Chibcha

Project coordinator (PC): Tomlinson, Ian (UOX)		Grant Agreement Nº:223678
Call: FP7-HEALTH-2007-2.4.1-14		Scheme: FP7-CP-SICA (collaborative project)
Total budget: 2,974.288,00€	Start date: 01/06/2009	Term: 5 years
Web site http://www.well.ox.ac.uk/CHIBCHA/
Project summary: Colorectal cancer (CRC) is common in both sexes, has relatively poor outcome and has no major avoidable risk factor. Recent studies have shown that common inherited single nucleotide polymorphisms (SNPs) can increase cancer risk. We have shown CRC risk to be associated with SNPs on chromosomes 8q23.3, 8q24.21, 10p14, 11q23.1, 15q14 and 18q21. These variants account for <5% of the genetic risk of CRC, but will be very important when their effects are added to those of other, as-yet undetected CRC SNPs. A few genome-wide association studies (GWASs) based on populations of European descent are trying to identify the remaining common CRC genes. Evidence suggests that these studies will not be large enough on their own to detect all CRC SNPs, as: relative risks associated with most SNPs are modest; some disease alleles are rare, at least in Europe; and many variants may lie outside conventional gene boundaries or haplotype blocks. The admixed LA population provides an exciting opportunity to identify new CRC genes that are more tractable to detection in LA, or have been missed by chance in European studies. In this project a combined GWAS and admixture mapping study for CRC predisposition genes in 6,000 LA cases and 6,000 controls was undertaken. Testing was carried out on the disease-associated variants in 3,500 cases and 3,500 controls from Europe. We aimed primarily to detect SNPs with effects in both LA and Europe, but also SNPs with effects specific to LA. Eventually, we aimed to develop a polymorphism panel for predicting the risk of CRC in the general population, so that those at increased risk could be offered effective measures to prevent cancer. CRC is increasing in frequency in LA and prognosis is poorer than in Europe. The aim was using our project as a focus for education about CRC, especially in LA. The study would also provide training for young LA researchers. Our work would provide a direct benefit both to medical science and the LA and Europe populations. Key Words: colorectal cancer (CRC), single nucleotide polymorphisms (SNPs), CRC cancer risk, EU/ Latinoamerican (LA) populations, CRC common genes, genome-wide association studies (GWASs), admixture mapping study (AMS), predictive polymorphism panel, prognosis; training and education of LA researchers

LIST OF BENEFICIARIES

Partner	Name	Acronym	Type/ Category
1	University of Oxford (UK) (Wellcome Trust Centre for Human Genetics)	UOX	Public/ higher education & research
2	University of Tolima (COL)	UOTL	Public/ higher education & research
3	Universidad Autónoma de Nuevo León (MEX)	UANL	Public/ higher education & research
4	Hospital do Cancer A.C. Camargo,  (BRA)	HACC	Public / healthcare & research
7	University of Santiago de Compostela (ESP) (National Genotyping Centre)	USC (CEGEN)	Public/ higher education & research
8	Fundació Clinic per a la Recerca Biomèdica (ES)	FCRB	Public / research
9	Portuguese Oncology Institute (PT)	IPOPFG	Public/ healthcare&research
10	University of the Republic of Montevideo (UR)	URM	Public/ higher education & reseach

TEAM (*)

Surname	Name	Title/ Position	Entity
Tomlinson	Ian	Profof Molecular and Population Genetics/ PC	WTCHG
Echeverry de Polanco	María M.	School of Science Prof., MSc, PhD/ PI	UOTL
Rojas-Martínez	Augusto	Prof of Biochemistry and Medical Genetics / PI	UANL
Aguilar	Samuel Jr.	Surgical Oncology, MD/ PI	HACC
Carracedo	Angel	Head of CeGen, PhD / PI	CEGEN
Ruiz-Ponte	Clara	Assistant Head of Laboratory, PhD	FPGMX
Quintela García	Ines	Affimetrix Platform CeGen, MsC	CEGEN
Lareu Huidobro	Mª Victoria	Prof of Legal Medicine, PhD	USC
Salas Ellacuriaga	Antonio	Population Genetics, PhD	USC
Castellví-Bel	Sergi	Head of CRC Research Lab, PhD / PI	FCRB
Teixeira	Manuel R.	Head of Genetics, PhD/ PI	IPOPFG
Sanz	Mónica	Prof of Biological Anthropology., PhD/ PI	URM

(*) For the sake of brevity and conciseness, only members of “Grupo de MedicinaXenómica” and  PIs from the different entities involved have been listed.PC: Project CoordinatorPI: Principal Investigator

Background to the project.

There were an estimated 3,566 people per 100,000 with a past diagnosis of any type of cancer in the European Union in 2003, equivalent to a prevalence of ~17.8 million. With increasing life expectancies and improvements in diagnosis and treatment, the number of cancer patients and survivors is expected to continue to rise. As the illness increasingly becomes a chronic disease, cancer patients’ quality-of-life needs to be addressed in a systematic manner in order to enhance their participation in society, including the workplace.

Being Radiotherapy an important curative treatment for cancer, however, irradiation of surrounding healthy tissue will cause toxic side effects. This toxicity varies in severity, from minor to severe, nature and in duration, from weeks to a lifetime. These long-term side-effects have been shown to impairQoLof cancer survivors.

The field also suffers from a lack of standardization in data collectionand, at present, it is not yet possible to predict who will develop long-term side-effects. Therefore a prospective multi-centre observational study isthe best way of developing and validating both clinical models and biomarkers that predict for risk of long-term side-effects following radiotherapy.This requires systematic reviews to identify approaches for ameliorating those and the design of interventional clinical trials to reduce them.

Finally, although a number of approaches have been explored, no biomarker has been validated for clinical use. Involvement of SMEs is important in this context to bring in technical expertise in assay validation and in development of marketable clinical tests.

Objectives.

The main goals, and central concept of CHIBCHA were to to identify and test genes that predispose carriers to CRC in the LA and European populations. By doing this, the aim was to prevent many CRC cases, to provide information that helps in developing new preventive strategies, and to understand how CRC develops.

CHIBCHA specific objectives as reflected in the project proposal were:

1. To collect well characterized series of CRC cases and controls in various LA countries. High-quality sample collection in large numbers is essential to any genetic project to identify and characterize common alleles that have individually modest, but collectively important, effects on disease risk.
2. To identify high-risk CRC genes in LA cohorts and to test European low-penetrance CRC SNPs in LA.
3. To map new CRC genes using a GWAS. Europe-based GWAS is highly unlikely to have detected all variants associated with CRC. We use a multi-phase association study in LA populations, followed by phases in European populations, to screen for additional CRC-associated SNPs. Our European study did not analyze CNVs and these will be analyzed in this project. The same analysis may also identify polymorphisms that influence the presenting features of the disease or patient outcome/survival.
4. To determine the locations of new CRC genes using admixture mapping.
5. To search for differences in somatic genetic pathways of colorectal tumorigenesis between LA and Europe.
6. To develop a method for allele-specific copy number estimation and SNP sets for population-based predictive tests. Provide the basis for testing CRC genes in other cancers.
7. To train LA researchers and disseminate knowledge within LA and Europe.
8. To raise the profile of CRC in LA and thereby to improve diagnosis and outcome. In LA, the study will be used as a vehicle to raise awareness of CRC, including symptoms, importance of early diagnosis and increased familial risk. This will provide immediate benefits to the LA population.

Work Plan

WP nr.	Title/ Name	Lead participant
WP1	Management	UOX (P1)
	Ethical considerations
	Coordination of consortium activities
	Data and sample flow
	Monitoring and review of progress and results
	Resolution of disputes
	Reporting &Finantial management
	Dissemination, training, education and IP issues
WP2	Patient recruitment, sample collection and resource building	UTOL (P2)
	Ascertainment and recruitment
	Blood sampling and extraction
WP3	Identification of CRC/CRA cases with known syndromes and effects of known CRC SNPs in LA populations	UANL (P3)
	Polyposis syndrome identification
	HNPCC (Lynch) syndrome identification
	Contribution of known low-penetrance alleles to CRC in LA
WP4	Genome-wide association study (GWAS)	USC (P7)
	Sample provision
	First phase of GWAS
	Initial quality control and data analysis
	Subsequent phases of GWAS in LA
	Cancer molecular pathways
WP5	Admixture Mapping Study (AMS)	UOX
	Native american genomes
	AMS &follow-up
WP6	Database, sample reception, data exchange, data storageand statistics	UOX
	Setting up common databases and sample reception
	Genotyping data storage and transfer
	AIM panel
	New GWA method in admixed populations
	Analysis of european SNPs in LA
	Analysis of data from AMS and GWAS
	Developing methods for allele- specific assessment of Copy Number change
WP7	Functional(work dependent on outcomes from statistical analysis in WP6)	UOX
	identify in silico, all real and predicted transcripts, including miRNAs and other ncRNAs	UOX
	identify in silico, all protein-coding genes	UOX
	use programs predicting missense change functionality (SIFT, PolyPhen, etc) to predict other effects of SNPs in each region	UOX
	use data (publicly available, where possible) to determine associations between gene and/or protein expression and genotypes at CTC SNPs	UOX
	undertake our own expression analyses (if indicated)
WP8	Dissemination, training and education	UOX
	Internal dissemination. Scientific reporting of project results
	Internal quality control and standards
	Training programmes& Visiting workers
	Educational and informational resources for the public and healthcare professions; publicising the project in the media
	Engagement of politicians and opinion formers
	IP and genetic testing in clinical practice

Main challenges faced and achievements of the project

Project Manager (L. Carvajal-Carmona) carried out all the managerial tasks and duties that focused on fulfilling the Objectives of the Management Work Package. Such duties included the co-ordination of all Consortium activities; the monitoring of the Scientific Directions that were set out by the Scientific Board; the constant monitoring of the results and progress of the scientific, training, managerial and dissemination aspects of the Consortium; the help in resolving Consortium disputes; the optimization of the data and sample flows and the timely reporting to the EU. Most of themanagerial effort during the first 24 months was setting up of timelines for patientand control sample collection and delivery of DNA samples for genotyping. It was focused on closely following thesample collection efforts carried out by the Partners in Portugal, Mexico, Colombia and Brazil. Inthe last phase of the studythe Project Manager dedicated his efforts to the coordination of sample preparation for thegenotyping with SNPs arrays by Partner 7 (USC), the organization and transfer of the basicclinic-pathological data for all the genotyped samples and to coordinate training activities withyoung European and Latin American Scientist in the UK and Spain.

A major challenge in the study was the sample collection in Latin America (Ecuador, Argentina and Mexico). Early on in the study, continual close monitoring of the progress in Mexicoresulted in improved recruitment in this country. The Project Manager worked closely with thisPartner in obtaining permission, from the National Mexican Government, to export the MexicanDNA samples to Europe. This was a major difficulty during this reporting period since a change inlegislation in Mexico required Partner 3 to obtain permission to export the samples. The projectmanager sent to Partner 3 all the necessary documents and information required to process and obtaintheir exporting license, which was obtained in April 2012.Delays in sample provision continued to dog the project until this day.It is essential for the project’s success to obtain sufficient samplesand to provide the means for them to be genotyped.

Consortium meetings.

-Kick-off meeting,at the Wellcome Trust Centre for Human Genetics (Oxford), during March 8-9, 2010. This was important to clarify the main goalsduring the early phase of the study, to standardize the information to be collected in the case-controlsamples and to establish timelines and goals in the study. During the meeting, we had two guestspeakers, who had expertise in statistical analyses (Prof. Esteban Parra) and admixture mapping(Prof. Paul MacKeigue). These experts shared their views on the challenges and opportunities ofgene identification in the admixed populations from Latin America.

– Consortium meetings (i) Cancun 2011:Business discussions around samples and genotyping platforms. Partners also gave selected background scientificpresentations and guest speakers presented their work on disease gene identification in Latinopopulations (Drs. Josh. Galanter, Andres Moreno and Karla Sandoval).(ii) Madrid 2012: Sample collection reports from the LatinAmerican Partners and to the design of the genotyping panel to be used in the study. CHIBCHA members were formally incorporated as members of COGENT, andplans agreed to perform combined data analysis, for example of rare coding variants typed by bothgroups.

– Final meeting of the Consortium(Sacramento, 2013). Thismeeting was mostly dedicated to discussion about the final results of the study, to the preparation ofthe final scientific report and to plans for the statistical analyses of the data.During this meeting a well-attended mini-symposium onadmixture mapping and cancer genetics took place and had guest speakers from CHIBCHA (IanTomlinson and Sergi Castellvi-Bel), the University of California San Francisco (Trevor Graham,Chris Gignoux and EladZiv) and the University of Southern California (Andrea Sottoriva).

Potential impact after main dissemination activities and exploitation results.

1. A new Latin American ancestry informative marker (AIM) panel has been developed by Partner 7, as part of a collaboration with groups in the USA. This panel has already been used and validated aspart of CHIBCHA with great success.
2. Partner 2 has worked extensively with Native American tribes in the region. She hastalked extensively to be tribes’ representatives about the project, in terms of the ancestry of theregion and the growing importance of cancer, especially bowel cancer, as a growing health problem.She has made videos of these activities that are available from her on request.
3. Tests for the known colorectal cancer predisposition genes from European populations are nowfully developed in the Latin American populations – these findings will allow the introduction ofgenetic testing for high-penetrance mutations into areas of previously low service provision and/oruptake, principally Colombia.
4. The known common polymorphisms associated with bowel cancer risk will be assessed in theLatin American populations. This will provide a direct assessment of the portability of thesepolymorphisms across populations and is likely to assist in identifying the functionally importantvariation close to each polymorphism. These activities may contribute to the development of newanticancer strategies, for example by targeted chemoprevention.
5. We have developed a new panel of polymorphisms, including some rare variants, that is tailored touse in Latin American populations. This panel builds on the commercially-available AffymetrixAxiom Latino array, using the latest data from public genotyping projects to ensure better coverageof the genome. In addition, content will be enriched for markers that are uncommon in Europeanpopulations, but more common in Latin Americans. Finally, the array includes tens of thousands ofrarer genetic variants (especially from protein-coding regions) that have been discovered by largesequencing projects in individual with Latin American ancestry.
6. The full GWAS analysis will be empowered to identify common colorectal cancer risk alleles thatare hard to find in European populations. The significant (or highly promising) findings will also beexamined in European and Asian populations, as well as in other cancers such as endometrial cancer,that share some genetic aetiology with bowel cancer.
7. The admixture mapping screen will deliver regions of the genome derived from Native Americanor European ancestors that are differentially represented in cases (and controls) compared with theoverall ancestry proportions for each individual. This method is an important alterative strategy tocancer gene identification for alleles that cannot be detected by methods such as GWAS.
8. Ultimately, by completing more of the genetic jigsaw of bowel cancer risk, we will bring closerthe time at which genetic risk can be used – ideally alongside demographics and environment – in amodel of risk at the level of the general population. We have begun to address this issue already inthe UK. Dr Ceres Fernandez has provided added value to CHIBCHA by obtaining a Marie CurieFellowship to study whether common polymorphisms can be used in a cost-effective way to stratifyscreening for bowel cancer. Should this appear feasible in the UK, it can be rolled out to othercountries, including the rest of Europe and Latin America.
9. A method for allele-specific copy number assessment using SNP typing on the ABI Taqmanplatform has been developed, based on fitting regression lines through data points generated byrelative allele intensity data. This method has been used and published in a different context.(Schödelet al. Nat Genet. 2012; 44: 420-5)
10. Somatic mutation next-generation sequencing data of a custom gene panel (Ion Torrent cancerpanel) will be obtained from about 25 Latin American colorectal cancers. Comaprison will be madewith our own and published data from European cancers. This work is likely to identify anymutations that are over-represented in Latin American cases, potentially suggesting selection ofchemotherapy or prediction of outcome for individuals.
11. Secondment of researchers from Colombia and Uruguay to European Partners for training andknowledge transfer has occurred. In addition, there has been continual transferof technical know-how, especially to Colombia and data analysis know-how to Uruguay.
12. There has been education of local clinicians (especially in Colombia) in the genetics of colorectalcancer, the potential benefits of prevention through targeted screening and the symptoms of thedisease. This has been achieved largely through recruitment of collaborators to the project fromseveral of the major cities in Colombia. The profile of genetic testing for bowel cancer has also beenraised in Mexico.
13. The aims and activities within CHIBCHA have been disseminated to the local scientific andpopular media, especially in Latin America.

Derived publications

1. Mutational spectrum of the APC and MUTYH genes and genotype-phenotype correlations inBrazilian FAP, AFAP, and MAP patients. Torrezan GT, da Silva FC, Santos EM, Krepischi AC, Achatz MI, Aguiar S Jr, Rossi BM, Carraro,DM. Orphanet J RareDis. 2013; 8:54.
2. High incidence of large deletions in the PMS2 gene in Spanish Lynch Syndrome families.Brea-Fernández A, Cameselle-Teijeiro J, Alenda C, Fernández-Rozadilla C, Cubiella J, Clofent J, Reñé J, Anido U, Milá M, Balaguer F, Castells A, Castellvi-Bel S, Jover R, Carracedo A, Ruiz-Ponte C. ClinGenet. 2013 Jul 9.
3. doi: 10.1111/cge.12232. [Epub ahead of print]
4. A colorectal cancer genome-wide association study in a Spanish cohort identifies two variants associated with colorectal cancer risk at 1p33 and 8p12.Fernandez-Rozadilla C, Cazier JB, Tomlinson IP, Carvajal-Carmona LG, Palles C, Lamas MJ, Baiget M, López-Fernández LA, Brea-Fernández A, Abulí A, Bujanda L, Clofent J, Gonzalez D, Xicola R, Andreu M, Bessa X, Jover R, Llor X; EPICOLON Consortium, Moreno V, Castells A, Carracedo Á, Castellvi-Bel S, Ruiz-Ponte C.BMC Genomics. 2013 Jan 26;14:55.

doi: 10.1186/1471-2164-14-55.PMID: 23350875 [PubMed – in process]

5. Genetic susceptibility variants associated with colorectal cancer prognosis.Abulí A, Lozano JJ, Rodríguez-Soler M, Jover R, Bessa X, Muñoz J, Esteban-Jurado C, Fernández-Rozadilla C, Carracedo A, Ruiz-Ponte C, Cubiella J, Balaguer F, Bujanda L, Reñé JM, Clofent J, Morillas JD, Nicolás-Pérez D, Xicola RM, Llor X, Piqué JM, Andreu M, Castells A, Castellví-Bel S; ; for the Gastrointestinal Oncology Group of the Spanish Gastroenterological Association. Carcinogenesis. 2013 Jun 24.

[Epub ahead of print] PMID: 23712746 [PubMed – as supplied by publisher]

6. BMP2/BMP4 colorectal cancer susceptibility loci in northern and southern European populations.Fernandez-Rozadilla C, Palles C, Carvajal-Carmona L, Peterlongo P, Nici C, Veneroni S, Pinheiro M, Teixeira MR, Moreno V, Lamas MJ, Baiget M, Lopez-Fernandez LA, Gonzalez D, Brea-Fernandez A, Clofent J, Bujanda L, Bessa X, Andreu M, Xicola R, Llor X, Jover R; EPICOLON Consortium, Castells A, Castellvi-Bel S, Carracedo A, Tomlinson I, Ruiz-Ponte C.Carcinogenesis. 2013 Feb;34(2):314-8.

doi: 10.1093/carcin/bgs357. Epub 2012 Nov 16.PMID: 23161572 [PubMed – indexed for MEDLINE]

7. Pharmacogenomics in colorectal cancer: a genome-wide association study to predict toxicity after 5-fluorouracil or FOLFOX administration.Fernandez-Rozadilla C, Cazier JB, Moreno V, Crous-Bou M, Guinó E, Durán G, Lamas MJ, López R, Candamio S, Gallardo E, Paré L, Baiget M, Páez D, López-Fernández LA, Cortejoso L, García MI, Bujanda L, González D, Gonzalo V, Rodrigo L, Reñé JM, Jover R, Brea-Fernández A, Andreu M, Bessa X, Llor X, Xicola R, Palles C, Tomlinson I, Castellví-Bel S, Castells A, Ruiz-Ponte C, Carracedo A.Pharmacogenomics J. 2013 Jun;13(3):209-17.

doi: 10.1038/tpj.2012.2. Epub 2012 Feb 7.PMID: 22310351 [PubMed – in process]

8. Much of the genetic risk of colorectal cancer is likely to be mediated throughsusceptibility to adenomas. Carvajal-Carmona LG, Zauber AG, Jones AM, Howarth K, Wang J, Cheng T; APC Trial Collaborators; CORGI Study Collaborators; Colon Cancer FamilyRegistry Collaborators; CGEMS Collaborators, Riddell R, Lanas A, Morton D, Bertagnolli MM,Tomlinson I. Gastroenterology. 2013 Jan;144(1):53-5.
9. LACE Consortium. Development of a panel of genome-wide ancestry informative markers tostudy admixture throughout the Americas.Galanter JM, Fernandez-Lopez JC, Gignoux CR, Barnholtz-Sloan J, Fernandez-Rozadilla C, Via M, Hidalgo-Miranda A, Contreras AV, Figueroa LU, Raska P, Jimenez-Sanchez G, Zolezzi IS, Torres, M, Ponte CR, Ruiz Y, Salas A, Nguyen E, Eng C, Borjas L, Zabala W, Barreto G, González FR, Ibarra A, Taboada P, Porras L, Moreno F, Bigham A, Gutierrez G, Brutsaert T, León-Velarde F, Moore LG, Vargas E, Cruz M, Escobedo J, Rodriguez-Santana J, Rodriguez-Cintrón W, Chapela R, Ford JG, Bustamante C, Seminara D, Shriver M, Ziv E, Burchard EG, Haile R, Parra E, Carracedo, A.

PLoSGenet. 2012 Mar;8(3):e1002554. Epub 2012 Mar 8.

10. Seeking genetic susceptibility variants for colorectal cancer: the EPICOLON consortiumCastellví-Bel S, Ruiz-Ponte C, Fernández-Rozadilla C, Abulí A, Muñoz J, Bessa X, Brea-Fernández A, Ferro M, Giráldez MD, Xicola RM, Llor X, Jover R, Piqué JM, Andreu M, Castells A, Carracedo A; Gastrointestinal Oncology Group of the Spanish Gastroenterological Association.Mutagenesis. 2012 Mar;27(2):153-9.

doi: 10.1093/mutage/ger047. PMID: 22294762 [PubMed – indexed for MEDLINE]

11. Susceptibility genetic variants associated with early-onset colorectal cancer.Giráldez MD, López-Dóriga A, Bujanda L, Abulí A, Bessa X, Fernández-Rozadilla C, Muñoz J, Cuatrecasas M, Jover R, Xicola RM, Llor X, Piqué JM, Carracedo A, Ruiz-Ponte C, Cosme A, Enríquez-Navascués JM, Moreno V, Andreu M, Castells A, Balaguer F, Castellví-Bel S; Gastrointestinal Oncology Group of the Spanish Gastroenterological Association. 2012 Mar;33(3):613-9.

doi: 10.1093/carcin/bgs009. Epub 2012 Jan 10. PMID: 22235025 [PubMed – indexed for MEDLINE]

12. COGENT (COlorectal cancer GENeTics) revisited. Houlston RS; members of COGENT (including Echeverry MM, Carvajal-Carmona, L, Tomlinson, I). Mutagenesis. 2012 Mar;27(2):143-51. Review.

PubMed PMID: 22294761; PubMed Central PMCID: PMC3269000.

13. TERC polymorphisms are associated both with susceptibility to colorectal cancer andwith longer telomeres.

Jones AM, Beggs AD, Carvajal-Carmona L, Farrington S, Tenesa A, Walker M, Howarth K, Ballereau S, Hodgson SV, Zauber A, Bertagnolli M, Midgley R, Campbell H, Kerr D, Dunlop MG,Tomlinson I.

Gut. 2012 Feb;61(2):248-54.

14. Refinement of the associations between risk of colorectal cancer and polymorphisms on chromosomes 1q41 and 12q13.13. Spain SL, Carvajal-Carmona LG, Howarth KM, Jones AM, Su Z, Cazier JB, Williams J, Aaltonen LA, Pharoah P, Kerr DJ, Cheadle J, Li L, Casey G, Vodicka P, Sieber O, Lipton L, Gibbs P, Martin NG, Montgomery GW, Young J, Baird PN, Morreau H, van Wezel T, Ruiz-Ponte C, Fernandez-Rozadilla C, Carracedo A, Castells A, Castellvi-Bel S, Dunlop M, Houlston RS, Tomlinson IP.Hum Mol Genet. 2012 Feb 15;21(4):934-46.

doi: 10.1093/hmg/ddr523. Epub 2011 Nov 10.PMID: 22076443 [PubMed – indexed for MEDLINE]

15. Genetic associations in the vitamin D receptor and colorectal cancer in African Americans and Caucasians.Kupfer SS, Anderson JR, Ludvik AE, Hooker S, Skol A, Kittles RA, Keku TO, Sandler RS, Ruiz-Ponte C, Castellvi-Bel S, Castells A, Carracedo A, Ellis NA.PLoS One. 2011;6(10):e26123.

doi: 10.1371/journal.pone.0026123. Epub 2011 Oct 27.PMID: 22046258 [PubMed – indexed for MEDLINE]

16. Analysis of DNA mismatch repair proteins expression and BRAFV600E mutation in a subset of early- and late-onset colorectal carcinoma patients in Mexico. Luévano-González A, Guzmán AQ, Ancer Rodríguez J, Ortiz López R, Rojas Martínez A, González, Guerrero JF, Flores Gutiérrez JP.Arch.Med Res. 2011 Aug;42(6):457-62. Epub 2011 Sep 22.
17. Case-control study for colorectal cancer genetic susceptibility in EPICOLON: previously identified variants and mucins.Abulí A, Fernández-Rozadilla C, Alonso-Espinaco V, Muñoz J, Gonzalo V, Bessa X, González D, Clofent J, Cubiella J, Morillas JD, Rigau J, Latorre M, Fernández-Bañares F, Peña E, Riestra S, Payá A, Jover R, Xicola RM, Llor X, Carvajal-Carmona L, Villanueva CM, Moreno V, Piqué JM, Carracedo A, Castells A, Andreu M, Ruiz-Ponte C, Castellví-Bel S; Gastrointestinal Oncology Group of the Spanish Gastroenterological Association. BMC Cancer. 2011 Aug 5;11:339.

doi: 10.1186/1471-2407-11-339.PMID:21819567 [PubMed – indexed for MEDLINE]

18. A two-phase case-control study for colorectal cancer genetic susceptibility: candidate genes from chromosomal regions 9q22 and 3q22.Abulí A, Fernández-Rozadilla C, Giráldez MD, Muñoz J, Gonzalo V, Bessa X, Bujanda L, Reñé JM, Lanas A, García AM, Saló J, Argüello L, Vilella A, Carreño R, Jover R, Xicola RM, Llor X, Carvajal-Carmona L, Tomlinson IP, Kerr DJ, Houlston RS, Piqué JM, Carracedo A, Castells A, Andreu M, Ruiz-Ponte C, Castellví-Bel S; Gastrointestinal Oncology Group of the Spanish Gastroenterological Association.Br J Cancer. 2011 Sep 6;105(6):870-5.

doi: 10.1038/bjc.2011.296. Epub 2011 Aug 2. PMID: 21811255 [PubMed – indexed for MEDLINE]

19. Multiple common susceptibility variants near BMP pathway loci GREM1, BMP4, and BMP2 explain part of the missing heritability of colorectal cancer.Tomlinson IP, Carvajal-Carmona LG, Dobbins SE, Tenesa A, Jones AM, Howarth K, Palles C, Broderick P, Jaeger EE, Farrington S, Lewis A, Prendergast JG, Pittman AM, Theodoratou E, Olver B, Walker M, Penegar S, Barclay E, Whiffin N, Martin L, Ballereau S, Lloyd A, Gorman M, Lubbe S; COGENT Consortium; CORGI Collaborators; EPICOLON Consortium, Howie B, Marchini J, Ruiz-Ponte C, Fernandez-Rozadilla C, Castells A, Carracedo A, Castellvi-Bel S, Duggan D, Conti D, Cazier JB, Campbell H, Sieber O, Lipton L, Gibbs P, Martin NG, Montgomery GW, Young J, Baird PN, Gallinger S, Newcomb P, Hopper J, Jenkins MA, Aaltonen LA, Kerr DJ, Cheadle J, Pharoah P, Casey G, Houlston RS, Dunlop MG.PLoS Genet. 2011 Jun;7(6):e1002105.

doi: 10.1371/journal.pgen.1002105. Epub 2011 Jun 2.PMID: 21655089 [PubMed – indexed for MEDLINE]

20. Novel MLH1 duplication identified in Colombian families with LynchSyndrome. Madrigal I, Jones AM, Echeverry MM, Velez A, Tomlinson I, Milà M, Wijnen J, Carvajal-Carmona, L, Castells A, Castellví-Bel S.
21. Genet Med. 2011 Feb;13(2):155-60. PubMed PMID: 21233718.doi: 10.1371/journal.pgen.1002105. Epub 2011 Jun 2. PMID: 21655089 [PubMed – indexed for MEDLINE].
22. COGENT (COlorectal cancer GENeTics): aninternational consortium to study the role of polymorphic variation on the risk of colorectal cancer.Tomlinson I, Dunlop M, Campbell H, Zanke B, Gallinger S, Hudson T, Koessler T, Pharoah PD,Niittymäki I, Tuupanen S, Aaltonen LA, Hemminki K, Lindblom A, Försti A, Sieber O, Lipton L,van Wezel T, Morreau H, Wijnen JT, Devilee P, Matsuda K, Nakamura Y, Castellví-Bel S,Ruiz-Ponte C, Castells A, Carracedo A, Ho JW, Sham P, Hofstra RM, Vodicka P, Brenner H, HampeJ, Schafmayer C, Tepel J, Schreiber S, Völzke H, Lerch MM, Schmidt CA, Buch S, Moreno V,Villanueva CM, Peterlongo P, Radice P, Echeverry MM, Velez A, Carvajal-Carmona L, Scott R,Penegar S, Broderick P, Tenesa A, Houlston RS. Br J Cancer. 2010 Jan 19;102(2):447-54. Epub 2009 Nov 17.

Future prospects.

Due to the delays in sample’s reception already mentioned some statistical analysis was still on- going.Functional annotation of GWAS and AMS “hits” will be performed once a full statistical analysis is complete.

We anticipate several “spin-off” studies and Partners have all recently joined an EU COST action which will ensurecontinuing collaboration. To take just one example, Colombian samples haveconsiderable data on phenotypes other than CRC (for example, anthropometric traits, other cancers).These samples may provide valuable insights into the genetics of these other traits, either asstand-alone projects or as parts of larger collaborative groups.