia in high-risk ulcerative colitis patients.

The "Genetic Susceptibility to Cancer" group is very active in setting up new workflows to improve genetic diagnosis. Currently the group is implementing different Next Generation Sequencing approaches with the aim of developing cost-effective algorithms for genetic testing in the context of hereditary cancer. Now two different strategies are being developed, one based in amplification by PCR of the gene/s of interest, and the other aimed to tackle all genes involved in hereditary cancer at the same time by using a liquid capture strategy. The implementation of these techniques is paramount both for diagnosis and research purposes and these approaches will be shared by the different groups of the programs.

Infections and cancer group: HPV tests for screening and research purposes. The group has 1) Done exercises on accreditation and validation of different HPV detection tests for use in the context of screening programs. 2) Created the Infections and cancer laboratory at ICO to train technicians in the HPV detection methods and opened a PhD research program and 3) Organized an international training program for PhD students to exchange training periods with major reference laboratories in the world.

Cancer is a group of complex diseases, associated with multiple life styles, environmental exposures, genetic and epigenetic factors. A better understanding of the etiological factors and the role of host susceptibility factors and the mechanisms of carcinogenesis will provide the clues for the identification of reliable biomarkers for early detection and methods of primary prevention. This endeavour will require an innovative approach and multidisciplinary teams. Groups included in the Program of Cancer Epidemiology and Prevention are integrated by physicians, epidemiologists, molecular and genetic biologists, nutritionists, statisticians, bioinformatics, psychologists, nurses, and public health specialist. This means that we are covering all the different backgrounds and skills needed for an integrative approach between groups for each of the main work packages, favouring and promoting positive synergies among them. Also, the fact that this program is covering a broad perspective of knowledge, from genetic epidemiology to cancer policy making, by focusing on epidemiological analytical skills, population based view of cancer prevention and control could result in a cross fertilization that will be able to produce a significant impact on cancer through the incorporation of scientific based knowledge in epidemiology. Finally, the past experience of cooperation between many of the researches included in this program, as shown in the previous RTICCC were several of the groups involved were cooperating successfully, could provide a further reassurance of the future prospect of the increased synergy would continue take place.

The coverage of most relevant and up to date research approaches in cancer epidemiology are covered in this program by the research groups, from genetic and molecular epidemiology, critical causal determinants of some cancer types such as infectious and environmental factors, as well as primary prevention, screening and health services related determinants of effective cancer care. The publications, research grants and involvement in different international collaborations show that the research experience of the groups is also a critical component of the epidemiological community in cancer.

Management of the program will be assured by the coordinator of the program, Dr. J.M. Borras. In addition, he will be member of the executive board of the RTICC. The leaders of each WP will support the management of the program assuring the internal organization of the different researchers involved in each WP from groups. The PI of each group involved in this program will be incorporated in the management structure, through an executive board, that will coordinate the different objectives, assessing compliance with deliverables. This Executive board will meet yearly taking advantage of the annual meeting of the RTICC. In summary, tasks and responsibilities of the coordinator are: To assure integration of the WP’s and to supervise the different activities of the WP’s, jointly with the executive board and WP’s leaders and communication with the RTICC coordinator and other programs.

The executive board should undertake an annual review of the activities of the WP’s and the compliance of the workplan.

Considering the number of groups, the past experience in cooperation among themselves as well as the workplan, this structure is considered sufficiently easy to manage.

Added value of the research groups from the cooperative structure:

• In the WP1, Descriptive Epidemiology, the group led by J.M. Borras will provide its large experience in the assessment of the impact of cancer using data from population cancer registries in Spain. The group led by F.X. Bosch will provide their expertise in monitoring the incidence of cancer and temporal trends and also about the use of innovative techniques for estimation of missing data and to predict cancer incidence in populations without cancer registries.
• In the WP2, Genetic and Molecular Epidemiology, the group led by N. Malats will provide its experience in the identification of genetic susceptibility factors and gene*gene and gene*environmental interaction involved in cancer development and progression as well as their expertise in integrating epidemiological, metabolomics, epigenetics, genomics, and clinical data. The group led by CA Gonzalez will provide their experience in the identification of genetic susceptibility factors using both candidate gene approach and genome wide analysis, on analysis of gene expression and functional studies to characterize causative variants. In the molecular field will provide their expertise in studies on DNA adducts and biomarkers of exposure. The expertise of F.X. Real group will contribute to identify new mechanisms of disease and new markers of potential clinical and epidemiological relevance. The groups led by C. Lazaro and G. Capella will provide their experience in the assessment of the genetic bases of susceptibility to cancer, the molecular bases of the functional impact of genetic susceptibility to cancer and the molecular pathogenesis of both breast and colorectal hereditary cancer. The current work of these groups in the identification of novel cancer genes and variants will enrich the work done at population level where new hypothesis will be tested. The group led by Juan C. Lacal will provides to the epidemiology program ample experience in all biochemical, molecular and cell biology approaches that complement the expertise of the other groups involved. The group led by F.X. Bosch will provide their expertise in molecular studies addressed to assess the connection between the cell cycle of tumour cells and life cycle of the infectious agents and identification of new DNA viruses in human and animal tumor samples.
• WP3 will continue the research activities undertaken in the HPV associate with different types of cancer with special emphasis in the analysis of the risks associated with head and neck cancers. Also, the impact of different vaccination strategies in the future trends of related cancers will be monitored thanks to the expertise of the group of F.X. Bosch and J. M. Borras.
• At the WP4 of Life style and Environmental factors, the groups led by N. Malats, F.X. Bosch and C.A. Gonzalez will provide their large experience in multicentric epidemiological case-control and cohort studies addressed to the identification and quantification of dietary, life style, environmental factors and biologic agents causally related with several cancer sites (cervix, oral cavity, oesophagus, pancreas, stomach, lung, breast, bladder), using traditional epidemiological questionnaires, as well as biomarkers of exposure. The group led by G. Capella will continue the fruitful cooperation with C.A. Gonzalez in the field of the molecular epidemiology of gastric cancer.
• At the WP 5, Cancer Prevention and Control, the group led by JM Borras will provide its experience in assessment of colorectal cancer screening and, together with the group of J Zulueta, will assess the feasibility of lung cancer screening, as well as on the assessment of new policy in cancer care and the impact of tobacco control. The group led by F.X. Bosch will provide their expertise in developing and monitoring the development of vaccines for prevention of cervical cancer and about the assessment of novel high performance HPV s detection and screening program for early detection of HPV infection. The group lead by J. Zulueta provides ample experience in lung cancer screening using LDCT, both clinically and from a research point of view. Members of this group have collaborated in this project since 2000, thus providing the needed experience to coordinate a research program on lung cancer screening within RTICC. The group led by C. Lazaro and G. Capella will provide their experience in early detection of hereditary cancer syndromes with special interest in the cost-effectiveness evaluation of their activities and the analysis of their impact on prevention. Finally, the group led by C.A. González will provide their expertise for promoting intervention studies, modifying life style habits for the reduction of breast cancer recurrence.

The impact of this program is expected at five different levels:

1. Improved knowledge of the cancer epidemiology of our country. The most relevant contribution with high expected impact will be on childhood cancer, prostate cancer, gastrointestinal cancer, bladder cancer and certain subtypes ofsarcomas.
2. Contribution to the progress in the knowledge of the genetic, environmental and lifestyle factors associated with some of the most relevant types of cancer. The most relevant contribution with high expected impact will be on head and neck cancer, gastric and oesophageal cancer, colorectal cancer, pancreas cancer, ovarian and endometrial cancer, breast cancer and bladder cancer.
3. Contribution to the progress in the knowledge of molecular mechanisms of carcinogenesis, progression and prognostic mainly in relation with gastric and oesophageal cancer, colorectal cancer, pancreas cancer, lung cancer, breast cancer and bladder cancer.
4. Contribution to the scientific progress in the identification of biomarkers for early diagnoses, progression and prognostic of these different tumours.
5. Assessment of the impact of preventive measures for cancer (both in primary prevention and screening) as well as the analysis if determinants of utilization of preventive and cancer care services. The most relevant contribution with high expected impact will be on cervical cancer, colorectal cancer, breast cancer, lung cancer and prostate cancer.

Dissemination of this research will be made through the classical strategies based on papers published in the international literature, either in high impact general cancer or in cancer epidemiology and prevention journals. Also, researchers of this program will be very active with presentations of the results of the projects at scientific meetings, both international and national. However, all this knowledge in order to have an impact on the preventive and clinical practice requires close relationship with the relevant cancer policy makers as well as the advisory boards with influence on funding of research and innovation. The position of several researchers from the groups involved in this program would be very important in order to promote a rapid transfer of the knowledge to the key decision makers to set priorities both in research and in cancer prevention and control.

As indicator for external evaluation, we suggest: Annual report on the activities of the program. Articles co-authored by components of two or more groups of the program. Evaluable articles should acknowledge specifically funding from the RTICC. Collaborative research proposals granted to two or groups of the program. Clinical trials with participation of components of two or more groups of the program. Patents co-invented by components of two or more groups of the program. As for the time-frame, we suggest evaluation in the second and fourth years.