Personalized Prevention and Treatment of Gallbladder Cancer
Chile has one the highest mortalities due to gallbladder cancer in the world. In order to personalize the prevention and treatment of gallbladder cancer, our group has initiated research collaborations with scientists from first-class international institutions (Karolinska Institutet, the US National Cancer Institute and University College London) and five Chilean universities (Universidad de Chile, Universidad de Tarapacá, Universidad Católica del Maule, Universidad Austral de Chile and Pontificia Universidad Católica de Chile). These collaborations will permit to integrate a unique range of scientific expertise, from the research on South American population genetics conducted by the Consortium for the Analysis of the Diversity and Evolution in Latin America (CANDELA), to the establishment of the Maule Cohort coordinated by Universidad Católica. Yearly symposia “Towards Personalized Prevention and Treatment of Gallbladder Cancer” are held at the Heidelberg Center for Latin America in Santiago de Chile.
Also the European Commission supports our research on gallbladder cancer through the project “Biobanking and Biomolecular Research Infrastructure – Large Prospective Cohorts“, 2016, which will provide access to samples and environmental, metabolic and genotype data from gallbladder cancer case-control pairs from seven European prospective cohorts (Estonian Genome Project, European Prospective Investigation into Cancer and Nutrition, Health 2000, The National FINRISK Study, The Nord-Trøndelag Health Study, The Swedish Twin Registry and UK Biobank).
Robust Logistic Regression for Genetic Case-Control Association Studies
In genetic case-control association studies, genotype relative risks are usually estimated by logistic regression. Maximum likelihood estimators of the genotype relative risk strongly depend on observations deviating from the majority of the data - so-called outliers - which are the rule rather than the exception in association studies.
Robust logistic regression methods are available to constrain outlier influence but they are scarcely used in the field. We have examined the benefits and limitations of robust logistic regression in genetic association studies. In particular, we applied the bounded Huber and extended the R package “robustbase” with the re-descending Hampel functions to down-weight outlier influence.
Robust logistic regression may represent a valuable alternative to standard maximum likelihood approaches when the focus lies on risk prediction rather than identification of new susceptibility variants.
Link to the publication: http://www.ncbi.nlm.nih.gov/pubmed/27543791
Selection of Study Individuals to be Sequenced in Order to Improve Imputation Accuracy
The addition of sequence data from own-study individuals to genotypes from external data repositories, for example the HapMap, has been shown to improve the accuracy of imputed genotypes. We have developed and investigated novel strategies to select individuals for sequencing that rely on the characterization of the ancestral kernel of the study population.
The simulated study scenarios consisted of several combinations of subpopulations from HapMap. HapMap individuals who did not belong to the study population constituted an external reference panel which was complemented with the sequences of study individuals selected according to different strategies. In addition to a random choice, individuals with the largest statistical depth according to the first genetic principal components were selected.
Link to the publication: http://www.ncbi.nlm.nih.gov/pubmed/25537753
Novel Breast Cancer Susceptibility Variants
In collaboration with the Research Group “Molecular Genetics of Breast Cancer” at the German Cancer Research Center (head Prof. Ute Hamann, http://www.dkfz.de/en/mammakarzinom/index.php), we have investigated the relationship between genetic variability in the chromosomal passenger complex and the risk of breast cancer. Fifteen polymorphisms in INCENP, AURKB, BIRC5 and CDCA8 were genotyped as part of the Collaborative Oncological Gene-environment Study (COGS). Possible associations were investigated in a fixed-effects model meta-analysis comprising 88,911 European women from 39 case-control studies of the Breast Cancer Association Consortium (BCAC).
Link to the publication: http://www.ncbi.nlm.nih.gov/pubmed/25586992
Personalized prevention of colorectal neoplasia by use of genetic variability
Genetic variants can modify the risk and disease outcome of colorectal cancer through interactions with non-steroidal anti-inflammatory drugs (NSAIDs, such as COX-2 inhibitors). In addition, certain variants seem to modify NSAID-related toxicity.
In a European consortium, we are taking advantage of COX-2-inhibitor intervention trials on secondary colorectal adenoma prevention to investigate the potential use of genetic variants as biomarkers for (a) colorectal adenoma recurrence, (b) COX-2 inhibitor-related treatment efficacy, and (c) COX-2 inhibitor-related toxicity.
We are investigating the potential of standard and robust principal component analysis to integrate genetic and clinical data because high-dimensionality complicates outlier detection, and outliers may strongly distort results from genetic studies based on standard statistics.
Prof. Nadir Arber, Tel Aviv Sourasky Medical Center and Tel Aviv University, Integrated Cancer Prevention Center, Tel Aviv, Israel
Prof. Jaroslaw Regula, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Department of Gastroenterology, Warsaw, Poland
Dr. Cristiano Crosta, European Institute of Oncology, Division of Endoscopy, Milano, Italy
Prof. Robert Benamouzig, Hopital Avicenne, Service de Gastroenterologie, Cedex, France
Prof. Angel Lanas, Instituto Aragonés de Ciencias de la Salud, University Hospital Zaragoza, Department of Gastroenterology, Zaragoza, Spain
Prof. Cornelia Ulrich, Huntsman Cancer Institute, University of Utah Health Care, Salt Lake City, USA